Monthly Archives: November 2011


Inflammation, degeneration repair – homeopathic approach

diseasesProf Dr R  Santhana Pandian
B.SC, D.M.S, M.B.S 

This is the basic process in all diseases.  Tissue response to noxious and injurious influences causes toxic chemical agents physical factors heat, cold, electricity radiation, trauma, microorganism and their metabolic by products immune response, hypersensitivity, immune complex, auto immune reaction.

Every tissue is susceptible to inflammation.  This is governed by a person’s state of health and severity of noxious influences.


  • 1. Localize, neutralize and in activate.
  • 2. Destroys or limits the growth of the micro organisms.
  • 3. Prepares the area for wound healing and repair.


  • 1. Pain and swelling causing various disabilities.
  • 2. Hemorrhage, excessive scar tissue.
  • 3. Fistula formation, empyema.
  • 4. Damages – glomerulo nephritis, arthritis, allergic reactions, muocarditis, encephalitis.


Acute inflammation
Vascular cellular events vasodiation, local heat, redness, increased vascular permeability, local oedema, swelling, influx of neutorphils, monocytes, and phagocytosis.

Cordinal signs heat, redness, swelling and pain.

Morphologic patterns

  • 1. Purulent exudation – abcess formation
  • 2. Fibrinous exudates- consequent scarring.
  • 3. Serous exudates (pleural, pers cardial, peritoneal)
  • 4. Catarrhal exudates- hig mucous content, allergic rhinitis, bronchitis.

Chronic inflammation

  • 1. Cells involved, monocytes, lymphocytes.
  • 2. Granulation tissue formation- tends to replace functional tissue.
  • 3. Scarring.
  • 4. Chronic inflammation co exists with acute inflammation- cholycystitis (gallstone) osteomyelitis.

Morphological patterns

  • 1. Non specific chronic inflammation. Ex chronic glomerulo nephritis-loss of functional tissue.
  • 2. Granulo matous inflammation eptheloid macrophages – giant cell formation- cause persistent antigen.

Unknown causes.

Cells involved in inflammation

  • A. Neutorphils
  • B. Basopails
  • C. Eosinophils- inanapylaxis
  • D. Mast cells 

I. Inflammatory response

  • 1. vaso contriction
  • 2. vaso dilation
  • 3. increased vascular permeability.

II. Cellular phase

Emigration of leucocytes. Phagocytosis.

Consequences of inflammation

Healing & repair

Factors inhibiting repair

  • Old age, immune depression, diabetes, malignancy.
  • Anti inflammatory drugs, anti neo plastic agents super imposed infection.

Untoward effects

Perforation, extensive fibrosis, keloids, bowel obstruction, sterility


Ascending pyelophlebites large abscess formation in liver, brain infection spreading through lympaatics.


1.Hydropic swelling – cloudy swelling, cells swell, cytoplasm contains coarse granules – then ctoplasm contains water vacuoles – Na sodium enters.

2.Fatty change

This is the accumulation of fat in non fatty tissues especially the parenchymatous organs, skeletal muscles.

Heart – inability of the non fatty tissues to metabolise the amount of fat presented to them resulting in accumulation.


  • 1.Bacterial toxins, chemical toxins chloroform, alcohol
  • 2.Anaemia, anoxia, cardiac failure cellular energy impaired, diminished enzyme activity.
  • 3.Respiration diseases – oxygenation diminished.
  • 4.Diabetes, starvation – incomplete utilization of fat, accumulation of fat in cells.

Organs affected

  • 1.liver
  • 2.Heart – rise in blood pressure.
  • 3.obesity – reduces life expectancy.

Amyloid deposition

  • Waxy substance – abnormal protein deposited around the fibres of blood vessels deposition progresses.
  • Organs pale, enlarged, firm waxy texture. Lugol’s iodine – deep brown.

Nature of amylod

  • a. protein
  • b. carbohydrate.

Pathological effects.

  • 1. pressure on adjacent cells causing atrophy.
  • 2. blood vessels narrowing.
  • 3. increased permeability from blood vessels- leading to trasudation of protein out of vessels.


  • 1. kidney – gross protinuria, nephritic syndrome.
  • 2. gastro intestinal tract – dyarrohea.
  • 3. heart enlarged, cardiac failure.

Causes of amyloidosis

Associated with chronic inflammatory diseases – tuberculosis, osteomyelity, rheumatoid arthritis.


1. Healing by first intention

In clean incised wounds with good opposition edges – blood clot fills up the small cleft. Mild hyperaemia few poly morphs – 2 to 3 days clot removed by macrophages – fibroblastic activity – fibrous union of edges- good fibrous union.

2. Healing by second intention

  • a. cavity fills with blood.
  • b. acute inflammation
  • c. new capillary loops – macrophages, polymorphs, fibroblasts.
  • d. loose connective tissue formed by fibrosis.
  • e. epithelial covering.
  • f.  wound contraction.

3. Fibrosis is the end results of wound healing, chronic inflammation and organization.

Factors influencing wound healing by fibrosis.

  • 1. Infection & poor blood supply
  • 2. Deficiency of vitamin C amino acids.
  • 3. Excess of adrenal gluco corticoids
  • 4. Zinc traces beneficial


  • Abies Canadensis – catarrhal inflammation of stomach.
  • Abies Canadensis – peptic ulcer aggravation heating
  • Abroma augusta – albuminuria, diabetes mellitus.
  • Abrotanum – tuberculous peritonitis, pleurisy with effusion
  • Acalypha indica – all pathological haemorrhages
  • Achyranthes aspera – boils, carbuncles
  • Aconite – inflammation acute
  • Actaeaspicata – wrist swelling
  • Adonis vernalis – cardiac dropsy
  • Aegle mar melos – amoebic dysentery, bacillary dysentery
  • Aethiops mercuralis, mineralis – hereditary syphilis
  • Aletris farinose – anaemia
  • Cholesterinum – gallstone colic
  • Bacillinum – tuber cular affections
  • Zinc met – brain, spinal degeneration – exhaustion
  • Veratrum viride – congestion base of brain, violent pains attending inflammation  meningitis.
  • Thuja – chronic inflammation – sycosis gonorrhoea
  • Theridion – necrosis, caryes
  • Terebinth – acute nephritis before cast appear
  • Tarentula – abscess, boils carbuncle
  • Syphilinum – craving for alchohol, falling of hair
  • Symphytum – injury to eye
  • Staphysagria – mechanical injuries, sharp cutting
  • Spongia – orchitis spermatic cord swollen, acute laryngitis
  • Spigelia, led, naja – rheumatic affections of heart
  • Silicea – fistula inflammation, suppuration, swelling of glands
  • Sarasaparilla – renal calculi
  • Sanguinaria, bellis, cac,eug. Jam, psor- eruptions on face of young women.
  • Sambocos – rhinitis, asthma of children
  • Sabadilla – allergic rhinitis
  • Sabina exuberant granulations ( thuja, nitric acid)
  • Ruta – warts with sorepains
  • Rumex – catarral inflammation of larynx
  • R.T – arthritis
  • Rhododendron – gout
  • Ranunculus – corns, shingles
  • Rataniha – fissure of anus
  • Pyrogen – septic fever
  • Puls – rheumatism –shifting pain
  • Plumbum – paint at night in limbs, ameleration pressure
  • Phytolacca – mammary glands inflammation
  • Phosphoric acid – caries
  • Petroleum – herpes of genitalia
  • Nitric acid – wrts, condylomata
  • Naja – rheumatic carditis
  • Mezereum – neuralgia after zona
  • Mercurus sulphuricus –hydro thora
  • Merc spl – chancre
  • Merc proto iodide – chancre
  • Merc cyanide – prophylactic in diphtheria
  • Merc dolcis – cattarahal inflammation of middle ear
  • Merc cor – nephritis
  • Medorrahinum – deep seated affections of gonorrhoea
  • Lycopdium – renal colic right side pneumonia base of right lung
  • Lobelia – chronic gastritis, asthma
  • Ledum – gout
  • Lac defloratum – fatty degeneration, obesity, chronic liver complain
  • Lac caninum – to bring back milk, useful to dry off milk
  • Lachesis – annually returning fever
  • Kalibick – catarrhal inflammation
  • Iodium – cancerof cervix, hard goitre
  • Hypericum – injuries of spine
  • Hydrortis – catarrhal inflammation
  • Helonias – diabetes, albuminuria
  • Helleborus – hydrocephalus
  • Hamamelis – effects of injuries
  • Gelsemium – motor paralysis
  • Fluoric acid – caries, necrosis
  • Euphrasia – conjunctivitis
  • Drosera – laryngeal TB
  • Doscorea – felon
  • Acoite – acute inflammation
  • Bell – acute inflammation
  • Arnica – apoplexy
  • Vanadium – increases hemoglobin stimulates phagocytosis a remedy indegerative Conditions of liver, arteries, brain softening, atheroma of arteries, neuro rentinits, blindness, tuberculosis, chrome rheumatism, fatty degeneration of liver.
  • Echinacea – goiter, exophthamia, gangrene lymphangitis
  • Eupion – chronic tubal disease, severe back ache
  • Fabiana imbricate – uric acid diathesis calculi, prostates
  • Variolinum – haemorrhagic fibroma, tubercular lupus, zona, preventive of small Pox.
  • Vaccinotoxinum – post zosterian neuralgia, (arsenic album, rananculus bulb,R.T)
  • B.C.G – always catarrhal, tuberculous back ground, every 15 days and calcphos bio. Infantile asthma
  • Tuberculinum residum – all the cases of chronic articular rheumatism, ligamentary rigidness, deformed by repeated attacks of arthirits, long lasting sclerosis, dupuytren’s disease.
  • Tuberculinum – afraid of dogs; head ache, chronic otitis media, aggravation in sun, reading , ugly eruptions on face, nephritic syndrome, chronic albuminuria, glomular nephritis, juvenile acne, repeated styes, changing places, bilateral ovarian pains.
  • Oscillo coccinum – varicose ulcer, beginning of rhinitis, beginning of otitits, sinusitis, acute rhinitis.
  • Osteo arthritic nosode – swelling of right wrist, right shoulder, aggravation first movement, tendo achilles, worse right side.

Concept of Cure and Disease and Drug relationship

Concept of Cure
Hahnemann’s distinction as a physician is marked not only by his recognition of the sole mission of the physician, but also by the ideals of cure envisaged by him. He walked ahead of time with his intuitive concepts build up with the bedrocks of inductive philosophy at a time when no streaks of logic had any shadow upon medicine.

Hahnemann opened his masterpiece work on Homœopathic Philosophy with a sharp statement of truth. “The physician’s high and only mission is to restore the sick to health, to cure, as it is termed.” With this benchmark of duty, he measured all physicians, all medical theories, methods and systems and he desired and demanded the same measurement for himself and his own method. He asked but one question, applied but one test, Do they cure the sick? Experience and observation of the men and methods of his day showed clearly that they did not cure. In the light of a vast and comprehensive knowledge and a bitterly disappointing personal experience, be pronounced the medicine of his day a failure and set about its reformation.

Cure was not then, as it has since become in the dominant school of medicine, an obsolete term. Physicians still talked and wrote of “cures,” but vainly sought to find them. “The Art of Healing” or “The Healing Art” were familiar phrases, but the thing itself, like a will-o’-the-wisp, eluded them-then as it has ever since. In the second paragraph of the Organon, Hahnemann gives, for the first time in medical history, an adequate and satisfying definition of the ideal expressed in the word “Cure:” “The highest ideal of cure is rapid, gentle and permanent restoration of the health, or removal and annihilation of the disease in its whole extent, in the shortest, most reliable, and most harmless way, on easily comprehensible principles.”

Distinction between Cure and Recovery
The favorable outcome of medical treatment may be either a cure or a recovery. To realize the ideal of cure, it is necessary to know the exact meaning of these terms and to be able to discriminate between them. The terms are not synonymous. Natural recoveries following treatment consisting of mere palliation of symptoms should not be mistaken for cure nor falsely paraded as such. A cure is always a result of art and is never brought about by nature. Nature, however, aided or unaided, often brings about a recovery, under the operation of natural laws. Fortunate indeed is it for humanity that this is true.

Recovery is the spontaneous return of the patient to health after the removal, disappearance or cessation of the exciting causes and occasion of disease, or as a result of treatment which is not directly and specifically curative in its nature. Recovery takes place by virtue of the existence of sufficient integrity of organs and inherent power of reaction in the patient to overcome the disease-producing agency without the aid of the homœopathic or healing art. Recovery is favored by the application of sound principles of mental and physical hygiene, judicious mechanical or surgical treatment when required, and avoidance of drugs used for their “physiological” (really pathogenic) effects, and by enlightened sanitation.

Relationship of cure to disease.
A true definition of cure must be based upon a right conception of the nature of disease. Disease is an abnormal vital process, a changed condition of life, which is inimical to the true development of the individual and tends to organic dissolution. The Standard Dictionary defines disease as “any departure from, failure in, or perversion of normal physiological action in the material constitution of functional integrity of the living organism”. This definition rightly focuses attention upon the dynamical aspect of the subject, for disease is essentially and primarily a morbid dynamical disturbance of the vital powers and functions, resulting in a loss of functional and organic balance.

Cure refers to the direct restoration of normal physiological action by medical art. Cures do not consist in the mere removal of the external, secondary, tangible products of disease, but in restoration of the dynamical balance, so that the functions of the organism are again performed normally and the patient is in a state of health. Disease is manifested perceptibly by signs and symptoms. Cure, is manifested by the removal of the symptoms. Strictly speaking the removal of all the symptoms of the case is equivalent to a cure, but if symptoms disappear and the patient is not restored health and strength it means either that some of the most important symptoms of the case have been overlooked, or that the case has passed beyond the curable stage. All curable cases present perceptible symptoms, but their discernment often depends upon the acuteness of the observer.

Cure relates to the case as a whole: A patient may have his hemorrhoids removed and be relieved of his rectal symptoms; but if the symptoms of the heart or liver disease which preceded and caused his hemorrhoids are not removed the patient is not cured; and so of innumerable other morbid conditions. Cure refers to the patient, not to some symptoms of his disease, nor to what may be called “one of his diseases.” To say that a patient is cured of his hemorrhoids, but still has his heart disease is absurd. Cure means complete restoration to health.

Cure is not affected by the removal surgically nor by any local means, of the external, secondary, pathological “end-products” of disease, such as tumors, effusions, collections of pus, useless organs or dead tissues; for the morbid functioning which produced those effects often remains unchanged, after such removal.  Cure is effected only by dynamical treatment according to fixed principles, directed to the primary, functional disorder as revealed by the complete symptom-picture preceding and accompanying the formation of the tangible products of the disease.

Cure is not merely the removal of the primary causes of disease, for even if all the causes of the disease are known and removable, the effects, having been begun, may continue as secondary causes after the removal of the primary causes. Spontaneous disappearance of the disease does not always occur in such cases, and dynamical treatment is required to restore the patient to health.

The Law of Cure
The accomplishment of even one true cure by medication implies the existence of a governing principle or law of cure by medication. The occasional occurrence of accidental cures very early attracted the attention of medical men, and led them to seek for such a law. Glimpses of the law were had by individuals from time to time down the ages, but it eluded the searches or failed of demonstration until Hahnemann finally grasped it comprehendingly and made it the basis for the therapeutic method which he named homœopathy.

Many were deluded by mistaking natural recoveries for cures. Their attempts to “imitate” invariably failed. Others abandoned the idea of a general principle of cure by medication and denied its existence, refusing to accept the demonstration when it was finally made. That is the attitude of the average member of the dominant school to-day. They deny the existence of a general principle of therapeutic medication. “We do not profess a cure,” they say; “we only aid nature to bring about recoveries.” In this they are at least honest, and consistent in their use of terms.

The Requirements of Cure
1) It shall be the result of the direct application of a definite general principle of therapeutic medication. The result may be accidental or intentional on the part of the prescriber in a given case, but its relation to the means employed must be capable of rational explanation and demonstration by reference to the governing principle. A general principle is capable of systematic demonstration, not only once but repeatedly and invariably, under stated conditions. Given the principle, it is always possible to formulate a method or technique, by means of which the principle may be successfully applied to every case within its scope.

2)  It must be individual. A general principle according to which any action takes place is always capable of being individualized. The ability to meet the varying requirements of individual cases proves the existence and truth of the principle involved. A true system of therapeutics must be able to adapt its basic principle and its remedy to the needs of each individual case. There are no cures for “diseases,” no remedy for all cases of the same disease. Cure relates to the individual patient, not to the disease. No two cases of the same disease are exactly alike. Differences of manifestation in symptoms and modalities always exist in individuals. It is these differences which give each case its individuality, and create the need for an individual remedy.

Manner and Direction of Cure
Cures take place in a definite, orderly manner and direction. Normal vital processes, cellular, organic and systemic, begin at the centre and proceed outwardly. Figuratively, if not literally, ‘life is a centrifugal force, radiating, externalizing, concentrating and organizing spirit into matter – “from above, downward.” In the same sense disease is a centripetal force, opposing, obstructing, penetrating toward the center and tending to disorganization. The progression of all chronic diseases is from the surface toward the center; from less important to more important organs “from below upward.” Curative medicines reinforce the life force, reverse the morbid process and annihilate the disease.

The symptoms disappear from above downward, from within outward and in the reverse order of their appearance. When a patient with an obscure rheumatic endocarditis, for example, begins to have signs and symptoms of acute arthritis soon after faking the homœopathic remedy and is relieved of his chest sufferings, we know that cure has commenced.

 The Hahnemannian ideal of cure by medication, according to the principle of symptom-similarity, largely lost sight of for a time in the dazzling accomplishments of modern surgery and laboratory research, has been passing through such a period of neglect and obscurity. But already there are signs of a revival of this great truth, as science, in its wider reaches, is beginning to correlate the results of its work. The whole trend of modern medical thought is toward the confirmation and acceptance of fundamental postulates and principles first enunciated by Hahnemann. Homœopathy is gradually being rediscovered by modem science.

Disease and Drug relationship
Every Inductive Natural Science (except those of classification) consists elementarily of 2 series of independent phenomena connected by the formula of their general relation. 

Connecting Links

Science                     Phenomena-1                      Link                  Phenomena-2

Therapeutics                         Sick phenomena               Therapeutic law            Drug phenomena

Physics                       Phenomena of sun            law of attraction                      phenomena of earth

Chemistry                  Properties of Pottassa      Law of chem.affinity       Properties of H2SO4

 Optics                          Properties of                           Law of light diffusion         properties of  Luminous body  Light receiving body. 

So it is evident that a science of therapeutics or a mode of treatment should indicate a relationship between the drug administered and the disease in question. This relationship can be similar, different, antagonistic and at times identical. Based on these relationships, Hahnemann classified the modes of treatment as homœopathic, heteropathic / allœopathic , antipathic and isopathic, respectively. Then he went on analyzing which of these relationships is ideal in the sense that it effects true cure. It was this search for the ultimate truth that landed in the discovery of Homœopathy as an effective system of healing.


Relationship of surgery with Pathology

surgeryDr G K Swethadri.
Prof. Deaprtemnt of Pathology
Fr. Muller Homeopathic Medical College

As is your pathology so is your practice. sir william Osler
Historical aspects
Clean water, asepsis, immunization
Rapid developments in the 20th century

Fast pace of life is demanding early detection and cure. Fortunately the role of pathologist is well defined and needed and accepted by the surgeon.

Relevance of pathology to surgeons is immense.let me try to analyse these aspects.

All organs can suffer.

  • Inflammation
  • Degeneration
  • Immune insult
  • Hemodynamic derangements
  • Nutritional ,chemical,radiation injury
  • Trauma
  • Neoplasia
  • Genetic defects.


  • Changes in the organ and body as a whole.
  • Changes are either gross or microscopic .they are called morphological changes.The changes all begin in the cell.
  • ’it is called THE CELLULAR BASIS OF DISEASE”by Virchow.
  • Briefly Inflammation,degeneration,vascular changes and neoplasia are the features one looks for.
  • THE MICROSCOPE helps seek these changes
  • acute appendicitis-neutrophils
  • parkinsonism-lewy body
  • thrombus in a vessel in gangrene
  • cancer cells in a tumour


Some basic aspects

  • Hypertrophy of the left ventricle
  • Hypertrophy (micro)
  • Hyperplasia of endometrium
  • Atrophy of thymus gland
  • Morphology of cell injury
  • Protein accumulation – Hyaline
  • Hyaline degeneration – structureless, glassy, extra or intracellular material.
  • Lipids accumulation
  • Fatty change – intracellular accumulation of droplets of neutral fat (macro- and microvesicular).
  • The most common cause is poisoning and hypoxia.
  • The proteins of the cell are denatured and the cell becomes coagulated or clotted.
  • Cytoplasm becomes hyper-eosinophilic and the nuclear changes appear.
  • The cells persist as cell ghosts
  • Dead tissue appears firm and pale.


  • Gangrene is necrosis affecting the areas connected with the air and adde putrefaction.
  • Dry gangrene – ischemia without infection
  • If infection (clostridial) and oedema – wet gangrene or gas-gangrene.

An understanding pathologic basis must.

  • Once clinicopathlogical correlation is established then patient management becomes easy and objective.
  • That is why pathology is needed for the surgeons.
  • Let us study a few examples of CPC

It took a long time for histopathology to be accepted as a prerequisite for diagnosis

•Well it is easy.if not….

Let us study the example -breast

The expectations have changed.

  • Earlier we used to see huge cancer,bilateral,late stage.
  • Now self examination,mammography,needle aspirations have made women seek screening.even obese and those on OCP are seeking early detection.
  • Expectation of surgeon on pathologist is increasedearly diagnosis is the order of the day.


As histopathologists become aware that lympo-vascular emboli are seen in sections ,they wondered at the possibility of dissemination .Then why radical; save the organ as much as mastectomy,quadrantectomy are being practiced with radiotherapy

Not only diagnosis but also grading staging ,prognostification, decision making for therapy is coming in the perview of pathologist.

Breast conservation is the order of the day.a precise diagnosis and extent of disease are essential for this.

  • Steps of diagnosis
  • Clinical exam
  • Mammography
  • Ultra sound
  • MRI
  • FNAC
  • Tru-cut biopsy
  • Excision
  • Clinical+cytology+mammography=99.9 accuracy

Nottingham prognostic index

  • Index=0.2xsize+grade+node.(no=1,1-3 nodes=2,4>=3)
  • Take for example 6 cm tumour,4 positive lymph nodes and moderate grade(2)
  • (.2×6)+2+3=6.2.
  • Look at the prognosis.
  • Good=<3.4;mod=3-4.5;poor=5.4.
  • Our example is of a poor prognosis i.e.13%15 yr survival.

Organize your teaching.

  • Definition
  • Classification
  • Pathogenesis
  • Pathology-gross and microscopy
  • Diagnostic investigations
  • Differential
  • Prognosis
  • Research
  • the need for precise diagnosis;
  • verruca v/s Cervix:
  • Infiltrating Carcinoma Cx:
  • Squamous Carcinoma:
  • Melanma

Clark’s levels

  • 1.confine to epidermis and appendages-in situ
  • 2.papillary dermis-microinvasive; between papillary and reticular dermis a few melanoma cells
  • 3.pap dermis and impinge upon ret dermis
  • 4.impinge and invade ret dermis
  • 5.subcutaneus fat invasion

Some examples are illustrated

  • Mystery and happiness
  • Intrigue.
  • The mimic
  • Let us see how to teach a topic,for example’ BREAST PATHOLOGY”
  • Given as separate power point presentation.
  • Intra op diagnosis in CNS.note.described as a separate paper.
  • Frozen.
  • Sheets of round to spindle cells
  • Cartilagenous lobules & spindle cell areas & infiltration to bony trabeculae with destructon
  • Chondrosarcomatous areas
  • Pleomorphic cells in chondroid matrix
  • Distinct chondroid and spindle areas


  • The mystery is solved to some extent by the pathologist.
  • Then the larger question;how can we together help people?
  • Registries;
  • Large medical force can contribute by educating and screening common man about cancer.
  • Aspects of curable-treatable cancer and spread of optimism.if detected early it can be cured.

Evolution of screening

  • One out of 10-13 people in India will be struck by cancer in their lifetime.
  • Tobacco,alcohol,diet,occupation,occupational disease,sexual and prevention.
  • NCCP was started in 1975-76. tobacco educaion,small family,18 yrs as marriageble age for female,use of condom
  • Secondary;cervical pap smear,pre invasive diseae is 100% curable.35% in advanced.
  • Detection centers in medical colleges(105 colleges),post partum centers,district hospital level is in the experimental stage.
  • In 1000 females-2.5-13.7 dysplasia was detected
  • Married ,asymptomatic,<40 yr,<20 yr married life,may be excluded from screeing.
  • Visual exam.13.7%of 67416 had unhealthy cervix.
  • FNAC for breast can cancer screen
  • Yearly occult blood for cancer.
  • 2 yearly videoscopic multiple biopsies for GIT


  • Premalignant
  • Head and neck-isotretinoin
  • NSCLC         13-cis-retinoic acid.
  • Ca colon-high fibre diet.calcium 1 diet.
  • Pt with adenoma;folic acid and vit-c.
  • Anal cancer-homosexuality
  • Breast;tamoxifen in high risk by 35 yr

Investigations in cancer

  • Good clinical exam.routine blood tests
  • BRCA-1 from leucocytes.electrophoresis.MM
  • Bacterial,viral,parasitic studies
  • Tumour markers.laparotomy.B.M.biopsy
  • Tissue biopsy.frozen section.
  • U.S and CT guided needle biopsy,endoscopic,video assisted biopsy,IHC,EM,Cytogenetics.
  • Tissue diagnosis,grading,staging

Surgeon looks at pathologist for

  • Anemia-GIT,Leukemia,MPP,polycythemia,renal bleeding gum-coagulation
  • Liver-PT,PTT,Platelets,bleeding disorders
  • Microbiology.H.pylori,AIDS.kaposi,NHL,genital cancer
  • HPV cervix cancer,schistosoma-bladder tumour.

Serum markers.

  • PSA,CA-125,HCG,AFP
  • Hormones
  • BM aspiration and biopsy.

Different types of tissue biopsy.

  • Core needle biopsy;cylinder of tissue 3-4 m wide and 1-2 cm long.liver,lung,mediastinum,lung,pancreas,breast,prostate. tru-cut
  • Do BT,CT,PT,PTT before biopsy.trans jugular 16 gauge 85 cm needle biopsy if bleeding.
  • Excision.can be diagnostic and,sub cutis,breastmelanoma,BCC.
  • Incision biopsy.if biopsy is difficult or dangerous a part of tissue is taken.ex.soft tissue.
  • Laparascopic biopsy.intraperitoneal organs.
  • Frozen section;brain breast to prevent second operation.
  • Endoscopic biopsy;nasal,pharyngeal,bronchial,esophageal,gastric,bile duct,colon etc.cystoscopy.
  • Spiral 3d CT can be used to guide fibroptic steriotactic biopsy forceps in glioma paracentesis
  • A tumour can present as an ascitis.repeat paracentesis is common in malignancy,study of effusion by cytology is of great help to dfferniate,transudate,exudate,tuberculosis,malignant ascitis.
  • Flow cytometry
  • Hematolymphoid neoplasms.detection and characterization,clonality,lineage,residual disease.


  • Ph CHROMOSOME-prognostic
  • Soft tissue.Ewings,PNET,alveolar rhabdo.
  • Minimal residual diseae.relapse.
  • FISH.
  • Down’s,AML,ALL.MDS,small round cell tumour.response to treatment.

PET scan

  • Using fluorodeoxyglucose.FDG.
  • Breast cancer for detection of metastasis.
  • Soft tissue.intralesional change,grade
  • Lung cancer.coin lesion.determining malignancy.
  • HD.treatment planning.

Cancer of unknown primary

  • 20%will never know about their primary.detection of primary also depends on history,clinical exam,endoscopy,FNAC,biopsy,
  • The microscopic feartures may give a clue about the primary.
  • STAGING-usefulness of biopsy
  • for stage i,ii,iiiA.
  • Chemotherapy-III and IV stages
  • SCLC.TNM staging is not used.
  • Oesophagus.if adventitia is involved stage iii.
  • iii and iv-chemotherapy.
  • Stomach.<6mm endoscopic resection
  • i,ii,iii with minimal LN.intestinal type give 5 mm margin.if diffuse type give 8 mm margin.
  • Margin should be free
  • Role of immunocytochemistry.


Basic antibody panel

Lymphoma panel

Pan-hematolymphoid marker

  • •CD45 (CD45RB):
  • –Leukocyte common antigen
  • –Positive in all normal lymphoid cells (B, T or NK lineage) except plasma cells
  • –Reed-Sternberg cells (Hodgkin lymphoma) are CD45-
  • –But usually not necessary to stain for LCA in a definite lymphoma: can proceed directly to lineage markers (e.g. CD20 + CD3)

Common B cell lymphomas

B lineage markers

  • •CD20 (e.g. L26):
  • –Very sensitive (>95% B cell lymphomas positive), although B-CLL may not stain well and B-cell lymphoblastic lymphoma may be negative
  • –Typically negative in plasma cells, plasmacytomas and plasmablastic lymphomas (thus CD20 negativity is a helpful clue to the diagnosis)
  • –Nucleolar staining alone should not be considered positive. With heat-induced epitope retrieval, any cell can show this phenomenon

B lineage markers

•CD79a (mb-1):

  • –B cell receptor complex: sensitive and specific B cell marker (normal plasma cells are positive; germinal center cells are stained weakly)
  • –~50% plasmacytomas are positive
  • –But can be positive in T-lymphoblastic lymphoma/leukemia
  • –Antibody expensive: Use as back-up
  • •Immunoglobulin (cytoplasmic and/or surface Ig)
  • •Other B-associated antibodies (LN1, LN2, MB1, MB2, 4KB5) are no longer useful

T-lineage markers

•Cytoplasmic CD3 (polyclonal against CD3e, monoclonal also available, e.g. PS1):

  • –Highly sensitive and specific for T lineage
  • –Staining stronger in perinuclear space, often accentuating the nuclear foldings
  • –Histiocytes may show faint cytoplasmic staining, but with no perinuclear accentuation
  • –Stains >90% of T and NK cell lymphomas
  • –May add other T markers (e.g. CD45RO, CD2) if CD3 is negative and yet T-cell lymphoma is suspected

T-lineage markers

  • CD45RO (e.g. UCHL1, A6):
  • –Highly sensitive for T lineage; some T cell lymphomas are CD3- CD45RO+
  • –But also stains histiocytes/myeloid cells and their tumors
  • •CD43 (e.g. MT1, DFT1, Leu22):
  • –Highly sensitive for T lineage, but not very specific
  • –Also stains histiocytes/myeloid cells and their tumors
  • –Expression in B cells can be upregulated in EBV infection
  • –More useful for diagnosis of small B-cell lymphomas (looking for aberrant expression)

T lineage markers

  • •CD4, CD8:
  • –Infrequently required for study of T cell lymphomas
  • •CD2:
  • –Sensitive and specific pan T cell marker
  • –More expensive than CD3 antibody: use as back-up
  • CD7:
  • –Pan T cell marker expressed early in T cell development
  • –Particularly helpful for demonstrating T lineage in lymphoblastic lymphoma (which can be CD3-)

Further typing of lymphoma

  • •Marker panel helpful for diagnosis of small B-cell lymphomas
  • –CD5
  • –CD23
  • –IgD
  • –Cyclin D1
  • –bcl-6 or CD10

Further typing of lymphoma

  • •Bcl-2:
  • –NOT helpful in classification of B-cell lymphomas, because many different lymphoma types are bcl-2 positive
  • –Only useful for distinguishing between follicular lymphoma (bcl-2+) and reactive follicular hyperplasia
  • •Diagnosis of plasmacytoma:
  • –LCA (commonly positive with sensitive immunostaining techniques, although classically considered negative)
  • –L26(-), CD79a(+/-), CD138(+), Oct-2(+), Bob.1(+), Ig(+)

Further typing of lymphoma

  • •CD10
  • –CD10 is the common acute lymphoblastic leukemia antigen, normally expressed by follicle center B cells and follicle center T cells
  • –Some spindly stromal cells are also CD10+ (serving as internal positive control)
  • –Value in lymphoma typing:
  • Follicular center cell differentiation (follicular lymphoma, Burkitt lymphoma, some large B-cell lymphomas)
  • Angioimmunoblastic T-cell lymphoma

Further typing of lymphoma

  • •Bcl-6
  • –Normally expressed (nuclear staining) in germinal center B cells, CD30+ perifollicular cells, and rare subpopulation of T cells
  • –Positive in the following lymphoma types:
  • •follicular lymphoma
  • some large B cell lymphomas
  • Burkitt lymphomas
  • some anaplastic large cell lymphomas

Further typing of lymphoma


  • –Valuable marker for understanding and characterizing histogenesis of B-cell lumphoma(identification of the transition from Bcl6 positivity to CD138 expression)
  • –Excellent marker for Hodgkin’s Reed-Sternberg cells of classical Hodgkin’s disease in combination with CD30
  • –Has prognostic value since the expression correlates with clinical outcome of patients

Further typing of lymphoma

  • Follicular dendritic cell markers (such as CD21, CD35, and more recently, clusterin) can aid in the diagnosis of:
  • –Follicular lymphoma
  • –Mantle cell lymphoma (loose or dispersed meshworks)
  • –Angioimmunoblastic T cell lymphoma (extrafollicular meshworks)
  • Diagnosis of anaplastic large cell lymphoma
  • –BerH2/CD30, ALK1


  • •A marker for activated lymphoid cells; some CD30+ cells are found in perifollicular region
  • •CD30+ cells are increased in lymphoid hyperplasia
  • •Staining should be in the cell membrane +/- Golgi zone; pure diffuse cytoplasmic staining should not be considered positive
  • •CD30 is positive in classical Hodgkin lymphoma, anaplastic large cell lymphoma and some large cell lymphomas

Anaplastic Large Cell Lymphoma

Further typing of lymphoma

  • Proliferation marker Ki67: can aid in diagnosis of Burkitt lymphoma (~100% cells positive)
  • Cytotoxic markers, e.g. TIA1, granzyme B, perforin: may add in the diagnosis of NK/T cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma
  • Most useful marker for diagnosis of lymphoblastic lymphoma/leukemia: TdT

TdT (terminal deoxynucleotidyl transferase)

  • Polyclonal antibody generally gives stronger staining than monoclonal antibody
  • Outside the thymus, there are practically no TdT+ cells except:
  • –Tonsil (present in small numbers, especially at the base)
  • –Bone marrow (hematogones)
  • –Lymph node in children (scattered cells)


  • For some lymphoma types, immunohistochemical markers may provide additional information important in prognosis
  • –Proliferation markers, e.g. high Ki67 index is associated with worse prognosis in mantle cell lymphoma
  • –Anaplastic large cell lymphoma: ALK+ subset has a much better prognosis than the ALK- subset

Summary: Most useful antibodies for identifying normal cell types and corresponding tumors

  • Mantle zone cell                                IgD
  • Immature precursor cell                     TdT
  • Plasma cell                             CD20-, CD138+
  • Histiocyte                              CD68 (PGM1 >KP1)
  • Follicular dendritic cell         CD21 + CD35
  • Langerhans cell                     S100, CD1a

Summary: Important markers for classification of lymphomas

  • Precursor lymphoblastic lymphoma: TdT
  • B-CLL: CD5, CD23
  • Mantle cell lymphoma: Cyclin D1
  • Follicular lymphoma: CD10 (or bcl-6)
  • Burkitt lymphoma: Ki67 (~100% proliferation index)
  • Angioimmunoblastic T cell lymphoma: CD10, follicular dendritic cell markers (extrafollicular meshworks)
  • Anaplastic large cell lymphoma: CD30, ALK

Carcinoma panel

“Specific” carcinoma markers

  • PSA              Prostate carcinomas
  • P504S     Stains both premalignant and malignant  prostate neoplasms,hepatocellular-, renal cell-, urothelial cell-, gastric- and                          colon carcinomas
  • TTF-1                  Thyroid and lung carcinomas
  • Thyroglobulin        Thyroid carcinomas
  • ER/PGR                 Breast, ovary, endometrial and cervical   carcinomas
  • Calcitonin               Thyroid medullary carcinomas
  • Chromogranin A   Neuroendocrine differentiation
  • Synaptophysin       Neuroendocrine differentiation

Antibody panel for carcinomas and mesotheliomas

  • BerEP4
  • Calcitonin
  • Calretinin
  • CEA
  • Chromogranin A
  • CK 5/6
  • CK 8/18
  • CK 20
  • CK 7
  • ER
  • Pan CK
  • PgR
  • PSA
  • PLAP
  • Synaptophysin
  • Thyroglobulin
  • TTF-1
  • VIM

Melanoma panel
Sarcoma panel

Antibody panel for sarcomas

  • CD117
  • CD31
  • CD34
  • CD45
  • CD57
  • CD99
  • Desmin
  • MyoD1
  • Pan CK
  • S-100
  • SMA
  • VIM


  • No immunostaining is 100% specific or sensitive
  • No panel is 100% specific or sensitive
  • No general rule is 100% applicable
  • Each specific diagnostic problem has to be addressed on individual basis
  • Each immunostaining has to be interpreted in its specific diagnostic context
  • Conclusion.pathologists approach to disease and how multidisciplinay approach is needed in the interest of the patient is discussed in brief

Purine Metabolism & Gout

Dr Sunila BHMS,MD(Hom)
Purine Metabolism
The chief purines found in the nucleotides and nucleic acids are adenine and guanine. Uric acid is the final oxidation product (in man) of these purines. Purines combine through their 9-nitrogen position with sugar residues →nucleoside. If the sugar residue is also phosphorylated a nucleotide results. Purines are occasionally found as free bases, more usually as nucleosides and nucleotides, and as nucleic acids.

Synthesis of purine nucleotides
The synthesis of purine nucleotides occurs along two pathways, referred to as the de novo and salvage pathways.
The de novo pathway involves synthesis of purines and then uric acid from non purine precursors. The starting substrate for this pathway is ribose-5- phosphate.

  • Formation of 5- Phosphoribosyl- 1- pyrophosphate (PRPP).    Ribose is converted by successive phosphorylations of C1 and C5 to form 5- phosphoribosyl-1- PP. ATP is required as phosphate donor.
  • The pyrophosphate in C1 is replaced by an NH2 group from glutamine to form 5- phosphoribosyl amine. This is a “committed step” in purine biosynthesis. It is subject to feed back inhibition by purine nucleotides.
  • Glycine combines with 5- phosphoribosyl amine to form glycinamide ribotide.
  • A formyl group is added to the N at position (7) to form formyl glynamide ribotide. This step requires tetra hydrofolic acid.
  • Glutamine will now add the NH2 of position (3) and closure of ring occurs between C8 and N9 to form aminoimidazole ribosylphosphate.
  • CO2 (from CO2 pool of the body) and NH3 from aspartic acid are added as carbamate to C5 to form the C6 and N1 and the compound now formed is 5- amino- 4- imidazole- carboxamide- ribotide. This requires biotin.
  • A formyl group is now added to the amino group of N3. This step requires tetrahydrofolic acid. The intermediate now formed is 5- formamido- 4- imidazole- carboxamide- ribotide.
  • Ring closure now occurs between N1 and C2 to form inosine monophosphate or inosinic acid.
  • Inosine is converted to adenine by taking an amino group at C6 from aspartic acid.
  • Inosine can be converted to guamine by oxidation C2 to C=O and later amination from glutamine to form C.NH2. Reactions 9 and 10 occur while still in the nucleotide (as inosinic acid). Hence the product formed in step9 is adenylic acid (AMP) and in step 10 it is guanylic acid (GMP).
  • The purine ribonucleotide is converted to deoxyribonucleotide by reduction of the second carbon of ribose. The reaction requires a protein cofactor called reduced thioredoxin’ which is converted to the oxidized form in the reaction. It is converted to the reduced form again by the enzyme ‘thioredoxin reductase’ using NADPH + H+ as coenzyme.
  • The erythrocyte, the polymorphonuclear leukocyte and the mammalian brain do not have the ability to synthesize the purine base. They depend on exogenous supply. The liver supplies the purine base to these tissues.

Purine Salvage Pathways
The salvage of these preformed purine compounds can occur by two general mechanisms. The quantitatively more important mechanism is the phosphoribosylation of the free purine bases by specific enzymes requiring PP riboseP as the ribose phosphate donor. The second general mechanism is the phosphorylation of purine nucleosides on their 5- hydroxyl group.

AMP : Phosphoribosylation of adenine catalysed by adenine phosphoribosyl transferase.

Phosphoribosylation of hypoxanthine and guanine to form IMP and GMP, respectively. The reactions are catalysed by the enzyme hypoxanthine- guanine phosphoribosyl transferase.

The salvage of purine ribonucleosides to purine ribonucleotides is carried out in humans by adenosine kinase only.

Phosphorylation of adenosine to AMP by adenosine kinase

In humans, there is a cycle in which IMP and GMP as well as their respective deoxyribonucleotides are converted to their respective nucloesides (inosine, deoxyinosine, guanosine and deoxy guanosine) by purine-5-nucleotidase. These purine ribonucleocides and 2-deoxy nucleosides are converted to hypoxanthine and guanine by purine nucleoside phosphorylase. The hypoxathine and guanine can then again be phosphorylated by PP ribose P to IMP and GMP to complete the cycle. In the human organism, the consumption of pp ribose P by this salvage cycle is greater than the consumption of pp ribose p for the synthesis of purine nucleotides de novo.

There is a lateral pathway of this cycle that involves the conversion of IMP to AMP with subsequent      conversion of AMP to adenosine. The adenosine thus protected is then either salvaged directly back to AMP via adenosine kinase or is converted to inosine by the enzyme adenosine deaminase.

Regulation of purine biosynthesis
The single most important regulator of de novo purine biosynthesis is the intracellular concentration of PP ribose P. The rate of the synthesis of PP ribose P is dependent upon the availability of its substrates, particularly ribose-5- phosphate and the catalytic activity of PP ribose P synthetase. The rate of utilization of PP ribose P is dependent to a large extent on its consumption by the salvage pathway that phosphorylates hypoxanthine and guanine to their respective ribonucleotides.

The first enzyme uniquely commited to de novo purine synthesis, PP ribose P amidotransferase, demonstrates in vitro sensitivity to feedback inhibition by purine nucleotides, particularly adenosine monophosphate and guanosine monophosphate. These feedback inhibitors of the amidotransferase are competitive with the substrate PP ribose P, and thus again, PP ribose P plays a major role in the regulation of de novo purine synthesis.

The conversion of IMP to GMP is regulated by 2 mechanisms. AMP feedback regulates its own synthesis at the level of adenylosuccinate synthetase; GMP regulates its own synthesis by feedback inhibition of IMP dehydrogenase. Furthermore, the conversion of IMP to AMP requires GTP. The conversion of xanthinylate to GMP requires the presence of ATP. Thus there is significant cross regulation between the divergent pathways in the metabolism of IMP. This regulation prevents the synthesis of one purine nucleotide when there is a deficiency of the other.

 Catabolism of Purins
The end product of purine metabolism in primates including Dalmatian dog is uric acid. In the lower animals, birds and reptiles this is further broken down by the enzyme uricase to form allantoin and other products. The oxidation of the purine ring can occur while it is still in nucleotide combination or nucleoside combination. Adenase is absent in men. Instead, adenosine deaminase will convert adenine to hypoxanthine while in nucleoside combination. Similarly adenylic acid deaminase will act while in nucleotide combination.

Disorders of purine metabolism

  • Those exhibiting Hyperuricemia.
  • Those exhibiting Hypouricemia.
  • Immunodeficiency diseases.

Hyperuricemia and Gout 

  • Individuals with hyperuricemia can be divided into 2 groups:
  • Those with normal urate excretion rate.
  • Those excreting excessive quantities of total urates.

Lesch- Nyhan Syndrome and Von Gierke’s disease
There are persons with identifiable enzyme abnormalities of PP ribose P synthetase, the HGPRTase (hypoxanthine- guanine phosphoribosyl transferase) deficiencies (both the complete- Lesch Nyhan syndrome and incomplete deficiencies) and glucose 6- phosphate deficiency. There exists also a group of patients exhibiting idiopathic overproduction hyperuricemia.

The Lesch Nyhan syndrome is an inherited X- linked recessive disorder characterized by cerebral palsy with choreoathetosis and spasticity, a bizarre syndrome of self mutilation and severe overproduction hyperuricemia. The mothers of affected children exhibit hyperuricemia but no neurological manifestations.

Gout (also called metabolic arthritis) is a disease caused by a disorder of purine metabolism resulting in hyperuricemia. In this condition sodium urate crystals are deposited on the articular cartilage of joints and in the particular tissue like tendons and clinically manifesting as recurrent acute arthritis progressing to chronic deforming arthritis, formation of tophi and development of systemic complications like renal failure.

Normally, the human bloodstream only carries small amounts of uric acid. However, if the blood has an elevated concentration of uric acid, uric acid crystals are deposited in the cartilage and tissue surrounding joints. Plasma levels of uric acid vary from 2-7 mg/ dl in health. The term hyperuricemia denotes values above 7 mg/ dl.


  • Primary or genetic gout (95%): It is either due to primary overproduction or under excretion of uric acid.
  • Secondary gout (5%): Hyperuricemia results from a demonstrable disorder, leading either to overproduction or defective excretion of uric acid.

Causes of overproduction of uric acid

  1. Increased break down of cellular nuclei occurs in malignant disease, especially when treated by anticancer drugs.
  2. Several inborn errors of metabolism lead to overproduction of uric acid:
  • 1)      Lesch Nyhan syndrome.
  • 2)      Type 1 glycogen storage disease.
  • 3)      Phosphoribosyl pyrophosphate synthetase over activity.

Impairment of excretion of uric acid

The excretion of uric acid is impaired

  • 1.  in chronic renal failure
  • 2. during intake of drugs like thiazides
  • 3. in lactic acidosis
  • 4. In miscellaneous conditions like hypertension, hyperparathyroidism, myxoedema, Down’s syndrome, toxemia of pregnancy, starvation and exercise. 

Although the exact cause of gout is not known, it is thought to be linked to defects in purine metabolism. The essential abnormality in primary gout is increased formation of uric acid without intermediary incorporation into nucleic acids. In secondary gout, there is an increased breakdown of nucleic acids leading to an excess of the end-product, uric acid.

Arthritis is caused by the deposition of monosodium urate crystals in the synovium. Polymorphonuclear leucocytes ingest the crystals. They release lysosymal enzymes which cause inflammation. Crystals are demonstrable in the synoviyum and articular cartilage in the stage of acute arthritis. In the chronic stage, erosion of the articular cartilage, proliferation of synovial membrane, pannus formation, cystic erosions of bone and secondary osteoarthritc changes develop. Tophi are nodular deposits found in and around the joints and in the articular cartilage. Histollogically these consists of monosodium crystals surrounded by mononuclear infiltration and foreign body giant cells. These lead to osteoarthritic changes, ankylosis of joints and tissue destruction.

Urate deposition and inflammatory reaction in the parenchyma of kidneys lead to hyalinization or fibrosis of glomeruli. Multiple urate calculi, chronic pyelonephritis and arteriosclerosis are other changes seen in long standing gout.

Clinical features

Gout has four distinct stages:

  1. asymptomatic
  2. acute
  3. intercritical
  4. Chronic.

In the first (asymptomatic) stage, plasma uric acid level increases, but there are no symptoms. The first attack of gout marks the second or acute stage. The classic picture is of excruciating and sudden pain, swelling, redness, warmness and stiffness in the joint. Low-grade fever may also be present. The patient usually suffers from two sources of pain. The crystals cause intense pain especially when the affected area is moved. The inflammation of the tissues around the joint also causes the skin to be swollen, tender and sore if it is even slightly touched. For example, a blanket draping over the affected area would cause extreme pain. Mild attacks usually go away quickly, whereas severe attacks can last days or even weeks.

After the initial attack, the person enters the intercritical stage or symptom-free interval that may last months or even years. Most gout patients have their second attack within 6 months to 2 years from their initial episode.

Gout usually attacks the big toe (approximately 75% of first attacks). The term podagra denotes painful affection of the foot occurring as a result of metatarsophalangeal arthritis. However it can also affect other joints such as the ankle, heel, instep, knee, wrist, elbow, fingers, and spine. In some cases the condition may appear in the joints of the small toes which have become immobile due to impact injury earlier in life, causing poor blood circulation that leads to gout.

In the last or chronic stage, gout attacks become frequent and become polyarticular (affecting multiple joints at one time). Large tophi can also be found in many joints. Most common sites of tophi are around the olecranon, ankles, tendo-achilles, and helix of the ear and over other joints.

In advanced cases of chronic gout, kidney damage, hypertension, ischemic heart disease and kidney stones can also develop.

The diagnosis is generally made on a clinical basis, although tests are required to confirm the disease. Hyperuricemia is a common feature; however, urate levels are not always raised. Hyperuricemia is defined as a plasma urate (uric acid) level greater than 420 μmol/L (7.0 mg/dL) in males (the level is around 380 μmol/L in females); despite the above, high uric acid level does not necessarily mean a person will develop gout. Additionally, urate falls to within the normal range in up to two-thirds of cases. If gout is suspected, the serum urate should be repeated once the attack has subsided. Other blood tests commonly performed are full blood count, electrolytes, renal function and erythrocyte sedimentation rate (ESR). This serves mainly to exclude other causes of arthritis, most notably septic arthritis.

A definitive diagnosis of gout is from light microscopy of joint fluid aspirated from the joint (this test may be difficult to perform) to demonstrate intracellular monosodium urate crystals in synovial fluid polymorphonuclear leukocytes. The urate crystal is identified by strong negative bi-refringence under polarised microscopy, and their needle-like morphology. A trained observer does better in distinguishing them from other crystals.

Radiological changes: in well developed chronic gout periarticular bone shows small punched out erosions due to urate deposits, with superadded osteoarthritic changes. 

All precipitating factors should be avoided. Dietary change can make a contribution to lowering the plasma urate level if a diet low in purines is maintained, because the body metabolizes purines into uric acid. Avoiding alcohol, high-purine foods, such as meat, fish, dry beans (also lentils and peas), mushrooms, spinach, asparagus, and cauliflower, as well as consuming purine-neutralizing foods, such as fresh fruits (especially cherries and strawberries) and most fresh vegetables, diluted celery juice, distilled water, and B-complex and C vitamins can help. Low fat dairy products such as skim milk significantly reduced the chances of gout.

Improved blood circulation in the immediate area of an affected immobile joint can be encouraged with a warm bath. This assists in the relief of swelling and reduction in uric acid crystallization. Ensure area is dry before putting on clothes.

Surgery For extreme cases of gout, surgery may be necessary to remove large tophi and correct joint deformity.

Hypouricemia is either due to enhanced excretion or decreased production of urate and uric acid. Deficiency of enzyme xanthine oxidase results in hypouricemia and increased excretion of the oxypurines; hypoxanthine and xanthine. A deficiency of the enzyme purine nucleoside phosphorylase is associated with hypouricemia.

Two immunodeficiency diseases associated with purine metabolizing enzymes; adenosine deaminase deficiency, purine nucleoside phosphorylase deficiencies have been described. Both of these diseases are inherited as autosomal recessive disorders.


  1. Samson Wright’s Applied Physiology
  2. A Textbook of Biochemistry by A. V. S. S. Rama Rao
  3. Harper’s Textbook of Biochemistry
  4. Text book of medicine- K V Krishna Das
  5. Harrison’s principles of internal medicine
  6. Pathologic basis of disease- Robbins, Cotran and Kumar

Thyroid Gland – Applied Pathology

Dr Sunila BHMS,MD(Hom)
The thyroid gland in an adult weighs 15-40 gm and is composed of 2 lateral lobes connected in the midline by a broad isthmus. Thyroid gland is composed of lobules of colloid- filled spherical follicles or acini. The follicles are the main functional units of the thyroid gland.

The major function of thyroid gland is to maintain a high rate of metabolism which is done by means of iodine containing thyroid hormones, thyroxine (T4) and Triiodothyronine (T3). T3 and T4 are formed by sequential reactions occurring in the thyroglobulin molecule under the control of TSH. Total plasma level of T4 is 4-8µ g/ dl. And T3 is 150-250 n g/ dl. Normal range of TSH is up to 5 µ units per ml.

Diffuse enlargement of the thyroid gland is described as goiter (goiter or bronchocele). It is derived from the Latin word, Gutter– the throat. Goitre is merely a symptom of a more serious thyroid condition, such as:

  • Hyperthyroidism
  • Hypothyroidism etc

Classification of Goitre

  1. Simple goiter
  • a.  Physiological goiter
  • b.  Parenchymatous goitre
  • c.  Colloid goiter
  • d.  Multinodular goiter
  1. Toxic goiter
  • a. Grave’s disease
  • b. Secondary thryotoxicosis in M N G
  • c. Solitary nodule
  1. Neoplastic goiter
  • a. Benign adenoma (follicular adenoma)
  • b. Malignant tumours
  •             i. Primary
  •            ii. Metastatic (Secondary)
  1. Thyroiditis
  •  i.    Autoimmune thyroiditis
  • ii.    Infectious thyroiditis
  • iii.   Granulomatous thyroiditis
  • iv.   Riedel’s thyroiditis

This may be endemic or sporadic. Puberty goiter, colloid goiter, and parenchymatous goiter are included in this group. The thyroid gland is diffusely enlarged, painless and non-tender. It may be soft or firm in consistency.

Etiology : Simple goiter is the result of iodine deficiency.

  • Endemic goiter:

Prevalence of goiter in a geographic area in more than 10% of the population is termed endemic goiter. Such endemic areas are high mountainous regions far from the sea where iodine content of drinking water and food is low. Some cases occur due to goitrogens and genetic factors. Goitrogens are substances which interfere with the synthesis of thyroid hormones. These substances are drugs used in the treatment of hyperthyroidism and certain items of food such as cabbage, cauliflower, turnips and cassava (tapioca) roots. Cabbage contains thiocyanates which inhibit iodine uptake. Cassava contains cyanogenic glycosides which are converted to thiocyanate.

  • Sporadic goiter:

Sporadic goiter is less common than the endemic variety. In most cases the etiology of sporadic goitre is unknown. A number of causal influences have been attributed. These include:

  • Suboptimal iodine intake in conditions of increased demand as in puberty and pregnancy.
  • Genetic factors.
  • Dietary goitrogens.
  • Hereditary defect in thyroid hormone synthesis and transport (dyshormonogenesis).
  • Inborn errors of iodine metabolism 

Pathologic Changes :Grossly, the enlargement of in simple goiter is moderate (weighing up to 100-150 gm), symmetric and diffuse. Cut surface is gelatinous and translucent brown.

Histologically two stages are distinguished:

Ø  Hyper plastic stage: It is the early stage and characterized by tall columnar epithelium showing papillary infoldings and formation of small new follicles.

Ø  Involution stage: This stage generally follows hyper plastic stage. This stage is characterized by large follicles distended by colloid and lined by flattened follicular epithelium.

The cells may undergo hyper involution. In this case the acini become filled with colloid and diffuse colloid goiter may develop. With repeated episodes of iodine depletion and repletion, multi nodular goiter may develop.

Preventive measures : Fortification of common salt with iodide (1 part to 100000 parts) and distribution in endemic areas has been partially successful in many regions.

Treatment : Administration of thyroxine up to .3mg/ day brings about a favorable response in 60% of subjects. The gland shrinks within 3 months of starting treatment. 

It is a complex of disorder which occurs due to increased levels of thyroid hormones (Hyperthyroidism) and manifests clinically with various signs and symptoms. The causes of thyrotoxicosis are:

  1. Primary thyrotoxicosis (Grave’s disease, exophthalmic goiter) 
  1. Secondary thyrotoxicosis secondary to multi nodular goiter (Plummer’s disease). 
  1. Solitary toxic nodule: Autonomous nodule which is not under the influence of TSH, but occurs due to hypertrophy and hyperplasia of gland (tertiary thyrotoxicosis).There is an increase in T3 and T4 level. Iodine 131 scan can demonstrate a hot nodule. Histological diagnosis can be made by FNAC. 
  1. Other causes of thyrotoxicosis 

      I. Thyrotoxicosis facticia: False thyrotoxicosis occurs due to over dosage of thyroxine, given for puberty goiter.

 II.Jod Basedow’s thyrotoxicosis: Jod means iodine in German language, Basedow means toxic goiter.Iodine induced thyrotoxicosis (iodine given for hyperplastic endemic goiters).

                         III.            Initial stage of thyroiditis.

                         IV.            Very rarely, malignant goiters can be toxic.

                            V.            Neonatal thyrotoxicosis occurs in babies born to thyrotoxic mothers.

GRAVE’S DISEASE (Diffuse toxic goiter, Parry’s disease, Base Dow’s disease).

Etiology : Exact etiology is unknown. Possible etiological factors are:

  1. Autoimmune disorder is the first possible cause due to the demonstration of auto antibodies in the circulation.
  1. Familial: The disease can run in families.
  1. Thyroid Stimulating Immunoglobulins (TSI) and long acting thyroid stimulator (LATS) are responsible for pathological changes in the thyroid gland in Grave’s disease.
  1. Exophthalmos producing substance (EPS) is responsible for ophthalmopathy which is seen in Grave’s disease.
  2.  Female sex, emotions, stress, young age also have been considered as the other factors responsible for the disease.

Thyroid is diffusely enlarged due to hyperplasia of acinar cells and increased vascularity. Histologically the acinar cells are hyper plastic, with absorption of colloid. Varying degrees of lymphocytic infiltration is also seen.

Thyroid associated eye disease is a frequent manifestation of thyroid disorders, particularly hyper thyroidism. Extra ocular muscles are the target of auto immune response. The interstitium shows diffused mono nuclear infiltration, primarily by activated T-cells with some B-cells and occasional macrophages. The retro bulbar fibroblasts and skin fibroblasts are affected by the auto immune process. Grave’s ophthalmopathy and dermopathy are strongly associated.

Clinical features : Grave’s disease is more frequent in young women. The general symptoms attributable to hyper metabolic state includes:-

  • Anxiety
  • Irritability
  • Fatigue
  • Weight loss
  • Good appetite
  • Palpitations
  • Heat intolerance
  • Tremor
  • Sweating
  • Diarrhoea
  • +/- Eye signs
  • Tachycardia

Rarely mental changes like sever agitations and frank psychosis may be the presenting features.

Examination of the neck shows the thyroid to be diffusely enlarged, but some times it may be asymmetrical. It is soft, warm, pulsatile and tender. Arterial thrills and bruit may be detectable. These phenomena indicate increased vascularity.

Thyroid associated eye disease may present in several ways, 90% have overt hyperthyroidism. 10% have no obvious thyroid dysfunction. Those with no signs of thyrotoxicosis are known as ophthalmic Grave’s disease. Main clinical features include diplopia with vertical separation of visual images, asymmetry of palpebral fissures, movement disorders of eye balls and lids and compression of the optic nerve. Sympathetic over activity leads to lid lag, stare, increased watering and infrequent blinking. These subside with correction of thyroid function. There is abnormal protrusion of eye ball (exophthalmos) and partial or complete ophthalmoplegia. In severe cases there is chemosis of the conjunctiva, prolapse of the eye ball, failure of closure of the eye lids, corneal ulsarations and blindness can occur. These constitute malignant exophthalmos.

Papilloedema may develop in advanced cases. Some cases may show optic atrophy.

Skin Changes
The skin is soft and moist. The hair is soft, sweating is excessive and the nails show thinning (Onycholysis). Sometimes localized myxoedematous deposits may occur. The common site is in front of the leg (hence called pretibial myxoedema). Over this site the skin is raised. The lesions may be pruritic. Examination reveals ‘peau de orange’ appearance. Pretibial myxoedema is attributed to local non-responsiveness of tissues to the thyroid hormones. Some cases show clubbing of fingers and toes and hypertrophic oesteoartropathy (thyroid acropachy).

Changes in Skeletal Muscles
There is excessive weakness and fatigue. The proximal muscles of pelvic and pectoral girdles may show myopathy. Myasthenia gravis may coexist with Grave’s disease.

Cardio-Vascular Changes
Cardiac out put increases out of proportion to the rise in basal metabolic rate. Atrial fibrillation occurs in up to 25% of the cases. Other arrythmias such as paroxysmal tachycardia and atrial flutter are also common. Some patients develop effort angina.

Alimentary System : Abdominal cramps, diarrhea and vomiting are common features.

Reproductive System
Menses may be scanty and fertility is reduced. In men libido and potency may be altered variably. Gynecomastia may develop, oligospermia may occur.

Bones : Osteoporosis may develop as a result of increased resorption of bone.

The general clinical picture produced by toxic diffused goiter and toxic nodular goiter is similar in many respects. However eye changes and pretibial myxoedema are more common in toxic diffuse goiter. Grave’s disease is more frequent in younger age group. Toxic adenomas occur usually in later age groups. In them cardiovascular manifestations are more prominent. In toxic adenoma local examination of thyroid may not reveal generalized hypervascularity and bruit, but the condition can be easily diagnosed by palpating nodules.

Diagnosis  : In florid cases clinical diagnosis is easy. In all cases it is advisable to confirm diagnosis and establish its severity by investigations.

Laboratory investigations : I 131 uptakes by the thyroid gland, levels of T4 and T3 are all increased. TSH is low.

Follicular adenoma: is the most common benign thyroid tumor occurring more frequently in adult women. 

Pathologic changes

It is characterized by four features so as to distinguish from a nodule of nodular goiter

  • a.   Complete encapsulation
  • b.   Solitary Nodule
  • c.   Clearly distinctive architecture inside and outside the capsule
  • d.   Compression of the thyroid parenchyma outside the capsule

Histologically the tumor cells are benign follicular epithelial cells forming follicles of various sizes or may show trabecular, solid and cord patterns with little follicle formation. Accordingly the following six types of growth patterns are distinguished.

  • 1)      Microfollicular (foetal) adenoma.
  • 2)      Normofollicular (simple) adenoma
  • 3)      Macrofollicular (Collloid) adenoma
  • 4)      Trabecular (embryonal) adenoma; resembles embryonic thyroid
  • 5)      Hurthle cell (oxyphilic) adenoma: composed of large cells having abundant granular or oxyphilic cytoplasm
  • 6)      Atypical adenoma: follicular adenoma which has more pronounced cellular proliferation so that features may be indicative of malignancy.

Papillary carcinoma
It is the most common type of thyroid carcinoma. It is typically a slow growing tumor, most often presenting as an asymptomatic solitary nodule. Involvement of the regional lymph node is common but distant metastases to organs are rare. 

Pathologic changes
Sometimes the tumor is transformed into a cyst, into which numerous papillae project and is termed papillary cystadenocarcinoma. Histologically the following features are present:

  • 1)      Papillary pattern
  • 2)      Tumor cells have overlapping pale nuclei (ground glass appearance) and clear or oxyphilic cytoplasm.
  • 3)      Invasion into the capsule and intrathyroid lymphatics.
  • 4)      Half of the papillary carcinomas show typical small, concentric, calcified spherules called psammoma bodies.

Follicular carcinoma  : It is more common in middle and old age and in females.

Pathologic Changes
It may be either in the form of a solitary adenoma- like circumscribed nodule or as an obvious cancerous irregular thyroid enlargement. Microscopically it is composed of follicles of various sizes and may show trabecular or solid pattern. However, variance like clear cell type and hurthle cell type may occur. Vascular invasion is common but lymphatic invasion is rare.

Medullary Carcinoma
It is a less frequent type derived from parafollicular or C- cells present in the thyroid. It has genetic association with genetic defect in chromosome-10. They secrete calcitonin, the hypocalcaemic hormone. These hormones elaborations are responsible for a number of clinical syndromes such as carcinoid syndrome, Cushing’s syndrome and diarrheoa and they have amyloid deposits in the trauma. The tumour may either appear as a unilateral solitary nodule (sporadic form) or have bilateral and multi centric involvement (familial form).

Anaplastic Carcinoma
Undifferentiated or anaplastic carcinoma comprises less than 5% of all thyroid cancers. The prognosis is poor. The tumour is generally large and irregular. There are three histological variants.

  1. Small cell carcinoma
  2. Spindle cell Carcinoma
  3. Giant cell carcinoma


Thyroiditis is classified into the following types:

  •  i.  Autoimmune thyroiditis
  •  ii. Infectious thyroiditis
  • iii. Granulomatous thyroiditis
  • iv. Riedel’s thyroiditis

I.      Autoimmune (Lymphocytic) Thyroiditis
This is a group of thyroiditis having, in common, infiltration of the thyroid by lymphocytes and plasma cells and occurrence of thyroid specific auto antibodies in the serum. Autoimmune thyroiditis includes:

  • a.  Hashimoto’s Thyroiditis
  • b.  Atrophic Thyroiditis
  • c.  Focal lymphocytic Thyroiditis

a. Hashimoto’s Thyroiditis: Also called diffuse lymphocytic thyroiditis, struma lymphomatosa or Goitrous auto immune thyroiditis.

  1. HLA association: Hashimoto’s thyroiditis has some association with HLA- DR5.
  1. Autoimmune Disease Association: Hashimoto’s disease has been found in association with other auto immune diseases such as Grave’s disease, SLE, Sjogren’s syndrome, rheumatoid arthritis, pernicious anaemia and Type I (juvenile- onset) diabetes.

The following auto antibodies against different thyroid cell antigens are detectable in the sera of most patients with Hashimoto’s thyroiditis:

  • Thyroid microsomal auto antibodies (against the microsomes of the follicular cells)
  • Thyroglobulin autoantibodies.
  • Less frequently TSH receptor autoantibodies
  • Less constantly found are thyroid autoantibodies against follicular cell membranes, thyroid hormones themselves and colloid components other than thyroglobulin.

Pathologic changes
Pathologically two varieties of Hashimoto’s thyroiditis are seen: classic form, more common and fibrosing variant found only in 10% cases of Hashimoto’s thyroiditis. Grossly, the classic form is characterized by diffuse, symmetric, firm and rubbery enlargement of the thyroid gland. The fibrosing variant has a firm, enlarged thyroid with compression of the surroundings tissues. Histologically, the classic form shows the following features.

There is extensive infiltration of the gland by lymphocytes, plasma cells, immunoblasts and macrophages, with formation of lymphoid follicles.

There is decreased number of thyroid follicles which are generally atrophic are often devoid of colloid.

The follicular epithelial cells are transformed into their degenerated state termed Hurthle cells (Askanazy cells, or oxyphil cells or onocytes). These cells have abundant oxyphilic or eosinophilic and granular cytoplasm due to large number of mitochondria and contain large bizarre nuclei.

There is a slight fibrous thickening of the septa separating the thyroid lobules.

Clinical features
The presenting feature of Hashimoto’s thyroiditis is painless, firm and moderate enlargement of the thyroid gland, usually associated with hypothyroidism, in an elderly woman. A few cases however develop hyperthyroidism, termed hashitoxicosis.

b. Atrophic thyroiditis ” In this type the gland is decreased in size and manifests clinically as spontaneous hypothyroidism.

c. Focal lymphocytic thyroiditis: The condition is characterized by focal aggregates of lymphocytes without significant alterations in the epithelium.

II.      Infectious Thyroiditis
Acute thyroiditis by microbial infection with bacteria, viruses and fungi is uncommon and is generally a complication of infection elsewhere in the body.

III. Granulomatous Thyroiditis (De Quervain’s or Subacute or Giant cell Thyroiditis)
It is a distinctive form of self limited inflammation of the thyroid gland. Etiology is unknown; but clinical features of a prodromal phase and preceding respiratory infection suggest a possible viral etiology. The disease is more common in young and middle aged women and may present clinically with painful moderate thyroid enlargement with fever, features of hyperthyroidism in the early phase of the disease and hypothyroidism if the damage to the thyroid gland is extensive.

Pathologic Changes
Grossly there is moderate enlargement of the gland. The cut surface of the involved area is firm and yellowish white. Microscopically the features vary according to the stage of the disease. Initially there is acute inflammatory destruction of the thyroid parenchyma and formation of microabcesses occurs. Later the more characteristic feature of granulomatous appearance is produced. More advanced cases may show fibroblastic proliferation.

Morphologically similar appearance may be produced in cases where vigorous thyroid palpation may initiate mechanical trauma to follicles, so called palpation thyroiditis.

VI. Riedel’s Thyroiditis  (Riedel’s Struma or invasive fibrous thyroiditis)
It is a rare chronic disease characterized by stony hard thyroid that is densely adhered to the adjacent structures in the neck. The condition is clinically significant due to compressive clinical features (e.g.: Dysphagia, dyspnoea). Etiology is unknown but possibly Riedel’s thyroiditis is a part of multifocal idiopathic fibrosclerosis. This group of disorders includes idiopathic retroperitoneal, mediastinal and retro-orbital fibrosis and sclerosing cholangitis, all of which may occur simultaneously with Riedel’s thyroiditis.

Pathologic Changes
Grossly thyroid gland is usually contracted, stony hard asymmetric and firmly adherent to adjacent structures. Microscopically there is extensive fibro-collagenous replacement, marked atrophy of the thyroid parenchyma, focally scattered lymphocytic infiltration and invasion of the adjacent muscle tissue by the process.

It is a hypo metabolic clinical state resulting from inadequate production of thyroid hormones for prolonged periods. The clinical manifestations depend on the age at the onset of disorder and are divided into two forms.

  1. Cretenism or congenital hypothyroidism: is the development of severe hypothyroidism during infancy and childhood. There is rise in TSH level and fall in T3 and T4 level. Child is dwarf and mentally retarded.
  1. Myxoedema: The adult-onset severe hypothyroidism causes myxoedema. The term denotes non-pitting oedema due to accumulation of hydrophilic mucopolysaccharides in the ground substance of dermis and other tissues. Here also, there is rise in TSH levels and fall in T3 and T4 levels. 

Treatment of goitre
Treatment depends on the cause, the size of the goiter, and whether it is causing symptoms. Goiter caused by iodine deficiency can be helped with the introduction of iodine-rich foods into the diet, such as seafood and iodized salt. Hyperthyroidism is managed with drugs that slow the activity of the thyroid. If these fail to work, part or all of the thyroid gland is surgically removed. Alternatively, some or all of the thyroid’s hormone-producing cells can be destroyed with radioactive iodine treatment. Hypothyroidism is treated by lifelong hormone replacement therapy. Benign thyroid nodules are shrunk with medications, destroyed with radioactive iodine treatment or surgically removed, depending on the type. Cancer of the thyroid is treated by surgical removal of the gland, followed by radioactive iodine treatment.

Diphtheria – Applied aspect

Dr Sunila BHMS,MD(Hom)

Diphtheria is an acute communicable disease caused by Coryne bacterium diphtheriae. It usually occurs in children and results in the formation of a yellowish-grey pseudomembrane in the mucosa of nasopharynx, oropharynx, tonsils, larynx and trachea. C.diphtheriae elaborates an exotoxin that causes necrosis of the epithelium which is associated with abundant fibrinopurulent exudates resulting in the formation of pseudomembrane. Absorption of exotoxin in the blood may lead to more distant injurious effects such as myocardial necrosis, polyneuritis, parenchymal necrosis of the liver, kidney and adrenals. The constitutional symptoms such as fever, chills, malaise, obstruction of air ways and dyspnoea are quite marked.

Coryne bacterium diphtheriae
Coryne bacterium diphtheriae are gram positive rods 3×3μm in size, pleomorphic, non-motile, non-sporing, non-capsulate, generally aerobic and facultatively anaerobic. These bacilli exhibit characteristic arrangement in smear preparations. Adjacent bacteria lie at various angles to each other giving ‘V’ or ‘L’ appearances which collectively resemble arrangement of Chinese letters or cuneiform writing. This arrangement is because of incomplete separation of daughter cells at the moment of division.

C.diphtheriae is classified into three main types based on the colony morphology on tellurite medium, bio chemical reactions and hemolytic property.

  • Gravis
  • Intermedius
  • Mitis

Virulent strains produce an exotoxin which is responsible for producing remote effects. Around 90-95% of the gravis and intermedius strains are toxigenic while only 80-85% of mitis are so. The toxin is a labile protein of molecular wt 62,000 and it is inactive when released by the bacterium.

The disease has been almost wiped out from developed countries, but in India it is still prevalent. Diphtheria is more common in children. In unvaccinated population, children below 2-15 years of age are at the highest risk. Disease is spread by droplets, contaminated vessels shared by children or by direct inoculation into skin abrasions or eyes. The organism is harbored by carriers and cases. Unimmunized children in a partially immunized community are highly susceptible. Untreated cases are infective for more than two weeks. During outbreaks susceptible individuals can be identified by the Schick intra-dermal test.

Schick test: This test was introduced by Schick in 1913 and is performed to assess the immunity against diphtheria in children above 2 months of age.

The test comprises of injecting intradermally 0.2 ml of diphtheria toxin which 1/50μLD of toxin in the left forearm. Similar dose of heat inactivated toxin is injected in the right forearm. Readings are taken after 24-48 hours and then after 5-7 days of inoculation. The following types of reactions may be observed:

  • In negative reaction there is no reaction of any kind in either forearm. This indicates the person is immune to diphtheria.
  • In positive reaction an erythematous reaction appears in the test arm within 24-36 hours, (1-3cm diameter) and persists for 7 days whereas there is no reaction on the control arm. This status is indicative of susceptibility of the individual to diphtheria.
  • Pseudo reaction develops in both the arms in less than 24 hours. Usually fades away in 4 days. This is also indicative of immunity to diphtheria.
  • In combined reaction both the arms show reaction during first 24 hours, after which in test arm, reaction continues to develop whereas in control arm it fades. This reaction is indicative of susceptibility to diphtheria. 

Pathogenesis and pathology

  • The organisms enter through the respiratory passages, eyes, middle ear, genitalia and skin.
  • Incubation period        – 3-4 days
  • But it may vary from 2-7 days

The exotoxin causes tissue necrosis, which favors further growth of the organism and toxin production. The epithelium degenerates and serofibrinous exudate develops which contains inflammatory cells and fibrin. The coagulation of these exudates on the ulcerated, necrotic surface creates a bluish white membrane over the involved area. The membrane is adherent and when removed forcibly it leaves a raw bleeding surface. Site of predilection for the primary lesions is the respiratory tract. Other sites of infection are nose, ears, conjunctiva, genitalia and skin.

  • Around the membrane, there may be necrosis, ulceration or haemorrhage. Sometimes the membrane may not be evident, but the pharynx may show hyperemia and oedema.
  • Regional lymph nodes are markedly enlarged. The toxin is absorbed from the primary site and it causes damage to the myocardium, kidneys, adrenal gland and the cranial and the peripheral nerves.
  • Myocardium shows cloudy swelling, fatty change, mild haemorrhage and round cell infiltration. This may lead to cardiomegaly and conduction disturbances.
  • Kidney shows cloudy swelling of the tubular epithelium and interstitial nephritis. 
  • The adrenal glands are enlarged with haemorrhage in the cortex. 
  • Liver cells sow degenerative changes with scattered area of focal necrosis; peripheral cells may show degeneration of the myelin sheath and axis cylinders, motor fibres being more affected.
  • The posterior column of the spinal cord may be involved.
  • Rarely cerebral haemorrhage, meningitis and encephalitis have been described.
  • Respiratory obstruction by the membrane or toxic myocarditis may lead to death.

Clinical features:
These depend on the primary site of involvement, duration of the illness, systemic effect of the toxin and resistance of the heart.

The disease starts with sore throat, low grade fever, head ache, malaise, vague aches and pains, and catarrhal symptoms. As the disease progresses, tachycardia, nausea, vomiting, pallor and weakness follows.

Pharyngeal Diphtheria:
It is the most common form and the membrane is present over the tonsils and the pharynx. Gross cervical lymphadenopathy (described as bull neck) is evident and respiratory obstruction may develop, especially in children. In severe cases circulatory collapse occurs. Local effects of the toxin lead to paralysis of the palate and pharynx.

The term ‘malignant diphtheria’ is given to condition characterized by marked oedema of the sub mandibular areas and anterior part of the neck. There is moderate leukocytosis (14,000-16,000/cumm) with polymorphs forming 60-80% 

Laryngeal Diphtheria:
This forms 25% of the cases. It produces respiratory obstruction early, which may be fatal. (Inflammation and necrosis of subjacent tissues permit dislodgement and aspiration of the membrane, result in acute respiratory obstruction.

The clinical features include barking cough, hoarseness, dyspnoea, stridor and cyanosis. Infants with laryngeal diphtheria may refuse to suck the breast due to choking.

Nasal Diphtheria:
It occurs in 2-3% cases. The membrane is limited to the septum or turbinate and is usually unilateral. The condition may present with a foul smelling serosanguinous nasal discharge or frank epistaxis.

Cutaneous Diphtheria:
Coryne bacterium diphtheria cannot penetrate the intact skin and it gains entry through wounds, burns or abrasions. It causes ulceration. The typical ulcer usually punched out and 0.5 cm or more in size. In the early stage the ulcer is covered by a grayish yellow or brownish membrane.

There may be coexistent pharyngeal diphtheria in 20% of the cases.

Other sites of lesion are the conjunctiva, vulva, vagina, uterine cervix, bladder, urethra, penis, middle ear, buccal mucus membrane and oesophagus. 

Complications: Mechanical obstruction of the air way by the spreading membrane is a dreaded complication.

  • The other complications are due to the systemic effects of the toxin. The incidence and severity of toxic manifestations increase in proportion to the extent of the membrane.
  • Toxic complications are more pronounced in the heart and motor nerves. Though 60% of the patients have pathological lesions in the heart, only 10-12% manifest clinically.
  • Myocarditis should be suspected if there is variation in the intensity of heart sounds, systolic murmurs, conduction defects, atrial fibrillation, ventricular ectopic beats or ventricular tachycardia. Sudden death may occur due to ventricular fibrillation. Congestive failure and cardiac dilation are less common. In infants and young children vomiting may be an early symptom of cardiac involvement.
  • Toxic peripheral neuritis: develops 2-6 weeks after the primary lesion. Third, sixth, seventh, ninth and tenth cranial nerves are commonly affected.
  • Palatal and pharyngeal paralysis may occur as early as the third day. 
  • External ophthalmoplegia and paralysis of accommodation are frequent.
  • Motor weakness may involve the limbs or respiratory muscles.
  • Ascending polyneuritic type of lesions may follow 2-3 months after the acute attack of diphtheria.

The diagnosis of diphtheria is essentially clinical. Confirmation of diagnosis depends on the demonstration of the oranges in the stained smears made from the membrane and by the culture using Loeffler’s medium. Fluorescent anti toxin staining provides a method for rapid diagnosis. Toxigenicity can be assessed by genuine pig inoculation, passive agar gel diffusion (Elekplate method) or counter immuno electrophoresis. 

Differential Diagnosis:
Acute follicular tonsillitis: In follicular tonsillitis the exudates is confined to the tonsils, it is yellowish and can be wiped off without being adherent. Fever is high in acute tonsillitis where as it is only mild in diphtheria. Regional lymphadenopathy is more marked in diphtheria than in acute tonsillitis.

Agranulocytosis and 3. Acute leukaemia: in these there is no true membrane. The tonsils are red, enlarged and necrotic or hemorrhagic. Hematological examination establishes the diagnosis.

It includes general active immunization and management of contacts. Active immunization is done with diphtheria, pertussis, and tetanus (DPT) vaccine which is also known as triple antigen. The first dose should be given at 2 months and thereafter two more doses at 4 weeks intervals. Booster doses should be given at the second and fifth year.


  • Text book of pathology- Harsh Mohan
  • Microbiology for dental students- Rajesh Bhatia; RL ichhpujani
  • Text book of medicine- Krishnadas
  • Harrison’s principles of internal medicine
  • Muir’s text book of pathology
  • Pathology illustrated/ Govan/ Mac Farlane/ Callander
  • Pathologic basis of disease- Robbins, Cotran, Kumar
children - Copy

Guillain Barre Syndrome & Homeopathy

childDr Sunila BHMS,MD(Hom)
Presenting Complaints

  1. Fever   (1 Week)
  2. Weakness of Lower limbs       (1 Week)
  3. Pain in the Popliteal Fossae    (1 Week)
  4. Pain in Abdomen                    (1 Week)

History of Presenting Complaint

Complaint started 6 years back with fever, which continued for 6 months. Fever used to come on especially in the evening along with upper respiratory tract infection including cough and coryza. Then she developed weakness in the lower limbs which is more on walking for a long distance and which progressed so that the patient feels weak even after walking for a short distance. The weakness is better by rest. Patient used to fall down due to weakness while walking. There was pain in the lower limbs, especially on the Popliteal Fossae which increased on walking. < On ascending stairs.

There was also swelling of joints like wrist, elbow, fingers, ankle, knee etc. which used to come recurrently and the joints would be hot to touch with pain and difficulty in bending the joints. The patient could not hold weight or write for longer durations.

There was puffiness of eyes also. < Morning, Better in the after noon.

Nerve conduction test was done on 29/ 03/ 2001; diagnosed as Chronic Inflammatory Demyelinating Polyneuropathy/ Guillain- Barre Syndrome and was given Allopathic treatment for relief.

Now she has weakness in the lower limbs since one week and is admitted in GHMC.

Past History

  • Measles- 5 years back
  • Urticaria in childhood
  • UTI- Two years back
  • Took Homoeopathic treatment for all complaints and got relief. 

Family History – Father has tuberculosis

Personal History
Born and brought up at Vengeri. Anupama is studying in 6th standard. Her father is a painter and mother, a house wife. She has an elder sister also.


  • Appetite – ↓
  • Thirst    – ↓
  • Desires cold drinks
  • Sleep- disturbed by dreams; cries during sleep
  • Stool- regular
  • Urine- no complaints
  • Desires- fish
  • Aversion- meat, egg, milk
  • Thermal reaction- chilly; she wants to cover the body always. Cannot bear cold water application 


  • Scalp- sensitiveness of scalp- cannot comb hair
  • Abdomen- Pain in abdomen < eating
  • Eyes- Puffiness of eyes < morning
  • Skin- Exfoliation of skin in the palm

She is mild, gentle, very active and enthusiastic in nature. She makes friends easily and cannot bear to be alone. When her mother goes out she is restless till she returns. She dislikes her father as he is an alcoholic, returns home drunk and quarrels with her mother. The patient cannot stand the rude behavior of her father.

After she and her sister were caught between a dog fight, the patient developed a fear of dogs and she has recurrent dreams of dogs. The patient is afraid of thunder storms since she was hit by a lightning and is very sensitive and fastidious.

Physical Examination

  • PR – 80/ mt
  • RR – 20/ mt
  • BP – 90/60 mm of Hg
  • General Survey
  • Patient is moderately built.
  • No pallor, No cyanosis, No jaundice and no clubbing.
  • Cervical lymphadenopathy present

Systemic Examination 

  • Child is conscious and alert, memory normal, no hallucination, delusion or illusion.
  • Speech normal, no dysarthria. Gait- Dragging (26/ 03/ 2001). Now normal steady gait. 

Motor System

  •                                    UL                                LL
  • Bulk                            N                                 N
  • Power                          G IV                             G IV
  • Tone                            Hypotonic                   Hypotonic
  • Beevor’s Sign              Negative

Superficial Reflexes

  • The plantar reflex:       Flexor Plantar Response
  • Corneal Reflex:           Present 
  • Signs of Meningeal Irritation: 
  • No signs of meningeal irritation

Investigations: 26/03/06


  • Hb-      11.1gm%
  • TC-      8.5x 10³ cells/ mm³
  • DC-     N43, L44, M11
  • ESR-    22 mm/ hr
  • CPK-   681 μ/L (Normal-20-200 μ/L) (Increased in blood in muscle diseases)
  • RBS-   98 mg%
  • SK-      4.4 m eq/ L (Pottasssium serum normal, 3.5-5.2 m eq/ L)


  • TC-      8800 cells/ mm³
  • DC-     P 36%, L 60%, E 4%
  • ESR-   60 mm/ hr
  • Hb-      12.1g%

Urine: RE

  • Albumin          –           Nil
  • Pus cells          –           1-2 HPF
  • Epithelial Cells-           0-1/ HPF

Lumbar puncture done on 26/3/01

  • Normal CSF values
  • No cells seen (Cells- 0-5/ mm³, all lymphocytes)
  • Proteins-          213.4 mg%             (Protein- 15-45 mg/ dl)
  • Sugar-              52 mg%                  (Glucose- 48-86 mg/dl) 
  • Albumino cytological dissociation

Nerve Conduction Test done on 29/ 3/ 2001

Probably C/C inflammatory demyelinating neuropathy (CIDP)

Nerve Conduction Velocity Test done
There are prolonged distal latencies (of CMPA) both in the nerves of legs and upper limb. F waves are not obtained. The velocity of conduction is reduced. The above features are suggestive of severe demyelinating neuropathy.

Provisional Diagnosis : Demyelinating Neuropathy/ Guillain- Barry Syndrome   

Analysis of Symptoms 

Symptoms of the patient Symptoms of the Disease


Fear of being alone Weakness of lower limbs
Fear of dogs
Fear of thunderstorm
Desire to work Stumble while walking
Chilly patient
Sleep disturbed Rise of temperature
Desires fish
Desires cold drinks

Evaluation of Symptoms

Mental Generals Physical Generals Particulars Common
1.Fear of dogs 

2.Fear of being alone


3.Fear of thunder storm


4.Desire to work




1.      Chilly patient; prefers covering always 

2.      Desires fish


3.      Desires cold drinks


1.   Evening rise of temperature 

2.   Pain in abdomen

< eating


3.   Pain in abdomen

< morning


1.   Weakness of lower limbs 

2.   Stumble while walking


 Totality of Symptoms

  • 1. Fear of being alone
  • 2. Fear of dogs
  • 3. Fear of thunder storms
  • 4. Fastidious
  • 5. Desire to work
  • 6. Sleep disturbed by dreams
  • 7. Chilly patient
  • 8. Desires fish
  • 9. Desires cold drinks
  • 10. Weakness of lower limbs
  • 11. Stumble while walking
  • 12. Evening rise of temperature
  • 13. Pain in abdomen< Morning
  • 14. Pain in abdomen< After eating

Miasmatic cleavage

symptoms psora sycosis syphilis tubercular
Fear of being alone +      
Fear of dogs +      
Fear of thunderstorm +      
Desire to work +      
Sleep disturbed by dreams +      
Chilly patient +      
Craving for cold drinks     +  
Weakness of lower limbs     +  
Evening rise of temperature       +
Pain in abdomen< after eating +

Predominant miasm: Psora 

Rubrics Selected (Synthesis) 

  • MIND, FEAR, alone of being
  • MIND, FEAR, dogs of
  • MIND, FEAR, thunder storm of
  • SLEEP, DISTURBED, dreams by
  • GEN, HEAT, vital, lack of
  • STOMACH, DESIRES, cold drinks
  • EXTREMITIES, WEAKNESS, lower limbs
  • EXTREMITIES, AWKWARDNESS, lower limbs, stumbling while walking
  • ABDOMEN, PAIN, morning
  • ABDOMEN, PAIN, eating after 


  • Phos        34/ 14
  • Nat. mur          –           31/ 13
  • Calcarea          –           27/ 10
  • Causticum       –           29/ 12
  • Lycopodium    –           24/ 10

Treatment taken

  • 9/ 7/ 2006        –           Gelsemium      30/ 4 d
  • 12/ 7/ 2006      –           phos                 30/ 1 d
  • 19/ 7/ 2006      –           phos                 200/ 1 d
  • Patient is relieved and discharged on 5/ 8/ 2006.



This is an acute anterior radiculopathy occurring as an allergic manifestation to a preceding viral illness. It is an autoimmune disease due to the production of antibodies against the myelin sheath.

This disease occurs in all parts of the world and in all seasons. It affects children and adults of all ages and both sexes. Its cause is unknown. A mild respiratory or gastrointestinal infection precedes the neuritic symptoms by 1 to 3 weeks in 60- 70% of the patients. Other preceding events include surgical procedures, viral exanthems and other viral illnesses including AIDS, mycoplasma infections, the spirochetal infection of Lyme disease and lymphomatous diseases particularly Hodgkin’s Disease.

The brunt of attack is borne by the anterior roots. About 10- 30 days after a viral illness, the patient complains of paraesthesia in the extremities. This is followed symmetrical ascending paralysis starting in the lower limbs, esp. in the proximal muscles.

The paralysis may ascend up gradually over days or abruptly within hours. Respiratory paralysis may occur. Majority of cases do not affect the cranial nerves and bilateral facial palsy may develop. Cases with rapid progress and those with respiratory paralysis have a poor prognosis.

Clinical examination reveals lower motor neuron signs such as hypotonia, weakness and areflexia. The disease may progress for upto 2 weeks. Usually fever is absent at the onset of paralysis.

Dysautonomic features may be present in the form of Brady or tachycardia and fluctuations in blood pressure. Objective sensory deficit and bladder involvement are uncommon. Respiratory paralysis may develop due to affection of the intercostals nerves.

Diagnosis : Any illness in which rapid or sub acute symmetrical polyneuropathy develops, should be suspected to be infective polyneuritis.

Differential Diagnosis

  • Poliomyelitis: Distinguished by an epidemic occurrence, meningeal symptoms, fever, purely motor and usually asymmetric, areflexic paralysis.
  • Acute Myelopathy: Marked by sensory motor paralysis below a given spinal level. Sphincteric paralysis may occur.
  • Acute Polyneuritis: Acute inflammation of several peripheral nerves simultaneously.
  • Transverse Myelitis: It is an acute inflammatory demyelinating disorder affecting the spinal cord over avariable number of segments. It presents with sub-acute paraparesis (Symmetrical partial paralysis of the lower limbs) with a sensory level.
  • Other demyelinating diseases:
  • Post Vaccinal Neuropathies

Investigations: Blood count and blood chemistry are non contributory. C.S.F shows albuminocytological dissociation if examined a week after the onset of the disease. This abnormality may persist for a few weeks. The term albuminocytological dissociation refers to the rise in proteins without a corresponding rise in cell count. EMG and nerve conduction studies help to distinguish the condition from myopathies and poliomyelitis.

Nerve conduction velocities are slowed soon after the paralysis develops, sometimes more in proximal parts of the nerves (abnormal H and F responses) than distal.

Nerve Conduction Studies

The basic requirements for motor nerve conduction studies are that a suitable muscle nerve is available and that its nerve supply can be stimulated at 2 points along its course. The time taken from the stimulus nearest to the muscle is known as the distal latency and includes not only the time taken by the impulse to travel down the nerve, but also the delay at the end plate and initiation of contraction. If the nerve is then stimulated higher up, a second latency can be obtained; the difference in the time taken being an accurate measurement of the time taken for the impulse to traverse a measured length of nerve. From this the conduction velocity in meters per second is easily calculated. Very carefully documented velocity ranges for all the nerves that can be studied in this way have been reported. These are the median and ulnar nerves in the arm and peroneal and tibial nerves in the leg. Nerves such as the radial and femoral can only be readily stimulated at one point and latency to an appropriate muscle is all that can be measured.

In general if a muscle is denervated and it can be shown that the lesions responsible are above the proximal stimulus, it is probably affecting the nerve root or ventral Lorn cell.

Nerve action potentials can be measured in 2 ways, orthodromically or antidromically. Here the main requirement is a nerve near enough to the surface to be picked up by a surface electrode or anatomically constant in position allowing needle electrodes to be inserted near to the nerve. Both the medial and ulnar nerve action potentials can be detected at the wrist by stimulating the inter-digital nerves of the appropriate fingers.

In the case of ulnar nerve lesions at the elbow or the peroneal nerve at the fibula neck, due to compression some points do not demonstrate slowed conduction through the damaged area. A very useful ancillary test is the study of quantitative muscle action potentials.

In about 10% of the cases rapid on set and progress, respiratory failure may threaten life. Mortality is around 5%. Vast majority of patients start improving after a week or so of onset and recovery is complete within 6 weeks; in about 25% of cases resolution is slow. In a smaller number, severe paralysis may persist and the patients may become crippled for life. Presence of axonal degeneration and occurrence of the disease at the extremes of age are associated with bad prognosis. 

During the period of progression the patient should be kept under close observation and respiratory failure should be managed with ventilator assistance. On recovery graded physiotherapy and rehabilitation should be started

Homoeopathic Management

1. Homoeopathic Medical Repertory by Robin Murphy

  • Diseases GUILLAIN-barre syndrome- carc, con, lath, thuja
  • Nerves, CONDUCTION, nerves delayed- alum, cocc
  • Nerves GUILLAIN- barre syndrome- carc, con, lath, thuja

2.  Repertory of Homoeopathic Materia Medica by J T Kent

  • EXTREMITIES, PARALYSIS, ascending: ars, con, kali-c, agar, hydr-ac, mang
  • EXTREMITIES, PARALYSIS, lower limbs: agar, arg-n, cann-i, nux-v, plb, rhust
  • EXTREMITIES, WEAKNESS, lower limbs: aesc, Alum, arg-n, Ars, Aur, Calc, Carb-ac, Caust, cocc, con, gel, alon, Nat-C, mur-ac, Nux-v, Phos, pic-ac, plb, Rhust, sil, Zinc

3.SYNTHESIS by Dr. Frederick Schroyens

  • EXTREMITIES, WEAKNESS, lower limbs
  • GENERALS COMPLAINTS, nervous system

§  accompanied by: polyneuropathy-brass-n-o (brassica napus oleifera.)

Indications of some important medicines for ascending paralysis

1.   CONIUM: It is an excellent remedy for ascending paralysis. There may be difficult gait, trembling; sudden loss of strength while walking, painful stiffness of legs etc.There may be weakness of body and mind. Muscular weakness; especially of lower extremities. Putting feet on a chair relieves pain.

2.   LATHYRUS: Affects the lateral and posterior columns of the cord. Does not produce pain. Reflexes are always increased. Paralytic affections of lower extremities. After influenza and wasting, exhaustive diseases where there is much weakness and heaviness, slow recovery of nerve power. Tremulous, tottering gait. Excessive rigidity of legs. Spastic gait. Knees knock each other when walking. Cramps in legs aggravation cold. Cannot extend or cross legs when sitting. Gluteal muscles and lower limbs emaciated.

3.   PHOSPHOROUS: ascending sensory and motor paralysis from ends of fingers and toes. Burning of feet. Weakness and trembling from every exertion. Can scarcely hold anything with his hands. Arms and hands become numb. Can be only on right side. Post diphtheritic paralysis. Joints suddenly give way.

4.   THUJA: When walking, limbs feel as if made of wood or glass and would break easily. Muscular twitching, weakness and trembling. Cracking in the joints. Pain in heels and tendo-Achilles.

5. CARCINOSIN: When apparently well indicated remedy fails to cure a case or produce a temporary amelioration carcinosin acts as complementary drug. Family history of cancer, Diabetes, syphilis or any other degenerative condition is traced, if symptoms agree carcinosin should be thought of.  Personal history of recurrent attack of bronchitis, pneumonia, wooping cough in childhood, even tendency to suffer repeatedly from measles, chicken pox, diphtheria, mumps, and tonsils in very early life is an indication for carcinosin.

  • Craving or aversion to salt, sweet, milk, egg, meat, fat and fruits.
  • Great desire to lie on the chest or knee-elbow position.
  • Tendency to insomnia in children occurring in early age.
  • Mind: There may be a back ground of fright, prolonged fear or unhappiness. Mental troubles may originate from anticipation.
  • Mentally the patient is very intelligent and artistic or very dull and idiotic. Display of spontaneous sympathy to others (phos) . The child if reprimanded reacts either mentally or physically or through both.

6.ALUMINA: Pain in arm and fingers, as if hot iron penetrated. Arms feel paralysed. Legs feel asleep, especially when sitting with legs crossed. Staggers on walking. Heels feel numb. Inability to walk, except when eyes are open or day time. Spinal degeneration and paralysis of limbs.

7. ARS ALB: Trembling, twitching, spasms, weakness, heaviness and uneasiness of extremities. Cramps in calves. Burning pains. Paralysis of lower limbs with atrophy.

8. CAUSTICUM: Paralysis of single parts. Heaviness and weakness. Unsteadiness of muscles of forearm and hand. Numbness and loss of sensation of hands. Contracted tendons, burning in joints. Slow learning to walk and unsteady walking and easy falling. Restless legs at night.

9.COCCULUS: Trembling and pain in limbs, one side paralysis, < after sleep. Hands are alternately hot and cold; knees crack on motion, lower limbs very weak.

10. GELSEMIUM: It causes motor paralysis. General prostration. Dizziness, drowsiness, dullness and trembling. Paralysis of various groups of muscles. Post diphtheritic paralysis. Muscular weakness. Lack of muscular co-ordination, fatigue after slight exercise.


  • Synthesis Repertory by Fredericke Schroyens
  • Homoeopathic medical repertory by Robin Murphy
  • Repertory of Homoeopathic Materia Medica by J T Kent.
  • Text book of medicine- K V Krishna Das
  • Harrison’s principles of internal medicine
  • Allen’s Key notes.
  • Boericke’s Materia Medica

Carcinoma Oesophagus

cancerDr Sunila BHMS,MD(Hom)
Name   : Ayisha
I P No: 678
D O A: 27/9/2005

Presenting Complaints

  • Obstructive feeling at throat (5 months)   < After eating
  • Difficulty in swallowing especially for solids (5 months)
  • Cough (1 week)                <lying down & night
  • Weakness (5 months)
  • Headache especially on right forehead (5 months)

History of presenting complaint
Obstructive feeling at the throat and difficulty in swallowing solids and liquids started 5 months back and diagnosed as carcinoma oesophagus. There is vomiting of food after eating.

History of past illness

1. History of asthma                : 3 years back      Took Ayurvedic treatment

2. H/O Rheumatic complaint   : 3 years back      Took Ayurvedic treatment

Personal History

  • Place of birth          : Balussery
  • Educational status: Illiterate
  • Religion                 : Muslim
  • Appetite     : good; Prefers warm food.
  • Thirst         : decreased; Prefers warm drinks.
  • Sleep           : decreased
  • Stool           : constipated
  • Urine          : no complaints
  • Sweat          : generalised 

Psychic features She is mild and gentle. She prefers company.


Endoscopy (26/05/05) 

Oesophagus: There is a large nodular growth arising from the oesophagus at 32cms and extending for about 6cms proximally.

Impression  : arcinoma oesophagus.

Provisional diagnosis  : Carcinoma oesophagus 

Physical examination 

Pulse: 70/mt         B P: 120/ 80 mm of Hg       Temp: 98◦ F 

General Survey

  • Moderately built and nourished
  • Pallor present
  • No cyanosis, not icteric.
  • No clubbing
  • No lymphadenopathy and No pedal oedema

Systemic Examination 

  • No congestion of nasal mucosa & no deviation of nasal septum & no nasal polyp.
  • Uvula centrally placed & no tonsillar enlargement.

Examination of lower Respiratory tract 


  • Trachea appears to be centrally placed; chest wall bilaterally symmetrical
  • No kyphosis, scoliosis or lordosis; no prominent vessels and visible pulsations

Palpation :   No palpable swelling. Trachea centrally placed. Apex beat palpable.

Percussion : Normal lung resonance over all lung fields

Patient is conscious, intelligent, normal behaviour, past and present memory present, orientation of time, place and person present, no hallucination, delusion, illusion and speech normal.

  • Gag reflex present
  • Uvula centrally placed
  • Hypoglossal Nerve: Can move tongue in all directions
  • Sensory System: With in normal limit
  • Examination of motor System: Within normal limits
  • Signs of meningeal irritation: No signs of meningeal irritation 

Analysis of symptoms 

Symptoms of the patient Symptoms of the disease
Prefers company Obstructive feeling at throat
Desires warm drinks Difficulty in swallowing solids
Desires warm food Vomiting of food; frothy vomitus
Desires pungent things Weakness

Evaluation of symptoms

Mental generals Physical generals Particulars Common
Prefers company Prefers warm drinks Cough< night Obstructive feeling at throat
Prefers warm food Cough< lying down Difficulty in swallowing solids
Prefers pungent things Right sided headache Vomiting of food
Weakness Weakness

 Totality of symptoms

  • 1.      Prefers company
  • 2.      Patient desires warm drinks.
  • 3.      Patient desires warm food.
  • 4.      Patient desires pungent things.
  • 5.      Weakness
  • 6.      Carcinoma oesophagus
  • 7.      Difficulty in swallowing solids
  • 8.      Obstructive feeling at throat
  • 9.      Vomiting of food
  • 10.  Cough < night.
  • 11.  Cough <lying down.
  • 12.  Right sided headache 

Miasmatic cleavage 

symptoms psora sycosis syphilis tubercular
Prefers company   +    
Prefers warm drinks +      
Prefers warm food +      
Prefers pungent things   +    
Weakness +      
Carcinoma oesophagus + + +  
Difficulty in swallowing solids   +    
Obstructive feeling at throat   +    
Vomiting of food   +    
Cough< night     +  
Cough< lying down   +    

Rubrics selected 

  • MIND COMPANY desire for
  • STOMACH DESIRE warm drinks
  • STOMACH DESIRE warm food
  • STOMACH DESIRE pungent things
  • HEAD PAIN forehead


  • Ars alb- 26/11
  • Lycopodium- 25/12
  • Lachesis- 20/7
  • Nuxvomica- 10/5
  • Pulsatilla- 14/5
  • Thuja- 8/6


  • 27- 9- 05- vomiting immediately after food- Nuxvomica30/ 2 dose
  • 28- 9- 05- vomiting relieved-sac lac/ 2 dose
  • 30- 9- 05- Ars alb 30/ 2 dose
  • 2- 10- 05- she has symptomatic relief- sac lac/ 2 dose
  • 15- 10- 05- Thuja 200/ 1 dose
  • 5- 11-05-Ars alb 200/ 1 dose
  • 8- 11- 05- she expired peacefully.

Carcinoma of the oesophagus
Cancer of the oesophagus is the ninth most common cancer in the world. It is in general a disease of mid to late adulthood with a poor survival rate. Only 5-10% of those diagnosed will survive for 5 years.

Squamous cell cancer and adenocarcinoma are the commonest types. Squamous cell carcinoma affects the upper ⅔rd of the oesophagus and adenocarcinoma affects the lower ⅓rd. But there are frequent exceptions to this rule. Oat cell cancer occurs occasionally.  World wide it is the squamous cell cancer that is the commonest, but adenocarcinoma is the commonest type in the westernized countries.


1)      Precancerous conditions: Reflux oesophagitis with Barrett’s oesophagus.

Reflux oesophagitis: Extensive inflammation of the lower oesophagus by the gastric acid refluxing into the lower oesophagus from the stomach. 

Barrett’s oesophagus: One of the complications of reflux oesophagitis. In this condition, columnar epithelium is present for more than 3cms above the cardio-oesophageal junction. It is due to metaplasia; (The entire oesophagus is lined with squamous epithelium except the last 3cms which is lined by columnar cells).

Plummer Vinson syndrome:  in which there is severe spasm of circular muscle fibers at the cricopharyngeal sphincter level and it is associated with the development of postcricoid web.

Achalasia Cardia: It is also called cardiospasm because of severe spasm of circular muscle fibers of the lower end of the oesophagus.

Corrosive strictures

2) Possible aetiological factors:

  • Chronic smoking, tobacco chewing, spicy food with spirits are the common causes of ca oesophagus in India.
  • Smoked salmon fish consumption is common in Japan, wherein the incidence of this carcinoma is high.
  • The cause of disease in the endemic areas is possibly due to the production of a carcinogenic microtoxin, together with nutritional deficiencies in the population.


  • 50%- middle ⅓rd of the oesophagus
  • 33%- lower ⅓rd of the oesophagus
  • 17%- upper ⅓rd of the oesophagus


  • 1. Epitheliomatous ulcer (carcimatous) with everted edges.
  • 2. Proliferative growth (cauliflower) which commonly bleeds.
  • 3. Infiltrative variety or annular stenosing variety, which gives rise to early dysphagia.

Clinical Features

1.Men above 60 years of age are commonly affected.

2. Dysphagia is the usual presenting feature and is generally a sign of advanced disease. Dysphagia mainly for solids. It takes 18 months for dysphagia to develop. It means ¾th of the circumference of the lumen involved by the growth.

3. Oesophageal regurgitation of the food contents.

4. Haematemesis not very common contains streaks of blood.

5. Melaena is rare.

6. Loss of appetite.

7. Loss of weight and cachexia.

8. Dehydration

9. Back ache indicates enlarged lymph nodes (Coeliac)

Patients with early disease may present with rather nonspecific dyspeptic symptoms or a vague feeling of something that is not quiet right while swallowing.

Hoarseness due to recurrent laryngeal nerve palsy is a sign of advanced and incurable disease.


1. Local spread or Direct spread

Mucosal ulceration spreads to submucosa. Later it causes fibrosis and the lumen gets narrowed. The spread occurs transversely and longitudinally. Once it spreads to the serosal coat, the structures in the vicinity are involved.

  • a) When trachea is involved, tracheo-oesophageal fistula develops (carcinoma upper ⅓rd).
  • b) Broncho-oesophageal fistula (carcinoma middle ⅓rd)
  • c) Oesophago-aortic fistula results in massive bleeding. (One of the causes of death.) 

All these complications are contraindications for surgery and radiotherapy.

2. Lymphatic spread

  • §  Upper oesophagus: drains to left and right supra clavicular nodes
  • §  Middle oesophagus: to the tracheobronchial nodes and paraoesophageal nodes
  • §  Lower oesophagus: drains into lymph nodes along the lesser curvature of stomach and then into celiac nodes. 

3. Blood Spread

It results in secondaries in the liver, which clinically appear as enlarged liver. Later ascites and rectovesical deposits occur. Palpable left supraclavicular nodes in advanced disease. This sign is described as Troisier’s sign.


  • 1. Hb% is low, which causes generalized weakness.
  • 2. Liver function test (LFT): if secondaries in liver occur.
  • 3. Ultra sound is done to rule out liver secondaries, lymph nodes in the porta hepatic, coeliac nodes etc.
  • 4. Barium swallow demonstrates irregular, persistent, intrinsic filling defect.
  • 5. Oesophagoscopy to visualize the growth and to take biopsy.
  • 6. Chest x-ray to rule out aspiration pneumonia and mediastinal widening.
  • 7. Bronchoscopy to rule out involvement of bronchus, as in carcinoma middle ⅓.
  • 8. C.T scans of the chest to find out local infiltration.

Treatment – A gastrotomy should never be carried out as the palliation for oesophageal cancer. Palliation in this disease demands relief of dyspagia.

Curative treatment involves radical surgery or radiotherapy.

             I.      Carcinoma upper ⅓rd of oesophagus:-

§  A growth (squamous cell) with secondaries in lymph nodes is treated by external radiotherapy.

§  Small mobile growth: Total oesophagectomy followed by gastric pull up and pharyngogastric anastamosis in neck.

          II.      Carcinoma middle ⅓rd of oesophagus:-

§  It is squamous cell carcinoma.

§  Surgery is difficult due to infiltration of surrounding structures.

§  Radiotherapy is given

§  Due to irradiation, oedema develops causing further narrowing of the liver.

§  Fibrosis develops later in the oesophagus which needs regular dilation by using gum elastic bougies. 

It is indicated for carcinoma involving lower part of middle ⅓ or upper part of lower ⅓ of oesophagus.

In this operation, abdomen is opened first, stomach is mobilized and the wound is closed. The patient is put in left lateral position, and right thoracotomy is done through 6th intercostal space. The growth is removed and oesophagogastric anastomosis is done inside thorax, above the level of aortic arch. Hence it is described as a two-stage Ivor-Lewis operation. 

       III.      Carcinoma lower ⅓ of oesophagus :-

a)      A mobile growth:-
Radical oesophagogastrectomy- lower end of oesophagus and upper part of stomach, often spleen; and involved lymphnodes are removed followed by oesophagogastric anastomosis.

b)  A fixed growth :- Celestin tube or Mousseau Barbin’s tube (MB tube) is introduced to reduce dysphagia. This is only a palliative treatment.

Homeopathic theraputics:-

1. Condurango It is given for tumors, stricture of oesophagus, with burning pain behind sternum, where food seems to stick. Vomiting of food and indurations in left hypochondrium, with constant burning pain.

2. Conium: It is mainly given for the paralysis of the oesophagus, difficulty in swallowing food. As the food is about to pass the cardiac orifice, it stops and enters with a great effort. Sense of stuffing in the throat as if something were lodged there. Sense of fullness in throat, pressure in oesophagus as if a rounded body is ascending from stomach. Conium will palliate cancer conditions.

3. Hydrastis:- It is a deep acting remedy given for malignant ulceration. Character of discharge is thick, viscid, ropy yellow mucous. It modifies the pain and restrains the destructiveness. No appetite, no thirst, loathing of food, vomiting all foods. Retains only water and milk. Obstinate constipation with no desire for stool.

4. Phosphorous: – It is given for stricture of oesophagus. Thirst for very cold water. Burning in oesophagus. Regurgitation of all foods, weak empty feeling across the abdomen with occasional shooting pains.

5. Platinum Muriaticum:- Dyspahgia and syphilitic throat. 

6. Baptisia: Constriction and contraction of oesophagus. Great difficulty in swallowing solids and foods. Can swallow liquids only; least solid food gags. Vomiting of solid foods due to spasm of oesophagus.

7. Baryta Carb: – Spasm of oesophagus when food enters causes gagging and choking. Can only swallow liquids.

8. Ars.alb: – Cramp or stricture of oesophagus. Deglutition painful. Burning when swallowing. Food either lodges in oesophagus, producing a feeling of pressure or is ejected as soon as it reaches the pharynx.

9. Ignatia: – Difficulty in swallowing solids or liquids. Sensation of a lump in the throat when swallowing. Hysterical patients.

10. Nuxvomica: – Rough and scraped feeing in the throat. Nausea and vomiting of food. Vomiting gives relief.


  • Synthesis Repertory by Fredericke Schroyens
  • Homoeopathic medical repertory by Robin Murphy
  • Repertory of Homoeopathic Materia Medica by J T Kent.
  • Allen’s Key notes.
  • Boericke’s Materia Medica
  • Bailey & love’s short practice of surgery.
  • Manipal surgery by Dr. Rajgopal shenoy

Carcinoma Larynx – case study

Dr Sunila BHMS,MD(Hom)
Email :


Admission No: 1317     Date of Admission: 26/ 03/ 05

Presenting Complaints

1.      Hoarseness of voice (5 months)

  • Hoarseness with obstructed feeling in throat
  • No pain in throat
  • No dysphagia
  • Hoarseness < evening

2.      Redness of left eye (1 month)

  • No itching
  • No pain
  • No lachrymation
  • There is sand sensation in left eye.
  • Dimness of vision for distant objects

History of presenting complaint
Complaint started 5 months back. He took allopathic treatment with radiotherapy.

Past History
No relevant complaints in the past

Family history
No similar complaint among the family members

Personal History
Born and brought up at Mankavu. He has the habit of smoking started at the age of 20. One packet of cigarettes a day and he is still continuing the habit.


  • Appetite                      :           Good; Desires pungent food
  • Thirst                           :           Good
  • Bowels                        :           Regular
  • Urine                           :           No complaints
  • Sweat                          :           N
  • Sleep                           :           Good
  • Thermal reaction         :           Not specific

Physical Examination:

Pulse Rate: 68/ minute    Respiratory Rate: 20/ minute

BP: 110/ 70mm of Hg    Temperature : 98.6ºF

General Survey

  • Moderately built and nourished
  • Pallor present
  • No cyanosis, No icterus.
  • No clubbing, No lymphadenopathy and No pedal oedema.

 O/E: Oral cavity and Oropharynx

  • Lips                 (N)                   Tongue      (N)
  • Gums               (N)                   Pillars        (N)     Tonsils    (N)

Internal Larynx Examination

Epiglottis         (N)

There is an ulceroproliferative growth involving the anterior commissures and anterior ⅔ of medial borders and superior surface of (L) vocal cord.

Vocal cords mobile B/L


No neck node

Carotid palpable (B/L)

Impression     : Carcinoma Larynx T2 N0 M0

Biopsy :

Squamous cell Carcinoma- moderately differentiated

Systemic Examination

Examination of Respiratory system

Examination of Upper Respiratory tract

  • No congestion of nasal mucosa, no deviation of nasal septum& no nasal polyp
  • Uvula centrally placed & no tonsillar enlargement.

Examination of lower Respiratory tract


  • Trachea appears to be centrally placed
  • Chest wall bilaterally symmetrical
  • No kyphosis, scoliosis or lordosis; no prominent vessels and visible pulsations.


No palpable swelling; Trachea centrally placed; Apex beat palpable.


Normal lung resonance


No wheeze heard

Examination of Central Nervous system

Examination of higher mental functions

Patient is conscious, intelligent, normal behaviour, past and present memory present, orientation of time, place and person present, no hallucination, delusion, illusion and speech normal.

Examination of Cranial nerves

Olfactory Nerve

No anosmia, parosmia and hallucination of smell.

Optic Nerve

There is no obstruction on the field of vision

Oculomotor Nerve, Trochlear Nerve, Abducens

Ocular movements are within normal limits, no nystagmus. Pupil reacts to light.

Trigeminal Nerve

Sensation over face is intact; corneal and conjunctival reflexes intact.

Jaw jerk present

Facial Nerve

Eye closure, frowning, raising the eye brow present

Can blow, whistle and show the teeth 

Vestibulocochlear Nerve

No impairment of hearing

Glosopharyngeal Nerves and Vagus

Gag reflex present

Uvula centrally placed

Hypoglossal Nerve  Can move tongue in all directions

Sensory SystemWith in normal limit

Examination of motor System: Within normal limits

Signs of meningeal irritation: No signs of meningeal irritation

Analysis of symptoms

Symptoms of disease Symptoms of patient
Hoarseness of voice Desires pungent things
Hoarseness of voice< evening

 Evaluation of symptoms

Physical generals Particulars Common symptoms
Desires pungent things Redness of left eye Hoarseness of voice

Totality of Symptoms

  • 1.      Patient desires pungent things
  • 2.      Hoarseness of voice
  • 3.      Hoarseness of voice < Evening
  • 4.      Redness of left eye
  • 5.      Ca larynx

Miasmatic cleavage  

Symptoms Psora Sycosis Syphilis Tubercular
Desires pungent    things +
Hoarseness of voice +
Carcinoma of larynx + + +  
Redness of left eye + + +

 Predominant Miasm: Syphilis

 Rubrics Selected

  1. STOMACH, DESIRE pungent things.
  3. LARYNX AND TRACHEA VOICE hoarseness evening.
  5. EYE REDNESS canthi.


  • Phosphorous- 9/3               Hepar sulph- 6/3
  • Carbo veg- 8/3                   Causticum- 6/2
  • Graphitis- 6/3                     Calcarea carb-


  • 26-3-05   Calcarea Carb 200/2 dose
  • 27-3-05    Sac lac 2 dose         (Hoarseness slightly relieved)
  • 28-4-05     Calc carb 200/2 dose
  • 15-5-05     Sac lac 2 dose  (Patient has symptomatic relief and discharged)

Tumors of the larynx
Benign tumours of the larynx are extremely rare and squamous carcinoma of the larynx predominates over all others, being responsible for more than 90% of tumours within the larynx. It is the commonest head and neck cancer and almost always occurs in the elderly male smokers. The squamous epithelium of the vocal folds and the respiratory epithelium of the supraglottis undergo dysplastic change stimulated by cigarette smoking and other factors. The incidence of laryngeal cancer in three compartments- supraglottis, glottis and subglottis, varies around the world; the glottis is generally the commonest site followed by the supraglottis. True carcinomas of the subglottis are very rare and most are a consequence of inferior spread from the glottis.

Clinical Features
The frequent glottic origin means that patients almost always present with hoarseness. This is of great importance because if a diagnosis can be made while the tumour is in the first stage. I.e. confined to only one vocal fold, these cancers have more than a 5 year disease-free cure rate when treated with radiotherapy alone. The cure rate drops dramatically once the lymphatically rich supraglottis or subglottis is involved, owing to spread to neck nodes. The appearance of more than one neck gland halves the overall prognosis of the patient.

TNM Classification of Laryngeal Cancer 

  • T          –           Primary Tumour
  • T x       –           Primary tumour cannot be assessed.
  • To        –           No evidence of primary tumour
  • T is      –           Carcinoma in site


  • T1 – Tumour limited to one sub site of supraglottis, with normal vocal cord mobility.
  • T2 – Tumour invades more than one sub site of supraglottis, with normal vocal cord mobility
  • T3 – Tumour limited to larynx with vocal cord fixation and/ or invades post cricoid area, medial wall of piriform sincit or pre-epiglottic tissues.
  • T4 – Tumour invades through thyroid cartilage and/ or extends to other tissues beyond the larynx, e.g. to oropharynx, soft tissues of neck.


  • T1 – Tumour limited to vocal cords, (may involve anterior or posterior commissures) with normal mobility
  • T1a- Tumour limited to one vocal cord
  • T1b- Tumour involves both vocal cords
  • T2 – Tumour extends to supraglottis and/ or with impaired vocal cord mobility
  • T3 – Tumour limited to larynx with vocal cord fixation.
  • T4 – Tumour invades through thyroid cartilage and/ or extends to other tissues beyond the larynx; e.g. to oropharynx, soft tissues of the neck.


  • T1 – Tumour limited to subglottis
  • T2 – Tumour extends to vocal cord(s) with normal or impaired mobility.
  • T3 – Tumour limited to the larynx with vocal cord fixation
  • T4 – Tumour invades through cricoid or thyroid cartilage and/ or extends to other tissues beyond the larynx; e.g. to oropharynx, soft tissues of the neck.
  • N   – Regional lymph nodes
  • M   – Distant metastasis

Stage Grouping  

  • Stage 0                        T is                  No                   Mo
  • Stage I             T1                    No                   Mo
  • Stage II           T2                    No                   Mo-
  • Stage III          T1                    N1                   Mo
  •                         T2                    N1                   Mo
  •                         T3                    No, N1                        Mo
  • Stage IV          T4                    No, N1                        Mo
  •                         Any T              No, N1                        Mo
  •                         Any T              Any N             M1 

Direct laryngoscopy, together with Hopkins rod examination allows precise determination of the extent tumours and biopsy confirms an exact histology. CT and MRI scanning give further details of the extent of larger tumours and suspicious nodal involvement within the neck which may not be determined on clinical examination.

Early supraglottis and glottis tumours are optimally treated with mega voltage radiotherapy. Five-year cure for Stages I & II are approximately 90 and 70% respectively, and the patient has an excellent voice following this type of treatment. If modern mega voltage radiotherapy is not available then early tumours may be excised by endoscopic laser surgery or open partial laryngeal surgery. With early bilateral supraglottic tumours a horizontal laryngectomy may be undertaken excising the supraglottic growth and the remainder of the glottis. The subglottic part of the larynx is then stitched tongue base to provide continuity. In most patients undergoing partial laryngeal surgery of this type the voice result is not satisfactory as that with radiotherapy.

Advanced Laryngeal Disease
Once the squamous carcinoma has caused fixation of the vocal fold or has infiltrated outside the larynx into adjacent such as thyroid gland and strap muscles, some form of subtotal or total laryngectomy is required to attempt to cure the disease. Total laryngectomy is frequently required when radiotherapy fails.  Part or all of thyroid gland and associated parathyroid glands may also need to be removed depending on the extent of the disease, so patients after this type of radical surgery may require oral thyroxin and calcium supplement for the remainder of their lives. Laryngectomy patients must obviously avoid immersion in water as this would flow directly into their tracheal stoma.

Homoeopathic Management 

1.Homoeopathic Medical Repertory by Robin Murphy

  • Diseases, CANCER general
  • Larynx, CANCER
  • Larynx, Cancer: ars, con, phytolacca, ars-I, bell, carb-an, clem, hydr, iod, kreos, lach, morph, nit-ac, phos, sang, thuja

2. Repertory of Homeopathic Materia Medica- J.T. Kent : LARYNX AND TRACHAEA; CANCER, larynx: ars, nit-ac, phos, sang, thuja

3. Synthesis – Dr. Frederick Schroyens  LARYNX AND TRACHEA, CANCER, larynx: arg-cy, ars, nit-ac, phos, sang, thuja

4. Synthetic Repertory :  Cancerous affections   +3 – Ars, Brom, carb-an, conium, Lycopodium, Nit-ac, phos, phytolacca, silicia

Indications of some important medicines in the treatment of     carcinoma larynx

1) Ars alb: Unable to lie down. Fear of suffocation. Air passages constricted. Cough< after midnight, lying on back. Extreme prostration & anxiety.

2)  Conium mac: Oppressed breathing, constriction & pain in chest. Expectoration only after long coughing. Dry cough; <evening & night; caused by dry spot in larynx with itching in chest & throat, when lying down. 

3) Phytolacca: Aphonia. Difficult breathing. Tickling cough < at night. Decrease of weight. 

4) Phosphorous: Hoarseness< evening. Larynx very painful. Tickling in larynx while speaking. Aphonia< evening with rawness. Cannot talk on account of pain in larynx 

5) Argentum met: Chronic hoarseness & aphonia< from use of voice. Larynx is a special centre for this drug. 

6) Causticum: Hoarseness with pain in chest; aphonia. Larynx sore. Difficulty of voice of singers & public speakers.

7) Carbo veg:  Cough with itching in the larynx. Deep, rough voice failing on slight exertion. Hoarseness< evening, talking.

8)  Calcarea carb: Painless hoarseness& bloody expectoration.

9)  Bromium: Dry cough with hoarseness & burning pain behind sternum. Difficult & painful breathing. 


  1. Synthesis Repertory by Fredericke Schroyens
  2. Homoeopathic medical repertory by Robin Murphy
  3. Repertory of Homoeopathic Materia Medica by J T Kent.
  4. Allen’s Key notes.
  5. Boericke’s Materia Medica
  6. Bailey & love’s short practice of surgery.

Myocardial Infarction

Dr Meera Narendran BHMS,MD(Hom)
The coronary circulation
The arterial supply of heart is derived from right and left coronary arteries. The left main coronary artery divides into the left anterior descending artery and the circumflex artery.

Left anterior descending artery

  • Gives branches to supply the
  • Anterior left vetricle
  • The apex
  • The anterior part of the septum

Left circumflex artery

  • Gives marginal branches to supply the
  • Posterior left ventricle
  • Inferior Surface

The right coronary artery

  • Gives branches to supply the
  • Right atrium
  • Right ventricle
  • Infero-posterior aspects of the left ventricle.

The SA node is supplied by the right coronary artery in 60% of individuals, and AV node in 90%.
So abrupt occlusion of the

  • 1. RCA Causes infarction of the inferior part of the left ventricle and right ventricle.
  • 2. LAD or LCX Infrarction in the corresponding territory.
  • 3. Occlusion of left main artery is usually fatal

Ischaemic heart disease or (coronary heart disese)
Ischaemic heart disese is defined as the accute or chronic form of cardiac disability arising from inbalance between the myocardial supply and demand for oxygenated blood.

IHD is invariably caused by disease affecting the coronary arteries, the most prevalent is atheroscleresis account for about 90% cases. So etiology of IHD can be consider under 3 headings.
1. Coronary atherosclerosis
2. Superadded changes in coronary atheresclerosis
3. Non-atherosclerotic causes

I. Coronary atherosclerosis
Coronary atherosclerosis resulting in fixed obstruction is the major cause of IHD in more than 90% cases.
Atherosclerotic leisions are distributed in one or more of the three coronary arterial trunks, the highest incidence in the descending branch of the left coronary followed by the right coronary artery and still less in circumflex branch of the left coronary. About 1/3 of cases have single vessel disease, most often in left anterior descending arterial involvement.
The atheroscerotic plaques in the coronary are more often eccentrically located bulging into the lumen from one side. The area of severest involvement is about 3 to 4 cm. from the coronary ostia more often at or near the bifurcation of the arteries. Significant stenotic leisions that my produce chronic myocardial ischamia show more than 75% reduction in the cross – sectional area of a coronary artery or its branch. Complication like calcification, coronary thrombosis, ulceration, haemarahage, rupture and aneurysm formation can occur in these vessels.

II. Superadded changes in coronary atherosclerosis
The attacks of acute coronary syndromes namely acute myocardial infraction, unstable angina and sudden ischemic death are precipitated by certain changes superimposed on a pre-existing fixed coronary atheromatous plaque.
1. Acute changes
Such as plaque haemarrhage fissuring or ulceration that result in embolisation of atheromatous debris.
2. Coronary artery thrombosis
Transmural acute myocardial infraction is often precipitated by partial coronary thrombosis. It occurs due to surface ulceration of fixed atheromatous plaque, ultimately causing complete luminal occlusion. The lipid core of plaque is highly thrombogenic

III. Non-atherosclerotic causes
A number of other leisions may cause IHD in less than 10% of cases.
1. Vasopasm
2. Stenosis of coronary ostia:- From extension of syphilitic aortitis or from aortic atherosclerotic plaques.
3. Arteritis – Like in rheumatic arteritis, polyarteritis nodosa, TAO etc.
4. Embolism – Embolism from elsewhere, which occurarely
5. Thrombotic disease – Eg:- Hypercoagulability of the blood.
6. Trauma
7. Aneurysm -Extension of dissecting aneurysm from aorta
8. Compression -By a primary or secondary tumour.

Effects of myocardial ischamia
Depending upon the suddenness of onset, degree, duration, location and extent of the area affected by myocardial ischamia, there can be two types of ischamic manifestations.
a. Myocardial infarction
b. Non-infract effects of myocardial ischamia which include.
Angina pectoris
Chronic ischamic heart disease
Sudden cardiac death

Major risk factors for coronary artery disease
Fixed Modifiable
1. Age 1. Smoking
2. Male Sex 2. Hypertension
3. Family history 3. Lipid dlisorder
4. Diabetes Mellitus
5. Haemostatic variables
6. Sedentary life style
7. Obesity
8. Dietary deficiencies of antioxidant ,vitamins and polyunsaturated fatty acids.

Myocardial infarction
Acute myocardial infarction is the most important consequence of coronary artery disease.
The incidence of Myocardial infarction correlates well with the incidence of atherosclerosis in a geographic area.
Age:- Occur in all ages incidence is higher in the elderly
Sex:- Males have an increased risk. After menopause sex difference gradually declines.
In 90% cases of MI, serve atherosclerosis (more than 75% compromise of lumen) of one or more of the the three major coronary arteries is the etiology.

1. Machanism of myocordial ischamia can be due to
a. Diminised coronary bood flow.
b. Increased myocardial demand.
c. Hypertrophy of the heart without simultaneous increase of coronary blood flow.

2. Role of platelets
Rupture of an atherosclerotic plaque exposes the subendothelial collegen to platelets which undergo aggregation, activation and release reaction and there will be production and release of thromboxane – A2 (local vosoconstrictor). The coagulation cascade is activated on exposure of tissue factor in damaged endothelial cells at the site of ruptured plaque, thus fibrin is formed from fibrinogen. The coronary artery eventually becomes occluded by a thrombus containing platelets aggregates and fibrin threads.

3. Complicated plaques
Two important complications in coronary atherosclerotic plaques are coronary thrombosis and haemarrhage.

4. Non-atherosclerotic causes
Like vasospasm, arteritis, embolism etc.

Types of infarcts
Infarcts have been classified in a number of ways.
1. According to the anatomic region of the left ventricle involved, they are called

  • Anterior
  • Posterior (inferior)
  • Lateral
  • Septal
  • Circumferential
  • and they can be Anterolateral
  • Posterolateral (inferolateral)
  • Anteroseptal

2. According to the degree of thickness of the ventricular wall involved infarates are of 2 types.

  • Transmural or full-thickness
  • When they involve – the entire thickness of the ventricular wall.
  • Subendocardial or laminar
  • When they involve the inner subendocardial half of the myocardium.

3. According to the age of infarcts, they are of 2 types.

  • Acute, recent or fresh infarcts
  • Healed or organised infarcts
  • Location of infarcts
  • Infarcts are most frequently located in the left ventricle. Right ventricle is less suceeptible. Atrial infarcts whenever present are more often in the right atrium. Left artium is protected because it is supplied by the oxygenated blood in the left atrial chamber.

There are three main regions of myocardial infarction
1. Stenosis of the left anterior descending artery (40-50%)

  • Infarction is seen in the
  • Anterior part of the left ventricle, including the apex
  • Anterior 2/3 of the interventricular septum.

2. Stenosis of the right coronary artery (30-40%)

  • It involves the
  • Posterior part of the left ventricle
  • Posterior 1/3 of the interventricular septum

3. Stenosis of left circumflex coronary artery (15-20%)

  • Lateral wall of the left ventricle
  • The early infacts (3 to 6 hours old) can be detected by histochemical staining for dehydrogenases by triphenyl tetrazolium chloride which imparts red brown colour to the normal heart muscle, while the area of infarcted muscle fails to stain due to lack of dehydrogenases.
  • The gross and microscopic changes in the myocardial infarction vary according to the age of the infarct and therefore described sequentially.

Sequential pathologic changes in myocardial infarction
Time Gross changes Light microscopy

First week

  • 0 – 6 hours No change or Pale No change. Stretehing and waviness of fibre
  • 6 – 12 hours No change or Pale coagulative necrosis begins. Neutrophilic in filtration. Oedema and haemarrhage
  • 24 hours cyanotic red-purple area of coagulative necrosis complete neatrophilic infiltrate well devel haemarrhage oped.
  • 4th day well defined yellow border prominent neutrophilic infiltrate some undergoing degeneration
  • 7th day Bright yellow to yellow green Being of resorption of necrosed fibres by macrophages onset of soft fibrovascular response neutrophils gradually disappear.

Second week
10th day Red-purple periphery Most of the necrosed muscle in a small infarct removed fibrovascular reaction more prominent. Pigmented macrophages, eosinophils, lymphocytes, plasma cells are present.
14th day Red-purple periphery Necrosed muscle mostly removed, neutrophils disappear fibrocollagenic tissue at the periphary.

Third week
Red-purple periphery Necrosed muscles from larger infarcts removed more in growth of fibrocollagenic tissue.
4th to 6th week Thin, grey-white, hard, shrunken fibrous scar. Increased fibrocollagenic tissue. decreased vascularity fewer pigmented macrophages lymphocytes and plasma cells.
By special techniques like electron microscopy chemical and histochemical studies, changes can be demonstrated in early infarcts before detectable light microscopic alterations appear. Injury become irreversible unless the blood flow is restored within 20-30 minutes.

1. Electron microscopic changes
They are evident in less than half an hour on onset of infarction.
a. Disappearance of perinuclear glycogen granules within 5 minutes of ischamia
b. swelling of mitochondria in 20 to 30 minutes
c. Disurption of sarcolemma
d. Nuclear alternations like peripheral clumping of nuclear chromation.
2. Chemical and histochemical changes
a. Glycogen depletion in myocardial fibres within 30 to 60 minutes of infarction.
b. Increase in lactic acid in the myocardial fibres.
c. Loss K+ from the ischaemic fibres
d. Increase of Na+ in the ischaemic cells
e. Influx of Ca++ into the cells causing irreversible cell injury

The diagnosis of acute MI is made by
1. clinical features
2. ECG changes
3. Serum-enzymes

1. Clinical features
In upto half of cases, a pericipitating factor appears to be present such as vigorous physical exercise, emotional stress or a medical or surgical illness. Mostly it is seen in the morning within a few hours of awakening, due to a combination of an increase in sympathetic tone and an increased tendency to thrombosis between 6 AM and 12 Noon.
a. Pain
Describe it as heavy, squeezing and crushing. Typically involves the central portion of the chest or the epigastrium and occasionaly it radiates to the arm. Less common sites of radiation include abdomen, back, lower jaw and neck. Pain is often accompained by weakness, sweating, nausea, vomiting and anxiety.
It can also be presented as indigestion, apprehension, shock, oliguria, low grade fever and acute pulmonary oedema
b. The combination of substernal chest pain persisting for more-than 30 mts. and diaphoresis strongly suggest AMI.

2. ECG changes
ST – elevation is the earliest change. There will be Q – wave MI & Non – Q wave MI in ECG. Most patients initially presenting with ST Segment elevation evolve Q waves on the ECG and diagnased as Q – wave MI.
A small proportion may show non – Q wave MI. When the obstructing thrombus is not totally occlusive, obstruction is transient or if a rich collateral network is present, S.T – elevation will be absent ECG changes are best seen in the leads which face the infarcted area.
If the infarction is in the
1. Anteroseptal area changes in leads V1 to V4
2. Anterolateral area changes from V4 to V6, AVL and lead 1.
3. Inferior area Lead II, III and AVF while lead I, a VL and anterior chest leads show reciprocal changes that is ST depression.
4. Posterior wall of the left ventricle Reciprocal changes of ST depression and a tall
R wave inleads V1 – V4.

3. Serum cardiac markeres
1. Creatine Phosphokinase
There are 3 forms of CPK of them CPK – MB is specific for heart muscles. CPK – MB has further 2 forms CPK – MBI and CPK – MB2. CPK – MB2 is the myocardial form. A ratio of CPK – MB2 : CK – MB1 above 1.5 is highly sensitive for the diagnosis of acute MI after 4-6 hours of onest of myocardial ischamia. It disappear from blood b4 48 hours.
2. Cardiac – Specific troponins (CTn)
Immunoassay CTn is more specific for MI. Troponins are contractile muscle proteins presents in human cardiac & skeletal muscle but cardiac troponins are specific for myocardium. There are 2 types of CTn.
a. Cardiac troponin T (CTnT)
b. Cardiac troponin I (CTnI)
Both CTnT and CTnI are not found in blood normally, but after myocardial injury, their levels rise very high around the same time, when CK – MB is elevated in after 4-6 hrs. Both troponin levels remains high for much longer duration.
CTnI for 7-10 days and CTnT for 10-14 days.
3. Lactic dehydrogenase (LDH)
Lacks specificity. LDH-I is myocardial specific. Estimation of ratio of LHD-I : LDH-2 above I is helpful in making a diagnosis.
LDH levels begins to rise after 24 hrs., reach peak in 3-6 days and return to normal in 14 days.
4. AST
AST starts to rise about 12 hrs. after infarction and reaches a peak on the first of second day returning to normal within 3 or 4 days.
5. Myoglobin
Though myoglobin is the first eardiac marker to become elevated after myocardial infarction, it lacks cardiac specificity and is excreated in the urine rapidly. Its levels, thus return to normal within 24 hrs. of attack of acute MI.


  • 1. Arrhythmias
  • 2. Cogestive heart failure
  • 3. Cardiogenic shock
  • 4. Conduction defects
  • 5. Mural thrombosis and thromboembolism
  • 6. Papillary muscle dysfunction
  • 7. Ventricular aneurysm
  • 8. Repture of the interventricular septum
  • 9. Repture of the left ventricular free wall
  • 10. Shoulder – hand dystrophy
  • 11. Pericarditis
  • 12. Post myocardial infarction (Dressler’s Syndrome)
  • 13.Persistent fever, pericarditis and pleurisy

Autoimmunity – Applied aspects

Dr P Muhammed Muneer  BHMS,MD(Hom)
Autoimmunity is a condition in which structural or functional damage is produced by the action of immunologically competent cells or antibodies against the normal components of the body.

The presence or absence of pathologic consequences resulting from self-reactivity determines whether autoimmunity leads to the development of an autoimmune disease. The essential feature of an autoimmune disease is that tissue injury is caused by the immunologic reaction of the organism with its own tissues. Autoimmunity, on the other hand, refers merely to the presence of antibodies or T lymphocytes that react with self-antigens and does not necessarily imply that the development of self-reactivity has pathogenic consequences.

Autoimmunity may occur as an isolated event or in the setting of specific clinical syndromes. Autoimmunity may be seen in normal individuals and in higher frequency in normal older people. In addition, auto reactivity may develop during various infectious conditions. The expression of autoimmunity may be self-limited, as occurs with many infectious processes, or persistent. In both circumstances there is a tendency to develop auto reactivity directed against a variety of different tissues or organs. As mentioned above, autoimmunity does not necessarily lead to tissue damage, and even in the presence of organ pathology, it may be difficult to determine whether the damage is mediated by auto reactivity. Thus, the presence of self-reactivity may be either the cause or a consequence of an ongoing pathologic process. Furthermore, when auto reactivity is induced by an inciting event, such as infection or tissue damage from trauma or infarction, there may or may not be ensuing pathology.

Mechanisms of autoimmunity
Since Ehrlich first postulated the existence of mechanisms to prevent the generation of self-reactivity in 1900, ideas concerning the nature of this inhibition have developed in parallel with the progressive increase in understanding of the immune system.

Autoimmunization can result under the following conditions :
Hidden or ‘sequestrated’ antigens may not be recognized as self –antigens. When such antigens are released into circulation, they may induce an immune response.

  • Cells or tissues may undergo antigenic alteration as a result of physical, chemical or biological influences. Such altered or ‘neoantigens’ may elicit an immune response.
  • Immunological damage may result from immune responses induced by cross reacting foreign antigens.
  • Breakdown of immunological homeostasis may lead to cessation of tolerance and the emergence of forbidden clones of immunocompetent cells capable of mounting immune response against self-antigens.
  • A variety of T and B cell defects have been suggested as possible mechanisms of autoimmunity.

Sequestrated are self-antigens present in closed system and are not accessible to the immune apparatus. E.g.: (a) lens antigen of eye, when the antigen leaks out following penetrating injury or cataract surgery it may induce an immune response causing damage to the lens. (b) Sperm antigens – as spermatozoa develop only with puberty, the antigen cannot induce tolerance during fetal life. This is the pathogenesis behind orchitis following mumps, as the virus damage the seminiferous tubule basement membrane leading to leakage of sperms and initiation of immune response.

can arise from (a) Physical agents like altered light and cold causing photosensitivity and cold allergy. (b) Chemicals including drugs, causing contact dermatitis drug induced anemia, leucopenia and thrombocytopenia have an autoimmune basis.(c) Biological factors include viral infections and bacterial enzymes such as neuraminidases.(d) may also arise by mutation.
In cross reacting antigen theory, the injection of heterologous organ specific antigens may induce an immune response damaging the particular organ or tissue in the host. E.g.: (a) neurological injury following antirabic immunization in some persons due to the cross reaction between human and sheep brain antigens.(b)heart muscle damaged by immune response induced by repeated streptococcal infection.

Autoimmunisation may result when tolerance to a self antigen is abrogated, as for instance by the injection of the self-antigen with Freunds adjuvant.
Alterations in antigen presentation may also contribute to autoimmunity. This may occur by epitope spreading, in which protein determinants (epitopes) not routinely seen by lymphocytes (cryptic epitopes) are recognized as a result of immunologic reactivity to associated molecules. For example, animals immunized with one protein component of the spliceosome may be induced to produce antibodies to multiple other spliceosome proteins. Finally, inflammation, drug exposure, or normal senescence may cause a primary chemical alteration in proteins, resulting in the generation of immune responses that cross-react with normal self-proteins.

Alterations in the availability and presentation of autoantigens may be important components of immunoreactivity in certain models of organ-specific autoimmune diseases. In addition, these factors may be relevant in understanding the pathogenesis of various drug-induced autoimmune conditions. However, the diversity of autoreactivity manifest in non-organ-specific systemic autoimmune diseases suggests that these conditions might result from a more general activation of the immune system rather than from an alteration in individual self-antigens.

A number of experimental models have suggested that intense stimulation of T lymphocytes can produce nonspecific signals that bypass the need for antigen-specific helper T cells and lead to polyclonal B cell activation with the formation of multiple autoantibodies. For example, antinuclear, antierythrocyte, and antilymphocyte antibodies are produced during the chronic graft-versus-host reaction. In addition, true autoimmune diseases, including autoimmune hemolytic anemia and immune complex-mediated glomerulonephritis, can also be induced in this manner. While it is clear that such diffuse activation of helper T cell activity can cause autoimmunity, nonspecific stimulation of B lymphocytes can also lead to the production of autoantibodies. Thus, the administration of polyclonal B cell activators, such as bacterial endotoxin, to normal mice leads to the production of a number of autoantibodies, including those directed to DNA and IgG (rheumatoid factor).

Primary alterations in the activity of T and/or B cells, cytokine imbalances, or defective immunoregulatory circuits may also contribute to the emergence of autoimmunity. Although the biochemical bases of many of these abnormalities have not been documented, they may contribute to the emergence of autoimmunity either alone or in concert. For example, decreased apoptosis, as can be seen in animals with defects in Fas (CD95) or Fas ligand or in patients with related abnormalities, can be associated with the development of autoimmunity. Similarly, diminished production of tumor necrosis factor (TNF) a and interleukin (IL)10 has been reported to be associated with the development of autoimmunity.

One of the mechanisms that regulates normal humoral immune responses is the production of anti-idiotype antibodies. These are immunoglobulin molecules directed against antigen-binding determinants of the specific antibodies originally elicited by the immunogen. Production of anti-idiotype antibodies may be dependent on helper T cell activity even when the initial immunogen is T cell independent. Therefore, it is possible that abnormalities in the generation of appropriate anti-idiotype antibodies, either at the B

Or T cell level, are responsible for the development of autoimmunity in certain circumstances.

It should be apparent that no single mechanism can explain all the varied manifestations of autoimmunity. Indeed, it appears likely, especially in systemic autoimmune diseases, that a number of abnormalities may converge to induce the complete syndrome. Moreover, one abnormality may cause a second, which, in concert with the first, facilitates the expression of autoimmunity. This possibility is consistent with recent findings in murine models of IDDM; systemic lupus erythematosus (SLE), rheumatoid arthritis, and multiple sclerosis in which multiple genetic regions, many of which are involved in controlling immune reactivity, appear to contribute to the development of autoimmune disease.

Despite the plethora of immunologic derangements identified in systemic autoimmune diseases such as SLE, the primary abnormality causing the disease remains unclear. In fact, detailed examination of a number of murine strains that spontaneously develop a lupus-like syndrome has failed to demonstrate a common immunologic abnormality. Additional factors that appear to be important determinants in the induction of autoimmunity include age, sex, genetic background, exposure to infectious agents, and environmental contacts. How all of these disparate factors affect the capacity to develop self-reactivity is currently being intensively investigated.

Autoimmune diseases
Autoimmune diseases are the result of body producing an immune response against it’s own tissue or individual tissue components. Sometimes it is an antibody response (auto antibodies); sometimes it is a cell mediated immune response. In many instances the cell damage is by a cell mediated cytotoxic response, and the abnormal antibodies are generated to internal cell constituents, which are not in themselves damaging to the cells. Such auto antibodies are useful in diagnosis and typing of certain immune-mediated disease.
Examples of auto antibodies in diagnosis of certain diseases are;

  • Graves disease Anti-TSH receptor
  • Diabetes Mellitus Type I Anti-islet cells
  • SLE Anti-double stranded DNA
  • Rheumatoid disease Rheumatoid factor (Anti-IgG)

Diseases of autoimmune origin usually exhibit the following features:
1. An elevated level of immunoglobulins.
2. Demonstrable autoantibodies.
3. Deposition of immunoglobulins or their derivatives at site of election, such as renal glomeruli.
4. Accumulation of lymphocytes and plasma cells at the site of lesions.
5. Temporary or lasting benefit from immunosuppressive therapy.
6. Occurrence of more than one type of autoimmune lesion in an individual.
7. Genetic predisposition towards autoimmunity.

Genetic considerations
Studies in IDDM, rheumatoid arthritis, multiple sclerosis, and SLE have shown that approximately 15 to 30% of pairs of monozygotic twins show disease concordance, compared with <5% of dizygotic twins. The occurrence of different autoimmune diseases within the same family has suggested that certain susceptibility genes may predispose to a variety of autoimmune diseases. These findings have led to an extensive search for genes that determine susceptibility to autoimmune disease.

The most consistent association for susceptibility to autoimmune disease has been with the major histocompatibility complex (MHC). Many human autoimmune diseases are associated with particular HLA alleles. It has been suggested that the association of MHC genotype with autoimmune disease relates to differences in the ability of different allelic variations of MHC molecules to present autoantigenic peptides to auto reactive T cells.

An alternative hypothesis involves the role of MHC alleles in shaping the T cell receptor repertoire during T cell ontongeny in the thymus. Additionally, specific MHC gene products themselves may be the source of peptides that can be recognized by T cells. Cross-reactivity between such MHC peptides and peptides derived from proteins produced by common microbes may trigger autoimmunity by molecular mimicry. However, MHC genotype alone does not determine the development of autoimmunity. Identical twins are far more likely to develop the same autoimmune disease than MHC-identical nontwin siblings, suggesting that genetic factors other than the MHC also affect disease susceptibility.

In humans, inherited homozygous deficiency of the early proteins of the classic pathway of complement (C1, C4, or C2) is very strongly associated with the development of SLE. In mice and humans, abnormalities in the genes encoding proteins involved in the regulation of apoptosis, including Fas (CD95) and Fas ligand (CD95 ligand), are strongly associated with the development of autoimmunity. There is also evidence that inherited variation in the level of expression of certain cytokines, such as TNF-a or IL-10, may also increase susceptibility to autoimmune disease.

A further important factor in disease susceptibility is the hormonal status of the patient. Many autoimmune diseases show a strong sex bias, which appears in most cases to relate to the hormonal status of women.

Immunopathogenic mechanisms
The mechanisms of tissue injury in autoimmune diseases can be divided into (1) antibody-mediated and (2) cell-mediated processes. The pathogenicity of autoantibodies can be mediated through several mechanisms, including opsonization of soluble factors or cells, activation of an inflammatory cascade via the complement system, and interference with the physiologic function of soluble molecules or cells.

It is important to note that autoantibodies of a given specificity may cause disease only in genetically susceptible hosts, as has been shown in experimental models of myasthenia gravis. Finally, some autoantibodies seem to be markers for disease but have as yet no known pathogenic potential

Classification of autoimmune disease
Based on site of involvement and nature of lesion, autoimmune diseases can be classified as (a) Hemocytolytic (b) localized or organ specific (c) systemic or non organ specific and (d) transitory diseases.

(a) Hemocytolytic autoimmune disease
1. Autoimmune hemolytic anaemias: Autoantibodies against erythrocytes are demonstrable in this condition. There are two groups; warm and cold antibodies.The cold autoantibodies are generally, complete agglutinating antibodies belonging to the IgM class and agglutinate erythrocytes at 4^C but not at 37^C. Cold agglutinins are seen in paroxysmal cold hemoglobulinuria typanosomiasis, blackwater fever and primary atypical pneumonia.

The warm autoantibodies are generally, incomplete non agglutinating antibodies belonging usually to the IgG class. It can be shown coating the erythrocytes in the direct Coombs test. Warm antibodies are frequently seen in patients taking drugs like sulphonamides, antibiotics, and alpha methyl dopa.
2. Autoimmune thrombocytopenia: In ITP autoantibodies against platelets are produced. Sedormic purpura is an instance of immune response against drug induced neoantigens on platelets.
3. Autoimmune leucopenia: Non agglutinating antileucocyteantibodies can be demonstrated in the serum of patients with SLE and rheumatoid arthritis.
(b) Localised (organ specific) autoimmune diseases.

Autoimmune diseases of thyroid gland:
(a) Hashimoto’s disease (Lymphadenoid goitre): more frequently seen in females and is associated with symptoms of hypothyroidism or frank myxedema. Antithyroid specific antibodies are detected.
(b) Thyrotoxicosis (Graves ds): the immunological basis of thyrotoxicosis is supported by the identification of the ‘long acting thyroid stimulator’ (LATS) which is an IgG antibody to the thyroid membrane antigen.

Addisons disease: the immunological basis is lymphocytic infiltration of adrenal glands and presence of antiadrenal antibodies which is directed against the cells of zona glomerulosa. The feature is hypoadrenocortism.
Autoimmune orchitis: after viral infections like mumps there is lymphocytic infiltration of the testis and circulating antibodies to the sperms and the germinal cells can be demonstrated.
Myasthenia gravis: In this disease there is an abnormal fatigability of muscles due to malfunction of the myoneural junction. Antibody against acetyl choline receptor on myoneural junction of the striated muscles is present in these patients. In neonatal myasthenia the auto antibody is passively acquired from the mother.

Autoimmune disease of the eye: Two types are seen
(a)Cataract surgery sometimes leads to intraocular inflammation caused by the autoimmune response to the lens protein, this is known as phacoanaphylaxis.
(b)Perforation injury of the eye, particularly those involving the iris and ciliary’s body are often followed by sympathetic ophthalmia of the opposite eye.

Pernicious anemia: Two types of antibodies are seen. The first is directed against the parietal cells of the gastric mucosa, which is likely to cause achlorhydria and atrophic gastritis. The second type of antibody is directed against the intrinsic factor and prevents the absorption of vitamin B12.
Autoimmune diseases of nervous system: The “neuroparalytic accidents” following rabies vaccination represent injury to the nervous system by the immune response against the sheep nervous tissue in the vaccine, which cross reacts with the human nerve tissue. Idiopathic polyneuritis (Guillian-Barre syndrome) is considered to be an autoimmune response against the peripheral nervous tissue.

8. Autoimmune diseases of skin: Phemphigus vulgaris may be caused by an antibody to the intercellular cement substance. In bullous phemphigoid, antibodies are directed against the dermal epithelial junction. Specific antibodies against dermatitis herpetiformis have not been identified.

(c) Systemic (nonorgan specific) autoimmune disease:
This group includes conditions characterised by immune response against a variety of self-antigens and damage to several organs and tissues systems.

1.Systemic lupus erythematosus
: Multisystem disease with remissions and exacerbations and terminating fatally. Patient have a variety of antibodies which are directed against cell nuclei, intracytoplasmic cell constituents, immunoglobulins, thyroid and other organ specific antigens. The first immunological feature is LE cell phenomenon, here LE cell is a neutrophil containing a large pale homogenous body (LE body). LE body is the immunologically damaged nucleus of a leucocyte. Anti nuclear antibody test are sensitive but not specific for SLE. High titre of anti-ds DNA antibody is relatively specific for SLE. Another SLE specific antibody is anti-sm antibody.

2. Rheumatoid disease:
There is a genetic predisposition, although the cause remains unknown. Women are more affected. Manifestations are dry eyes, pulmonary fibrosis, anemia, scleritis, vasculitic skin rash, rheumatoid nodules, hypersplenism and osteoporosis. Joints are affected giving rise to rheumatoid arthritis.

3. Polyarteritis nodosa:
Necrotising angitis involving medium sized arteries, ending fatally due to coronary thrombosis, cerebral hemorrhage or gastrointestinal bleeding. IT is suggested to have an autoimmune basis, but the autoantibodies are not indentified.
4. Sjogren’s syndrome: Triad of conjuctivites sicca, dryness of the mouth, with or without salivary gland enlargement, and rheumatoid arthritis. Antinuclear antibodies and rheumatoid factor commonly occur in sera.
5. Progressive systemic sclerosis: The main abnormality is excess formation of fibrous tissue, particularly collagen and leads to rigidity of the affected part. Vessel wall thickening and perivascular fibrosis are characteristic features, and are responsible for slowly progressive ischaemic damage.

(d) Transitory Autoimmune process:
Includes condition like anaemia, thrombocytopenia and nephritis following certain infection or drug therapy. The infecting agent sets up antigenic alterations and causes tissue damage. The disease is transient and undergoes spontaneous cure when the infection is controlled.

1.Text book of microbiology by R.Ananthanarayanan & C.K Jayaram Paniker
2.Basic Pathology by Kumarotran Robbins
3.Harrisons Principles of Internal Medicine


The ovaries – applied pathology

loveDr Bindu K  BHMS,MD(Hom)
Each ovary measures about 35mm in length, 25mm in width and 18 mm in thickness.The ovary is almond- shaped, pearly gray due to a compact tunica albugenea and the surface is slightly corrugated. Before puberty ovaries are small. After menopause they atrophy and become shrunken and the grooves and furrows on the surface become well marked. The ovary is attached to the back of the broad ligament by a thin mesentry, the mesovarium. Laterally the ovary is related to the fossa below the bifurcation of the common iliac artery and ureter. Medially it is close to the fimbriae of the fallopian tube, which is stretch over it around ovulation. It is attached to the cornua of the uterus by the ovarian ligament. The infundibulo pelvic ligament is the outer border of the broad ligament and contains the ovarian vessels, nerves and lymphatics. The ovaries are not normally palpable during bimanual examination.

The ovary of the new born:
At term the foetal ovary measures 10 – 16 mm in length and it is situated at the level of the brim of the pelvis. If a section is taken through the ovary and examined histologically the following divisions can be recognized.
1. surface epithelium : – this is a single layer of cuboidal cells, which gives rise later to surface epithelium of the adult ovary, and which is morphologically continuous with the mesothelium of the peritoneum.
2. The sub epithelial connective tissue layer :- This layer gives rise to the tunica albuginea of the adult ovary and to the basement membrane beneath the surface epithelium.
3. The parenchymatous zone :- This area is the most important, as it contains the sex cells. It can be sub divided into three zones.
a) Immediately beneath the surface epithelium the sex cells are still grouped together in bunches to form nests.
b) Below this area the sex cells take the form of primordial follicles and are packed together without orderly arrangement.
c) In the deepest part of the parenchymatous zone, developing follicles can be seen.
4. The zona vasculosa :- This area contains the blood vessels which pass into the ovary from the mesovarium. It constitutes the medulla of the ovary, the other layers forming the cortex.

Malignant tumours of the genital tract account for one fifth of all cancers in women. Although the incidence of the ovarian cancer is lower than that of cervix and uterine endometrium, the mortality from ovarian carcinoma exceeds the combined mortality from cervical and endometrial carcinoma in the metropolitan cities of India. However in the country as a whole, carcinoma cervix continues to hold the premier position amongst all gynaecological cancers.
Ovarian tumour is not a single entity but a complex wide spectrum of diseases, involving a variety of histological tissues ranging from epithelial tissues, connective tissues, specialised hormone secreting tissues to germinal and embryonal tissues.
Unfortunately patients with ovarian tumours are often non specific, hence by the time ovarian malignancy is diagnosed, about two thirds of these have already become far advanced and the prognosis in such cases continues to be unfavourable. A high index of clinical suspicion and the assiduous skill with which the clinician pursues the diagnosis will go a long way in reducing the ravages from ovarian cancer.

Epidemiology :
Incidence :ovarian cancers account for about 5% of all gynaecological cancers in India, as against 15% observed in the west.
Racial factors:Higher among in the white population,as compared to the negroes in USA.I ncidence of ovarian carcinoma among Hispanics.and Asian women is half to one third of that observed among Caucasians.

Economic status
The incidence is higher among women from affluent classes, and the highly industrialized countries. This has been attributed to the higher animal fat content in their diets.

Environmental factors
Industrial pollutants have been implicated and chemical irritants like asbetos and talc have been identified to cause ovarian neoplastic disease.

Clinical observations
Ovarian cancer is associated with nulliparity, infertility, marked premenstrual tension,abnormal breast swellings, marked dysmenorrhoea, pelvic irradiation, and history of rubella and mumps.
It is well known that repeated gonadotropic stimulation of the ovaries and uninterrupted cycles of ovulation predisposes to cancer of ovary. Factors suppressing ovulation such as pregnancies , lactation , oral contraceptives , are known to be protective.

High risk factors:
Recognition of high risk factors include
1)family history of ovarian cancer
2) history of ovarian or breast neoplasm
3)history of abnormal ovarian function
4)presence of ovarian neoplasm in adolescent and perimenopausal women .
5)presence of a palpable enlarged ovary in post-menopausal is suspicious of ovarian cancer.

[major group]
A.Serous tumours.
B.Mucinous tumours
C.Endometrial tumours
D.Clear cell[mesonephroid tumours]
E,Brenner tumours
F.Mixed epithelial tumours.
G.Undifferentiated carcinoma.
H.Unclassified epithelial tumours.

A.Granulosa- stromal cell tumours.
B.Androblastomas: sertoli – Leydig cell tumours.


B.Endodermal sinus tumour.
C.Embryonal carcinoma.
G.Mixed forms.

B.Mixed with dysgerminoma or other germ cell tumours.





Histologically these tumours are intermediate between truly benign neoplasms and those with invasive characteristics.They account for 10 – 20% of all epithelial tumours.
Characteristics of Borderline Ovarian Tumour [Grade – o]
1.Patients have a high survival rate.
2.Tumours run a typical indolent course.
3.Spontaneous regression of peritoneal implant is known.
4.Diagnosis must be based exclusively on the examination of the ovarian tumour.
5.Multiple sections must be examined to exclude invasion.

1.Tumours of the surface epithelium.
Epithelial ovarian neoplasms arise from the mesoepithelial cells on the ovarian surface.They recapitulate the histology of the female genital tract.They constitute about 80% of all ovarian cancers.The most common histologic type is the papillary serous cystadenocarcinoma accounting for almost 50% of all epithelial tumours.Mucinous cystadeno carcinomas account for 12-15%,clear cell and endometrioid combined about 10% and the unspecified types,25-27% of cases.

a)Serous cystadenoma and cystadenocarcinoma.
These are amongst the commonest of cystic ovarian neoplasms, accounting for about 30% of all ovarian tumours.Out of these 60% are benign,15% borderline and 25% are malignant.
Serous cystadenomas occur in the third,fourth and fifth decades of life;malignant cystadenocarcinomas tend to occur more frequently with advancing age.In about half of the cases they are bilateral.apillary excrescences may be seen on the surface and with in the loculi.In cases of serous cystadenocarcinoma, spread to the peritoneal surface is known.Histologically the benign variety shows the cystic spaces, and lining of the tumour toconsist of tall columnar ciliated epithelium resembling the endosalpinx.The loculi contain a serous straw coloured fluid,which may be blood stained when malignant transformation occurs.Unless cellular atypia exceeds four cell layer thickness or stromal invasion, the tumour is classified as borderline.

b) Mucinous Tumours
These tumours are lined by epithelium resembling the endocervix.Formerly they were reffered to as pseudomucinous, as their contents are not chemically true mucin.The tumours are not infrequent, can grow to a large size, are often pedunculated, and may be associated with a dermoid cyst or a Brenner tumour.They are usually unilateral,only 5% are bilateral.The tumours are essentially benign, only 5-10% are malignant and 10-15% are of low maqlignant potential.
Mucinous tumours occur in middle aged woman.They have a glistening surface, and the cut section reveals loculi filled with mucinous contents.If the tumour ruptures, it may lead to formation of pseudo myxoma pritonei and show extensive adhesions.This condition may be associated with a mucocele of the appendix.

c) Endometrial tumour :
These tumours account for about 20% of all ovarian cancers. They are lined by a glandular epithelium resembling the endometrium. The tumours are of moderate size and are essentially solid with cystic areas in between. In 15% of cases ovarian endometriosis may co-exist.

d) Clear cell carcinoma :
it is an uncommon tumor of the ovary. It is composed of large cuboidal epithelial cells with abundant clear cytoplasm characteristically forming tubules, glands, small cystic spaces lined by clear cells showing large dark nuclei protruding into the lumen (hobnail cells).

e) Brenner tumour :
This is a solid tumour accounting for about 1 – 2 % of all ovarian neoplasms. On gross appearance, it resembles a fibroma of the ovary, its cut surface appears gritty and yellowish gray. It is generally unilateral, small to moderate size, essentially benign and having no endocrine function.
The tumour is generally seen in women around the age of menopause and causes post menopausal bleeding. Occasionally it may be associated with ascites and hydrothorax – pseudo Meig’s syndrome.
Histologically the tumour shows a background of fibrous tissue, interposed within it are nests of transitional epithelium (Walthad cell nests). These cells demonstrate a longitudinal groove resembling puffed wheat. This tumour may be associated with mucinous adenoma of the ovary.

Spread of epithelial tumours of the ovary
These tumours extend through the capsule and may be seeded on to the peritoneal surface, omentum, intestinal viscera and by trans-coelomic spread reach the subdiaphragmatic space. The ascitic fluid shows presence of clusters of tumour cells. the tumour cells may spread to the lymph nodes and metastasize to the liver, lungs, gastrointestinal tract and other areas. In over half of the cases that come to light, the opposite ovary is involved.

These accounts for about 15 – 20% of all ovarian tumours. The majority of tumours in this group are the benign cystic teratomas (about 90%), also called dermoids. Below the age of 20years, 60% of all ovarian tumours belong to this group and are almost invariably malignant growths.

a) Teratoma : All germ cell tumours show diffenciation principally along embryonic rather than extraembryonic pathways. These are grouped together as teratomas and divided into 3 categories.
i) Benign or mature eg: dermoid cyst.
ii) Immature (essentially malignant) eg: solid teratoma
iii) Monodermal or highly specialized eg: Struma ovarrii.
i) Dermoid cyst :- of all cystic tumours of the ovary, 5 – 10% are dermoids. Dermoid cysts are usually unilocular swelling with smooth surfaces, seldom attaining more than 15cm in diameter.

They contain sebaceous material and hair and the wall is lined in part by squamous epithelium which contains hair follicle and sebaceous glands. Teeth, bone, cartilage, thyroid tissue and bronchial mucous membrane are often found in the wall. Sometimes, the sebaceous material may be collected together in the form of small balls, and as many as 1000 sebaceous balls of this type have been counted in a dermoid cyst. The inner surface of the dermoid cyst is always irregular and contains what is called a ‘focus’ or ‘embryonic node’ from which hairs project and in which the teeth and bone are usually found. The nomenclature ‘dermoid cyst’ is inaccurate for in addition to ectodermal tissues, tissues from both the mesoderm and endoderm are usually found in some part of the tumour. Moreover, though squamous epithelium usually lines the cyst, columnar and transitional types are also found. It is extremely rare for pancreas or liver tissues and intestinal mucous membrane to be found in the wall of a dermoid. Dermoid cysts frequently arise in association with mucinous cystadenomas to form a combined tumour, part of which consists of a dermoid cyst while the rest has the characteristic structure of a mucinous cystadenoma. Perhaps as many as 40% of dermoid cysts are combined tumour of this kind. This association suggests that the origin of the two forms of ovarian tumours is related.

Multiple dermoid cyst in the same ovary are well recognized and it is often quite usual to find 2 -3 separate dermoids, extra – ovarian dermoid cysts arise occasionally in the lumbar region, in the uterovescical septum, in the parasacral region and in the recto vaginal septum. The combined tumours tends to arise in patients between the ages of 20 and 30, while simple dermoid cysts have a maximum age incidence between 40 and 50. the tumours may, however arise at any age. They are not infrequently bilateral, 12 – 15%.
Dermoid cysts are innocent ovarian tumours but epidermoid carcinoma occurs in 1.7% of all dermoids and sarcomatous changes have also been described. Usually a squamous celled carcinoma develops from the ectodermal tissues but mammary carcinomas and malignant thyroid tumours have been described.

ii) Solid teratoma of the ovary :- These tumours are very rare. They are mainly solid and cut surface has a peculiar trabeculated appearance. Almost invariably large loculi are found beneath the capsule. The solid part of the tumour contains cartilage and bone, while hair and sebaceous material are found in the cystic spaces. The solid area also contains plain muscle, brain tissue, glia, piamater and intestinal mucous membrane. The attempted formation of rudimentary eye has been described and even recognizable pattern of a foetus has been simulated. The so-called embryoma. Most solid teratomas of the ovary are malignant tumours because of sarcomatous change, but a fair proportion, probably about 20% are innocent.

iii) Struma ovarii :- This tumour consists of thyroid tissue similar to that of a thyroid adenoma. The tumour is solid, consisting almost entirely of thyroid tissue and should be clearly distinguished from a dermoid cyst with thyroid tissue in its wall. To the naked eye the tumour resembles a small pseudo-mucinous cystadenoma, but the material contained in the vesicle is colloid and gives reactions for iodine. Most of the tumours have been recorded. The histogenesis is supposedly a dermoid in which the thyroid tissue preponderates at the expense of other elements.
Carcinoid tumours of ovary :- it may be primary or metastatic tumour of the ovary, known as argentaffinoma. It occurs as a malignant change in a benign dermoid cyst and presents as a solid yellow tumour with the characteristic histological property of reducing silver salts being derived from the specialized Kultschitzky cells of the intestine. It produces 5-hydroxy tryptamine which causes attacks of flushing and cyanosis.

b) Endodermal sinus (yolk sac tumour) :
It is a rare tumour and the second most common of germ cell origin. It is thought to originate from a multipotential embryonal tissue as a result of selective defferenciation of yolk sac structures. This explains why the tumour is rich in alpha-fetoproteins and alpha-1- antitrypsin. Histologically, the tumour characteristically presents with pappillary projections composed of a central core of blood vessels enveloped by immature epithelium. Conspicuous intracellular and extracellular hyaline droplets present in all tumours. The alpha- fetoprotein contents can generally be stained by immuoperoxidase techniques. Most of these patients are children or young women, presenting with abdominal pain and a pelvic mass. The tumours are known to grow rapidly.

c) Choriocarcinoma:
Rarely seen in a pure form. Generally it is a part of a mixed germ cell tumour. Its origin as a teratoma can be confirmed in pre-pubertal girls, when the possibility of its gestational origin can be definitely excluded. The tumours are often very vascular.
Histologically they show a dimorphic population of syncytio-trophoblast and cytotrophoblasts. They secrete large quantities of human chorionic gonadotrophin which forms an ideal tumour marker in diagnosis and management of the tumour. The tumours are highly malignant, before they are recognised and diagnosed; they generally have metastasized by the blood stream to the lungs, brain, bones, and other viscera.

d) Embryonal cell carcinoma :
It is a rare tumour accounting for about 5% of all germ cell tumour. It generally occurs in prepubertal girls. It elaborates both alpha-fetoproteins and chorionic gonadotropins. It is known to be associated with the symptoms of precocious puberty and menstrual irregularities.

e) Dysgerminoma :
This tumour corresponds exactly to the seminoma of the testis and its incidence is one third that of the granulosa cell tumour. It usually arises in young women or in children, with an average incidence at the age of 20. the tumour is solid with a peculiar elastic rubbery consistence with a smooth, firm capsule. The cut surface is yellow or grey with areas of degeneration and haemorrhage. The size is variable, usually moderate; thogh large tumours have been described. They are usually unilateral, occasionally undergo torsion and may like all solid tumours, be associated with ascites. The tumour consists of large cells arranged in bunches or alveoli. The lumphocytes and giant cells are always found amongst the tumour cells. This appearance of large dark-staining nuclii with clear almost translucent cytoplasm and lymphocytic infiltration of the fibrous septa, is immeadiately diagnostic. The tumour is nutral and does not secrete either male or female sex hormones. A number of patients with a dysgeminoma of the ovary have been reported to show genital abnormality, with hypoplsia or absence of some part of the genital tract. It has been repoerted in pseudo-hermaphrodites. Such congenital abnormalities are not caused by the dysgeminoma and its removal has no beneficial effect upon them. The malignancy of dysgeminoma is similar to that of granulosa cell tumour and depends largely on the findings at laparotomy.

i) A unilateral tumour confined to one ovary is relatively benign.
ii) The presence of active invasion of pelvic viscera is naturally of grave importance though not hopless.
iii) The presence of extra pelvic metastases in the general peritoneal cavity and glands, omentum or liver renders the outlook hopeless. A fair estimate of the malignancy is 33 – 50% .

f) Mixed germ cell tumour :
These tumours contain two or more recognizable germ cell entities, eg: combination of dysgeminoma teratoma, endodermal sinus tumours and choriocarcinoma.

III. Sex cord stromal tumours :
These tumours originate either from the sex cord of the embryonic gonad (before the differenciation of the gonadal mesenchyme into male or female) or from the stroma of the ovary. Since theca cells are the source of ovarian steroids, many of these are functional and exert feminising effects. The embryonic sex cords may differenciate along the male line, giving rise to sertoli or Leydig cell tumours called androblastomas. These tumours are also referred to as mesenchymomas.

Tumours arising from primitive mesenchyme (mesenchymoma)
A) Feminising functioning mesenchymoma
a) Granulosa cell tumour:-are composed of cells closely resembling the granulosa cells of the graffian follicle .
clinical features:common tumours represent 10 % of all solid malignant ovarian tumours. Thgey can occur at any age and before and after menopause. The main clinical features depend upon the oestrogenic activity of the tumour and only the larger ones cause pain and abdominal swelling. Feminising tumours secreate oestrogen which the tumour has metabolised from progestrogen in the same manner as the normal ovary
i) when occuring before the puberty,a precocious puberty results with secondary sexual characteristics, hypertrophy of breast,external genetalia,pubic hair and myohyperplasia of the uterus. The endometrium shows an oestrogenic anovulatory pattern. Removal of the tumour causes regression of all these manifestations.

ii) when occuring in adult life, the oestrogenic effect is less remarkable than in the prepubertal stage. There is no change in rthe secondary sexual characteristics since these are already established. The effect on the endometrium is that of hyper oestrogenism in general,ie, an exaggerated proliferative pattern with cystic glandular hyperplasia. Thus there may be a super threshold level of blood oestrogen , leading to amenorrhea followed by prolonged bleeding. In fact ,the behaviour of the endometrium closely resembles that of metropathia haemorrhagica, another condition in which hyper oestrogenism occurs.

iii) In the post menopausal patients, the most remarkable feature is post menopausal bleeding. The secondary sexual characteristics are less affected though hypertrophy of the breast is sometimes seen. The uterus shows myohyperplasia and cyastic glandular hyperplasia exactly as in metropathia. Removal of the tumour causes a regression of all these symptoms and sometimes the additional symptoms of a second menopause.

Macroscopic features
The tumours vary in size from tiny to gross, the average being 10 cm in diameter. The shape is oval and consistence soft.T he cut surface is reticular or trabeculated with areas of interstitial haemorrhage and it often shows yellow areas.The outer surface is smooth and often lobulated.
The cells are arranged either in cords or trabeculae , and are often surrounded by structureless hyaline tissue, which resembles the glass membrane of an atretic follicle. Small call-exner bodies can usually be found in some part or other of the tumour. It will be remembered that these small cyst like spaces are a characteristic feature of graffian follicle.

Three histologic types of granulosa cell tumours are identified
a) An early undifferentiated form which consists of a solid mass of granulosa cells .
b) A trabecular form
c) A folliculoid type in which the granulosa cells are grouped around spaces filled with secretion.

Most granulosa cell tumours are encapsulated and appear to be clinically benign. This appearance of the gross specimen and the histological picture may both be misleading as judged by the subsequent recurrence of the tumour.This recurrence may be delayed for many years,long after the arbitrary five year period has passed.50% of granulosa cell tumours are malignant [A well differentiated folliculoid pattern is 10% malignant while an anaplastic, almost sarcomatous appearance is 65% malignant.]
The metastases are interesting, because the opposite ovary first becomes involved, then metastases develop in the lubar region and finally, secondary deposits become scattered in the mesentry, the liver and mediastinum.

Association Of Carcinoma Of The Endometrium With Granulosa Cell Tumours :- There is strong evidence that carcinoma of the endometrium may be associated with feminizing tumours of the ovary in post-menopausal women.It has been estimated that in 1/5th of oestrogenic ovarian tumours, an endometrial cancer will develop.A theca cell tumour is four times more commonly associated with endometrial cancer than the granulosa tumour.

b) Theca cell tumour
Seen rarely and usually arises after the menopause.It is nearly always unilateral and forms a solid mass.The cut surface is often yellow in colour and if stained selectively, lipoid material is characteristically present.The tumour consists of spindle-shaped cells reminiscent of an ovarian fibroma together with fatladen polyhedral cells which resemble the theca lutein cells of the Graffian follicle.The tumour is intensely oestrogenic and causes post menopausal bleeding. It is usually innocent, but malignant forms have been described.It has been shown recently that both granulosa cell tumours and theca cell tumours may show luetinization of their cells,with the result that progestrone is secreted and secretory hypertrophy can be demonstrated in the endometrium.

B. Viriilizing mesenchymoma [And other virilising tumours of the ovary]
a) Arrhenoblastoma.
Rare tumours which secrete androgens which secrete androgens which cause defeminization followed by masculinization.Women in the child bearing age may complain of altered body contours, flattening of breasts, scanty and irregular menstruation ending ultimately in amenorrhoea.Later signs of masculinization like increased hair growth on the face(hirsuitism) appear.Coarsening of the features, enlargement of the clitoris and even breaking of the voice may occur.Removal of the tumour can reverse the above features except voice change.Gross appearance is like that of other mesenchymomas.Generally only one ovary is affected.Its association with pregnancy has been reportede.The incidence of malignant transformation is rated to be higher than with feminizing tumours.
Histologically, the tumour reveals all grades of differentiation from the testicular adenoma showing perfectly formed seminiferous tubules to a sarcomatous anaplastic variety, wherein lipoid containing cells are seen.The diagnosis is usually made on the basis of the endocrine behaviour of the tumour.

b) Adrenal cortical tumours of the ovary:
These tumours have some resemblance to adrenal cortex when examined microscopically and have been called hypernephroma,masculinovoblastoma ,virilizing luteoma or clear celled tumour.Very rare tumours which are sometimes masculinizing.

c) Hilus cell tumour:
Rare.Arising from cells in the ovarian hilum especially in women past the menopause.One interesting feature of the hilus cell tumour is the presence of Reinke crystals in the cells, a distinguishing feature of the Leydig or interstitial cells of the testis.

d) Gynandroblastoma:
This tumour has the combined characteristic of the granulosa cell tumour and an arrhenoblastoma.

IV. Tumours arising from the connective tissue of the ovary.

a) Ovarian fibroma:
Of the innocent connective tissue tumours of the ovary,fibromas are the most common and comprises about 3% of ovarian neoplasms.Has no particular age incidence.The tumour is oval in shape with a smooth surface and large veins which are always noticebale in the capsule.The consistence is firm and harder than that of uterine myoma .The tumour frequntly undergoes degeneration so that cystic spaces are found towards the centre and calcareous degeneration is not uncommon. The tumours are usually about 15cm in diameter but they sometimes become much larger than this and weigh as much as 25kg.Torsion may occur with the larger tumours.Microscopical examination shows the tumour to be composed of a net work of spindle shaped cells which closely resemble the spindle cells of the ovarian cortex.The cellular pattern is strikingly uniform and there is no attempt at nuclear activity.The combination of an ovarian fibroma with ascites and hydrothorax, is referred to as meig’s syndrome.

Three types of fibromas are recognized.
1) surface papilloma on the ovary
2) small encapsulated fibroma ; Normal ovarian tissue can be seen at one pole of ovary.
3) fibroma replaces the ovary completely.

Rare.Many tumours labelled as sarcomas have been misdiagnosed histologically and were in reality granulose cell tumours or anaplastic carcinomas.Sarcomas arise most frequently after the menopause,particularly in multiparae.They give rise to multiple metases.Rhabdomyosarcoma of the ovary has been described.This is probably more accurately to be considered as one form of mixed mesodermal tumour.

Ovarian metastases are commonly from primary growths of the gastrointestinal tract,notably the pylorus,colon and rarely, the small bowel;they occasionally occur from the gall bladder and pancreas.They may also occur in late carcinoma of the breast,as seen in 30% of all autopsy material from breast cancer.Carcinomas of the corpus [10%] and cervix [1%] also metastasize to the ovary owing to the close relationship of their lymphatic drainage. Carcinomas of the corpus is 10 times more likely to metastasize to the ovary than that of the cervix.

Antigen antibody reaction

These reactions serve several purposes. In the body they form the basis of antibody mediated immunity in infectious diseases or of tissue injury in some types of hypersensitivity reaction and autoimmune diseases. In laboratory it is used for diagnostic purposes. These reactions can be used for detection and quantitation of either antigen or antibody.

Practical Importance
1. Diagnosis of infectious diseases, hyper sensitivity states through identification of either Ag or Ab.
2. Quantitation of Ag or Ab.
3. Classification of bacteria on the basis of antigenic constitution.
4. Detection of adulteration of food stuffs.
5. Detection of hormones and enzymes by antibodies prepared against them.
6. Determination of compatibility between blood cells, tissues and organs of two individuals of the same species.

Antigen antibody reaction 
Occur in 3 stages
Primary stage:
Initial interaction between the two without any visible effect. Reversible reaction. This can be detected by estimating free or bound antigen or antibody separately.

Second Stage :
Leading to demonstrable events
Precipitation, Agglutination , lysis of cells, killing of live antigens, neutralization of toxins, fixation of complement, enhancement of phagocytosis, immobilization of motile organisms.
Tertiary stage :
Neutralization or destruction of injurious Ag. Tissue damage include clinical allergy, other immunological diseases.

General features of antigen-antibody reaction
1. Reaction is specific : Ag combines with homologous Ab
2. Entire molecules react, not fragments.
3. No denaturation of Ag or Ab during reaction.
4. Combination occurs at the surface. So surface Ag are immunologically relevant
5. Combination is firm, but reversible.
6. Both Ag and Ab participate in formation of agglutinate or precipitate.
7. Ag and Ab can combine in varying proportions. Both are multivalent (Different binding sites)

Measurement of Ag and Ab
Measurement may be in terms of mass (mg.or Nitrogen units or titre).The antibody titre of a serum is the highest dilution of serum which gives an observable reaction with the Ag in the particular test.
Important parameters of serological tests are specificity and sensitivity.

Isolation of pure antibodies
This is done by sequential protein fractionating steps include
1) Precipitation of gamma globulins in 30-50% amm. sulphate
2) Gel filtration to obtain molecule of correct size
3) Ion exchange chromatography to isolate molecules which are +vely charged at neutral pH
4) Affinity chromatography

Serological reactions.
1. Precipitation reaction
2. Agglutination reaction
3. Complement fixation tests
4. Neutralization tests
5. Opsonisation
6. Immunofluorescence
7. Radio immuno assay
8. Enzyme immuno assays
9. Immuno electro blot techniques
10. Immuno electron microscopic tests

Precipitation reaction
Based on the ability to precipitate when Ag and Ab combined in proportions at or near equivalence. Soluble Ag combines with its Ab in the presence of electrolytes (Nacl) at a suitable tempt and pH, the Ag-Ab complex form an insoluble precipitate. Precipitation can take place in liquid media or in gels.

To the same amount of antiserum in different tubes an increasing concentration of Ag. are added then the amount of immune complex precipitated rises and then falls. The precipitation curve generated in this have 3 zones.

Ab excess zone – Free ab can be detected in the supernatant
Equivalence zone – Added antigen is sufficient to combine with and precipitated all the Ab ,so neither free Ab nor Ab can be detected in the supernatant
Antigen excess zone – reduced amount of precipitate as excess Ag.
cause solubilisation of Ag-Ab complex.
This is called zone phenomenon

Practical application :
May be carried out as qualitative or quantitative test
Sensitive for detecting Ag as 1 microgram of protein can be detected by precipitation reaction
Forensic application in – identification of blood and seminal stains
Testing for food adulterants
Less sensitive for the detection of Ab

1. Ring test : pouring Ag solution over a column of antiserum, precipitate forms at the junction of both liquids
2. Slide test : Eg. VDRL test for syphilis
3. Tube test

Immuno diffusion (precipitation in gel)
Advantage :
Reaction is visible as distinct band of precipitation, can be stained for preservation.
Each Ag-Ab reaction gives a line of precipitation .The number of different Ag in the reacting mixture can be identified.

1.Single diffusion in one dimension
Ab is incorporated in Agar gel in a test tube and Ag solution is layered over it. Ag diffuses downward through agar gel forming a line of precipitation appears to move downward. It dissolves when Ag. concentration increases

2.Double diffusion in one dimension
Ab is incorporated in gel, above which placed a column of plane agar. Ag. Solution is layered on top. Ag and Ab move towards each other through plane agar and form a band of precipitate where they meet at optimum concentration

3.Single diffusion in 2 dimension
Ab incorporated in agar gel poured on a flat surface. Ag is added to the wells cut on the surface of gel. Ag diffuses radially and form ring shaped band of precipitation. The diameter of halo gives the estimate of Ag concentration.
Eg: used for screening sera for Ab to influenza virus.

4. Double diffusion in two dimensions
Widely employed method. Helps to compare different Ag and  antiserum directly. Agar gel is poured on slide ,wells are cut. Anti serum is placed in the central well and different Ag. In the surrounding well. If two adjacent Ag. are identical, the lines of  precipitation formed by them will fuse. If they are unrelated the  lines will cross each other. Eg : Elek test for toxigenicity of  diphtheria bacilli, precipitation occurs when it is toxigenic  Immuno electrophoresis
Involves the electrophoretic separation of a composite Ag into its constituent proteins.

1. Ag are separated in an agar gel by placing an electric charge across it. The gel’s pH is chosen so that +vely charged proteins move to the –ve electrode and vice versa
2. A trough is then cut between wells and filled with the Ab which is left to diffuse.
3. Ag and Ab form precipitation arcs.

Agglutination reaction
When a particulate antigen is mixed with its Ab in the presence of electrolyte at suitable temperature and pH the particles are agglutinated.More sensitive for the detection of Ab. Agglutination occurs optimally when Ag and Ab react in equivalent proportion. zone phenomina can be seen. Monovalent Ab do not cause agglutination, but they combine with Ag.

1.Slide agglutination
A drop of antiserum is added to particulate Ag in a drop of saline on slide.Clumbing occur if the test is +ve and is used for blood grouping and cross matching
2.Tube agglutination
Quantitative method for the measurement of Ab :
Principle; when a fixed volume of a particulate Ag suspension is added to an equal volume of dilution of an antiserum in test tubes. Agglutination titre of the serum can be estimated.(used in typhoid, brucellosis & typhus fever)
eg : Widal test is typhoid
(Flagellar) H Ag and O Ag of typhoid bacilli is used
Use : Measurement of H & O antibodies in patient’s sera. Two tubes are used. Dreyer’s agglutination tube for H agglutination and Felix tube for O agglutination . Equal volumes (.4ml) of dilution of serum and H & O antigen are mixed in corresponding test tubes & incubated in water bath at 370c overnight. Control tubes containing the Ag. and normal saline are set to check autoagglutination. The H agglutination leads to the formation of loose cotton woolly clumps, while O agglutination form a disc like pattern at the bottom of the tube.

Interpretation of results of widal tests.
1. Agglutination titre depend on stage of disease .Agglutinins usually appear by the end of first week. The titre increases steadily till 3rd or 4th week, after which it declines.
2 .Demonstration of a rise in titre of Ab by testing 2 or more serum samples is more diagnostic.
3.Titires 1/100 or more for O agglutinins and 1/200 or more for H agglutinins are significant.
4.Agglutinin may be present on account of prior disease, inapparent infection or immunization. H agglutinin persists longer than O.
5.Cases treated with chloramphenicol may show poor response.

Paul Bunnel test – in IMN
There are agglutinins to sheep erythrocytes in patient’s sera, which are adsorbed by Ox red cells but not by guinea pig kidney extract.
Cold agglutination test in primary atypical pneumonia
patients sera agglutinate human O group erythrocytes at 4o C is reversible at 37oC.
The antiglobulin (Coombs) tests

Principle :

Rh +ve erythrocytes are mixed with incomplete antibody, then Ab coats the cell, cannot produce agglutination. On addition of antiglobulin serum which is complete antibody to immunoglobulin, agglutination takes place.

Types- Direct & indirect
Direct – sensitization of erythrocytes with incomplete Ab takes place in VIVO, as in disease due to Rh incompatibility. When the red cells of erythroblastotic infants are washed free of unattached protein and then mixed with a drop of Coombs serum, agglutination takes place.
In the indirect Coombs test sensitisation of red cells with Ab globulins is performed in vitro, for detection of anti Rh Ab(agglutination takes place). Coomb’s test for detection of incomplete & non agglutinating Ab.

Rose Waaler test – RA
Auto antibody (RA factor) appears in serum, which acts as an Ab to gamma globulin. RA factor is able to agglutinate red cells coated with globulins.
Complement fixation test

Principle :
Ability of Ag – Ab complexes to fix complement .CFT needs five reagents : Ag, Ab, complement, sheep erythrocyte, amboceptors (rabbit Ab to sheep red cell)
eg : Wasserman reaction (in syphilis)
Inactivated patient’s serum is incubated at 37oC for 1 hr with the Wassermann Ag and a fixed amount of guinea pig complement. If the serum contains syphilitc Ab the complement will be utilized in Ag-Ab reaction. If the serum does not contain syphilitc Ab, the complement will be left free.

Then testing for complement in the post incubation period is done by adding sensitized cells (sheep erythrocytes) incubating at 370C for 30mts. Lysis of erythrocyte indicate, complement was not used in the first step, so no syphilitic Ab (negative CFT).

1.Antigen + Test serum(contain Ab) – Complement fixed
+ Complement
+ Hemolytic system – no haemolysis; +ve test
2. Ag + Test serum ( not contain Ab) – Complement not fixed
+ Complement
+ haemolytic system – Haemolysis; –ve test.

Neutralization test
Virus neutralization tests
Neutralization of viruses by their Ab can be demonstrated. Toxin neutralization: eg : Schick test in diphtheria
Based on ability of circulating antitoxin to neutralize the diphtheria toxin given intradermally and indicate immunity or susceptibility to disease. Now it is not used, can be done by neutralization in cell culture.
Intradermal injection of skin test dose of diphtheritic toxin on the forearm. Reading on 1-2 days and 5-7 days later. (Similar injection of inactivated toxoids in other arm)
1.No reaction on either arm indicate negative reaction
2.No reaction in control arm ; circumscribed erythematic reaction on test arm after 1-2 days, persisting for 7 days , positive test.
3.Pseudo reaction in both arm
appearing within 24 hrs fades by 4th day –ve, indicating immunity.
4.Combined reaction in which both areas initially showed pseudo reaction; followed by +ve reaction, denote susceptibility and hypersensitivity.

Immuno fluorescence 
Fluorescence is the property of absorbing light rays of one particular wave length and emitting rays with a different wave length. Fluorescent dye can be conjugated to Ab ,such labeled Ab can be used to locate and identify Ag in tissues. It can be used for the identification of bacteria, viruses or other antigens by direct immuno fluorescence.
eg : detection of rabies virus antigens in brain smears

Separate fluorescent conjugate have to be prepared against each Ag to be tested. This is overcome by indirect immuno fluorescent test by using an antiglobulin fluorescent conjugate eg : Fluorescent treponimal Ab test. (Fluorescent dyes, convert UV light to visible light)
A drop of test serum is placed on a smear of T. pallidum on a slide After incubation the slide is washed off, leaving antibody globulin if present, coated on the Treponima pallidum. Smear is then treated with fluorescent labeled antiserum. Then fluorescent conjugate react with antibody globulin. After washing away all the unbound fluorescent conjugate ,when the slide is examined under UV light treponems will be seen as bright object against a dark back ground., +ve test.
Fluorescent dyes may also be conjugated with complement. Labeled complement can be employed in detection of Ag & Ab

Commonly used fluorescent dyes are
1) fluorescein isothiocyante (blue green fluorescence)
2) Lissamine rhodamine (exhibit orange red fluorescence )

Radio immuno assay (RIA)
Measurement of Ag and Ab by using radio isotopes ‘Binder-ligand assay’ is the term used for these reactions. The substance (Ag) whose concentration is to be determined is called analytic or ligand. The binding protein (ab) binds to ligand is called binder.

Application : Quantitation of hormones, drugs, tumour markers IgE and Viral antigens.
Fixed amount of Ab and radio labeled Ag react in the presence of unlabelled Ag. Both Ag’s compete for the limited binding site on Ab. This is determined by the level of unlabelled (serum) Ag present in reacting system. After the reaction, Ag is separated into free and bound fractions and their radio active count is measured. The concentration of the test Ag is calculated by ratio of bound and total Ag labels.

Enzyme immuno assay
Enzyme labeled conjugates are used for localization of Ag in tissues . So there is no radiation hazard. This includes all assays based on the measurement of enzyme labelled Ag, hapten or Ab.
Two types
Homogenous: There is no need to separate bound and free fractions
Hetergenous: Requires separation of free and bound fractions by
centrifugation or by absorption on solid surface.
eg : Enzyme linked immunosorbent assay (ELISA)

It involves an immunosorbent – absorbing material specific for one of the component of reaction, Ag or Ab
Application :
ELISA is done using 96 well microtitre plates.Detection of Ab by ELISA can be illustrated by the anti HIV antibody test.

Purified inactivated HIV Ag is adsorbed into microassay plate wells. Test serum diluted in buffer is added to the well and incubated at 370C for 30mt. The well is then washed. If the serum contains anti HIV Ab, it will form a stable complex with HIV Ag on the plate.A goat antihuman immunoglobulin Ab, conjugated with peroxidase enzyme is added and incubated for 30 mts. After thorough washing the substrate,
O – phenylene diamine dihydrochloride is added and after 30 mts, the colour that develops is read using a micro assay plate reader.
A simple modification of ELISA is cylinder or cassette ELISA Testing one or a few samples of sera at a time. Result obtains within 10mts (2 hrs in ELISA). This is used for HIV type I & 2 Ab.

Immuno electro blot techniques
eg : Western Blot test : definitive test for HIV infection
HIV proteins separated according to their electrophoretic mobility are blotted into strips of nitro cellulose paper. These strips then made to react with test sera and then with enzyme conjugated anti human globulin. Suitable substrate is then added which produces a prominent colour band when the Specific antibody has reacted with the separated viral protein. The position of the band on the strip indicate the Ag with which the Ab has reacted.

Immuno electron microscopic test:
1.Immuno electron microscopy :
Viral particles mixed with specific antisera one observed under electron microscope. Application : study of viruses . Hepatitis 2.Immunoferritin test :
Ferrtin can be conjugated with Ab and such labeled Ab reacting with Ag can be visualized through electron microscope.
3.Immuno enzyme test
Some stable enzymes such as peroxidase can be conjugated with Ab. Tissue sections carrying corresponding Ag can be visualized under electron microscope.

Reference :
Immunology – Roitt- Brostoff-Male
Basic pathology by Kumar , Cotran, Robbins
Text book of Microbiology by Jayaram Panikkar
Boyd’s text book of pathology

Complement system – applied aspect

Dr Anitha MA BHMS,MD(Hom)
Dr.Padiyar Homoeopathic Medical College.Kerala

This term ‘complement’ is coined by Ehrlich, because this factor complemented the action of antibody. ‘Complement’ refers to a system of factors which occur in normal serum, activated by antigen antibody interaction and subsequently mediate a number of biologically significant consequences. These complement factors are heat labile (Ab. are heat stable) Majority of these complement proteins are inactive. They require proteolytic cleavage to become active. Enzymatically active form is represented by putting a ‘bar’ above its notation eg C-lr. Cleavage products of complement are represented by, a (large fragment) and b(small fragment) eg: C3a, C3b (exception to this rule is C2 where large fragment is b & small one is a).

Complement constitutes about 5% of normal serum protein and is not increased as a result of immunization. Heat labile complement proteins are destroyed in 30mts at 56oC.Serum deprived of its complement activity by heating at 560 for 30 mt is said to be inactivated.
C is activated by binding with the Fc portion of Ab. C is combined with antigen. It binds with IgM, IgG1, IgG2, IgG3 antibodies (not with IgG4, IgA, IgE,IgD)

Components of complement
Complement is a complex of fractions of proteins, C1 – C9
C1 has 3 subunits : Clq, Clr,Cls serves as a recoginition unit.C2, C3,C4and C5 serves as an enzymatic activation unit which will lead to the sequential assembling of C5, C6, C7,C8,C9. C9 serves as attack unit for alteration of the cell membrane.

Complement Activation
Begins with the reaction of complement attached to the Fc portion of Ab binds to antigen. Thereafter the proteins of complement or component of complement act as a cascade, where each enzyme act as a catalyst for the next, cleaving them into dissimilar fragments. Larger fragments join the cascade and smaller fragments contribute to defence mechanisms by favoring inflammatory process. Net result of complement activation is alteration of target cell membrane that permits excess fluid to enter the cell and leads to lysis of cell. There are 2 main pathways for complement activation. Classical and alternative pathways. Classical pathway is related to adaptive immune system through binding of immune complexes to c1q. The alternative pathway is activated by C 36 to the surface of micro organism and is concerned with innate immunity. (Inflammatory cells like phagocytes, polymorph and macrophages have complement fragment receptors on their surface, so they move towards the target cell and cause lysis).
Complement can distinguish self from non self antigens by rapid binding of C3 b to non self (micro organisms or immune complexes). But the individuals own cell surface are protected from limiting C3b deposition

Classical pathway
Explained by taking the eg : of lysis of erythrocyte (E) sensitized by its antibody (A).This is an antibody directed mechanisms for complement activation. C1 is the first enzyme complex in the cascade. C1 is Ca 2+ dependent complex consisting of a single C1q molecule, two Clr and two Cls molecules.

I step :

Binding of C1 (1q) to the antigen antibody complex. clq is the recognition unit. Clq has 6 combining sites. At least 2 binding sites should be attached to Ab for effective activation. This binding takes place in the presence of Ca 2+ leads to sequential activation of Clr and Cls

11 step :

Activated Cls (Cls) is an esterase which cleave C4 to C4a (anaphylatoxin) and C4b which binds to cell membranes along with C1

111 step
C14b in the presence of Mg+ cleaves C2 into C2a, which linked into C4b and C2b is released into fluid.C4b2a has enzymatic activity and is referred to as classical pathway C3 convertase.

1V step
C3 convertase splits C3 into C3a (anaphylotoxin) and C3b which remains bound to C4b2a to form C14b2a3b and is called C5 convertase

V step:

The membrane attack phase begins with this stage. C5 convertase cleaving C5a to anaphylatoxin, released into the medium and C5b which remain with the cascade (C14b2a3b5b) C6 and C7 then join with it.C5b react with other complement components to produce a macromolecular complex(membrane attack complex) that has the ability to alter cell membrane permeability. C8 is the most active component producing maximal cell lysis.

Mechanism of cytolysis is the production of holes on the cell membrane. Host cell bear membrane protein which protect against lysis by MAC.Other than antigen antibody complexes, classical pathway can be activated by DNA, CRP, trypsin like enzyme or some retroviruses.

Alternative Pathway
Activation of C3 is achieved without the prior participation of C142.
The internal thioester bond in native C3 is susceptible to spontaneous hydrolysis by water, generating an activated form of C3. This spontaneous C3 activation is plasma is called tick over reaction and the product is named as C3i. Then C3i binds with factor B to form C3iB. This binding B Factor is cleaved by Factor D and release Ba. The remaining complex is C3iBb which act as C3 convertase. This enzyme is labile. The factor P (properdin) stabilize this enzyme which convert C3 to C3a and C3b. Further steps occur as in the classical pathway.

Lectin Pathway
Homologous with the classical pathway., but it is activated in an antibody independent fashion ie Clq is able to bind directly to certain micro organism including mycoplasma and some retroviruses in an independent process.
So in short all these pathways lead to the formation of C3 convertase.

Regulations of C activation :
By 1. inhibitors which stops the progressive complement activation.
Eg : Serum protein
Cl-esterase inhibitor

By 2. Inactivators : enzymes that destroy complement proteins.
Eg : Factor I
C4 binding protein etc.

Biological effects of complement
Major beneficial activities:
1. Promotion of killing of micro organism
2. Efficient clearing of immune complexes
3. Induction and enhancement of antibody responses

Harmful effects:
1. If activated systematically on a large scale, anaphylactic reaction occurs eg : in gram –ve septicemia
2. If activated by tissue necrosis eg : MI
3. If activated by an autoimmune response to host tissue.

Complement promote killing of micro organism by :
1. By generation of anaphylatoxins, induce chemotaxis
2. By opsonising the micro organisms to enhance phagocytosis.
3. By insertion of MAC into cell membrane of organism

Deficiency of Complement system
Deficiency commonly causes bacterial infections. Complement is of less importance in host defense against viral infection.Deficiency of MAC are associated with increased susceptibility to Neisseria meningitides

Clinical syndromes associated with complement deficiency

  • C1 inhibitor – Hereditory angio neurotic oedema
  • C2, C4 – SLE and other collagen vascular diseases
  • C3 and C3b inactivator – Severe recurrent pyogenic infections
  • C5 to C8 – Bacteremia with gram –ve diplococci ,toxoplasmosis
  • Cq – No particular disease

Complement activity of serum is measured by estimating the highest dilution of serum lysing sheep erythrocytes sensitized by antierythrocytic antibody. Estimation of individual complement components also uses hemolytic activity in a system containing excess of all complement components except the one to be measured

Biosynthesis of Complement

  • C1 – from intestinal epithelium
  • C2, C4 – Macrophages
  • C5, C8 – Spleen
  • C3, C6, C9 – Liver
  • C7 – not known

Rise in C level (particularly C4, C3, C5, C6) is seen in acute phase of inflammation

References :
Immunology by Roitt-Brostoff- Male
Basic pathology by Kumar , Cotran, Robbins
Text book of Microbiology by Jayaram Panikkar
Boyd’s text book of pathology

Antigen and antibody

Dr P Pramod BHMS,MD(Hom)
Antigen : The immune response is characterized by the production of proteins and specifically reactive lymphocytes when an animal encounters foreign macromolecule or cell. The inducing substances are called antigens-antibody generators or immunogens.

The term antigenicity implies both the ability to induce an immune response (immunogenicity) and the ability to react with products of that response.
Examples: blood group antigens A,B,D; bacterial capsular antigen; bacterial cell wall etc

Sites either on or within the antigen with which antibodies and T-cell receptors react are called epitopes. The epitopes are antigenic determinants. They are small areas in antigen having four or five amino acids that has a specific chemical structure, electrical charge and stearic configuration capable of sensitizing immunocyte and of reacting with its complimentary site on specific antibody or T-cell receptor. The epitopes are generally very small. They may have a linear or conformational arrangement. Linear means continuous in amino acid sequence. Conformational denotes spatial arrangement is close, but discontinuous in amino acid sequence. Each antigen may have multiple epitopes, each coding for different antibody. The number of such epitopes determines the valence of the antigen. New antigens can be produced by altering just the epitope. This is possible by conjugating molecules to antigen or by enzymatically removing portion of antigen.

Types of antigen

  • Autologous antigen:Antigens that are native to body do not induce immune reaction in the same body. Example: skin graft from thigh to chest of same person.
  • Syngeneic antigen:Antigen in genetically identical twins.
  • Allogeneic antigen: Antigens in genetically different members of a species. Example: graft from mother to son.
  • Xenogeneic antigen: Antigen found in different species. Example monkey kidney transplant to human being.
  • Heterophile antigen:Antigens that have one or more epitopes in common. Since antibodies identify epitopes only, antibodies against one antigen will cross-react with other antigen having identical epitope.

Syphilis screening test: Cardiolipin antigen is a lipid with which spirochaetes share epitope.So this antigen is used to test antisyphilitic antibodies – Khan test, VDRL Test
Infectious mononucleosis screening tests Ebstein Barr virus that causes infectious mononucleosis induces antibody in the host that cross react with similar epitopes present on sheep RBC membrane.
Weil Felix reaction: serum from patients with Rickettsial infection agglutinate certain strains of Proteus vulgaris antigen. This heterophile reaction is used in the diagnosis of Rocky mountain spotted fever.
Organ specific antigen: antigens seen only in certain organs of the body. Eg thyroglobulin ( thyroid), myelin basic protein ( brain).
Sequestrated antigen: they are organ specific antigens that are not normally exposed to the immune system.

But once they are available in the circulation antibodies develop against them. Eg. Puncture wound to left eye causes release of certain ocular antigens that result in sympathetic uveitis in the right eye.
Thymus dependent antigen: they require T cells to induce antibody production by B cells. They have a complex structure. Their immunologic action is active over a wide range of doses. They can induce production of different classes of antibodies. They induce good immunologic memory. These antigens require processing by macrophages. Examples: erythocytes. serum proteins etc.

Thymus independent antigen: those that can directly stimulate B cell proliferation.They are generally simple in structure. They are active only in high doses. These antigens induce production of certain antibodies (IgG3,IgM).They do not require prior processing by macrophages. They are poor in inducing immunologic memory. Examples: flagellin, pnueumococcal capsular polysaccharide.

Factors determining antigenicity
1. Immunogenicity of antigen
2. Foreignness
3. Chemical nature
4. Size of antigens
5. Biodegradability
6. Structural stability
7. Route of administration

chemical nature of antigen

  • Proteins are the strongest immunogens.
  • Lipoproteins are complex proteins seen in cell membranes. They are also strongly immunogenic.
  • Capsular polysaccharides seen in bacterial capsules.
  • Lipopolyasccharides seen in the cell wall of gram negative bacteria.
  • Glycoproteins blood group antigens A and B.
  • Nucleoprotein especially significant in systemic lupus erythematosus.

Size of antigen
The larger the size, the greater the number of epitopes and hence the antigenicity.
Larger molecules are easily phagocytosed by antigen presenting cells, thereby inducing antibody production.

Antigens with low molecular weight ( 5-10 k Da) cannot induce antibody response. But they can react with preformed antibodies. Such partial antigens are called haptens. Eg. Antibiotics, analgesics etc.
If haptens are coupled to an immunogenic carrier, the immunogenicity is amplified.
Eg penicilline if degraded in the body produce penicilloyl moiety that joins with serum albumin ( immunogenic carrier) inducing allergic response.

They are immunogenic carriers and used in vaccines.
Examples: aluminium hydroxide,aluminium potassium tartrate, aluminium phosphate,calcium phosphate.

To become an antigen it is not sufficient to be a macromolecule,but it should also be capable of being metabolised by body.Polystyrene is a large molecule but it cannot be it is non-antigenic.

The stability of molecule is also essential to induce immunogenicity.Gelatin is good protein, but it is quite unstable.So it is non-antigenic.In fact the adjuvants are stable in serum for long periods and their action lasts longer.

Immunoglobins are defined as proteins of animal origin endowed with known antibody activity and for certain other proteins related to them by chemical
structure including myeloma protein, macroglobulin, cryoglobulin etc. Antibodies are glycoproteins present in gamma globulin fraction of the serum.
The structure of antibody was studied by Rodney Porter,Gerald Edelman and co.They were awarded Nobel prize for this discovery.Rabbit antibody to egg albumin was treated with proteolytic enzyme pappain that yielded two fragments-Fc and Fab.
Antibodies are produced by modified Bcells called plasma cells.

The basic structural unit of an antibody consists of four polypeptide chains covalently linked by disulphide bonds.
The monomeric immunoglobulin is composed of two identical heavy polypeptide chains (H chain) and two identical light polypeptide chains
( L chain)
Chain H chain L chain
Mol. Weight 50-75 k Da 25 k Da
Amino acid 400 200
Types 5 ( alpha,gamma, delta, mu, epsilon) 2 (kappa, Lambda)

Each H chain and L chain has two parts, a variable portion and a constant portion. The variable portion is the amino terminal while the constant portion is the carboxyl terminal. The variable portions of heavy and light chains are close together. The lambda chain has three hypervariable areas: aminoacid sequence-30-35,50-55,95-100 in the initial 107 aminoacids which constitute the variable portion. Similarly the hypervariable areas of heavy chain is located in same three corresponding areas of heavy chain. Within the variable portion lies a hypervariable region called complementarity determining regions ( CDR ). The amino acid sequence in CDR is highly variable and hence multiple antibodies according to specificity can be produced.

Both L and H chains have peptide loops enclosed by disulphide bonds. These loops are called domains. Each L chain has two domains – one variable and one constant. H chains of alpha, delta and gamma have one variable and three constant domains. H chains of Mu and epsilon have one variable and four constant domains. The given immunoglobulin has a pair of either kappa or lambda light chains.

The junction of the domains which are at an angle to each other is highly flexible and susceptible to fragmentation by enzymes. This junction is called hinge.

Antibodies are functionally divided into two fragments – Fab and Fc fragments. Fab fragment consists of entire L chain and amino terminal of H chain. This is the antigen binding site called Paratope
Fc fragment is the carboxy terminal of heavy chain. It activates complement cascade via classical or alternate pathway. It decides the biological activity of the antibody. This portion also contains the carbohydrate moiety of the glycoprotein.
J Chain : these are the connecting proteins in a polymeric immunoglobulin. Eg J chain joins the two Ig A molecules in a secretory Ig A

Ig G

  • Heavy chain: gamma
  • Ig G monomer consisting of one pair of L chain. 75 % of total serum immunoglobulin is IgG. It is subdivided into IgG1, IgG2, IgG3, IgG4, based on the gamma chains 1,2,3,4, respectively. Most common Ig G is IgG1. It has a half life of 21 days. Molecular weight – 150000. Serum concentration of 7-19 gm/lit. It has four domains.
  • Functions : 
  • the only antibody that crosses the placenta
  • complement fixation, precipitation, neutralization of toxins
  • intracellular killing by NK cells require IgG.
  • Is a major opsonising immunoglobin


  • Heavy chain alpha.
  • Has a a half life of 6 days. There are two types of IgA – IgA1 ( alpha1) and IgA2 (Alpha 2). It has four domains. Serum concentration is 1-5 gms/lit.It is usually a dimer. 
  • Serum IgA_ It constitutes mainly of IgA1. it can be inactivated by gonococci, pneumocci, meningiococci, Haemophilus infleuenzae.
  • Secretary IgA : this is usually a dimer. It is the liner of the epithelial tract. It is seen in secretions like the saliva, tears, colostrums, bronchial, genitourinary, intestinal. The dominant class is IgA2.
  • Functions:-
  • The epithelial cells have receptors with affinity for secretory IgA.
  • Secretory IgA protects mucosal surfaces by reacting with adhesion molecules on the potential pathogens and interfering with their adherence and colonization on the epithelium. Neutrophils have receptors for IgA.


  • Heavy chain Mu. Has a half life of 5 days. Serum concentration is 0.5 – 2 gms/litre.
  • Molecular weight is 90000. it is also called millionaire molecule. It has 5 domains . there are 2 classes, IgM1, and IgM2. it is a pentamer with 5 monomeric units linked by J chain and by disulphide bonds in the Fc fragment.
  • Functions: 
  • It is the first antibody that an immunologically competent B lymphocyte can produce.
  • It is the predominant antibody in the primary immune response. The predominant antibody produced in the fetus from 20th week onwards.
  • This is 1000 times more effective than IgG in immune hemolysis.
  • It is 500- 100 times more effective than IgG in opsonisation.
  • It is 100 times more effective than IgG in bactericidal action.
  • It is 20 times more effective than IgG in bacterial agglutination.
  • Some IgM secreted by glands.
  • Monomeric IgM is an antibody receptor on the surface of B lymphocyte.


  • Heavy chain Delta. 
  • Half life 2-8 days. Serum concentration is 100 microgram /litre. It exists as a monomer. Molecular weight is 160000. it has four domains. 
  • Function:
  • Antigen receptor in B cell membrane.


  • Heavy chain epsilon
  • Serum concentration is 5 microgram /litre. It has a molecular weight of 170000. it is a monomer with 5 domains. It is produced by B cells and plasma cells in the spleen, lymphoid tissue, tonsils adenoids, respiratory tract and gastrointestinal tract. The production begins early in the fetus. It is the only heat labile antibody (56degree Celsius)
  • Functions:
  • It is seen associated with atopic diseases like, asthma, anaphylaxis. On combining with allergen, they induce histamine release from mast cells and basophils. They have affinity for attaching to membranes of basophils and mast cells. 
  • They have an important role in immunity against helminthic diseases

Multiple myeloma:
This defined as abnormal proliferation of neoplastic plasma cells resulting in the production of monoclonal antibodies associated with multifocal lytic lesions through out the skeletal system. The serum electrophoresis which normally shows a raised peak of albumin, here there is an additional peak of gammaglobulins. In 60% cases Ig G is raised while in 16% Ig A and in 14% Ig M is raised .Both heavy and light chains are increased here. The increased light chains are called Bence Jones proteins. This protein is excreted in the urine .It is soluble at room temperature ,precipitates at 60 degree C and redissolves at 80 degree C.
Waldenstrom’s macroglobulinaemia: In this condition there is increased production of Ig M class antibodies.
Cryoglobulinaemia: Here the antibodies are precipitated on cooling and redissolves on warming.
Agammaglobulinaemia:  Deficiency in the production of antibodies.

Hybridoma: It is a modern technique of large scale production of specific antibodies. The spleen cells from a mouse previously sensitized with chosen antigens is grown with mouse myeloma cell in a culture medium. The culture media like polyethylene glycol are destabilizing. So the myeloma cells fuse with the splenic cells and this is then transferred to a tissue culture medium where only hybrid myeloma cells survive. These hybridoma cells continue to produce specific antibodies.

The inborn errors of metabolism and phenyl ketonuria

Dr Anitha MA BHMS,MD(Hom)
Dr.Padiyar Homoeopathic Medical College.Kerala

Inborn errors of metabolism
In the nucleus of every cell lie DNA molecules, which are the storehouses of genetic information. DNA is made up of a double helix of two polynucleotide chains, which are bound together. Each nucleotide is composed of a sugar molecule, a nitrogenous base, and a phosphate radical. The nitrogenous bases in the DNA are the purines and the pyrimidines. Adenine and guanine are the purines and cytosine and thymine are the pyrimidines.

A part of the DNA that codes for a particular protein is called a gene. The primary action of a gene is to synthesize a protein by various combinations of 20 different aminoacids. Genetic information is stored in the DNA molecule in the form of a triplet code such that a sequence of three bases specifies the structure of the aminoacid.

An inherited mutational event can result in an alteration of the structure of a primary protein or even affect the synthesis of the particular protein. The protein, which is affected, can be an enzyme, a receptor, transport vehicle, membrane pump, or a structural element. In the absence of the normal constituent or presence of the abnormal constituent, so many metabolic processes are interfered with, resulting in the various inborn errors of metabolism.

Clinical findings associated with inborn errors of metabolism
Clinical findings are non specific and similar to infants suffering from infections. Symptoms like poor feeding, lethargy, convulsions, and vomiting may develop soon after birth. A history of clinical deterioration in a previously normal infant should raise the suspicion of an inborn error of metabolism. Most of the affected infants loose their lives within the first two years of life.

  • Neurologic abnormalities
  • Metabolic acidosis with ketosis
  • Pernicious vomiting
  • Liver disease
  • Miscellaneous

Miscellaneous : clinical

  • Dislocated lenses
  • Renal stones
  • Thrombosis
  • Deafness
  • Microcephaly
  • Cataracts
  • Hematuria
  • Self mutilation
  • Abnormal urine color / odor
  • Coarse facies
  • Persistent eczema
  • Abnormal hair

Laboratory findings

  • Osteoporosis
  • Rickets
  • Hypoglycemia
  • Unexplained jaundice
  • Bony x-ray changes
  • Increased anion gap
  • Ketoacidosis
  • Abnormal liver function

Clinical approach to a newborn infant with a suspected metabolic disorder
The consequences of important errors in metabolism include:-
1. Absence of an end product Eg. albinism
2. Accumulation of intermediate compounds Eg.The storage diseases
3. Increased use of a minor pathway with detrimental consequences Eg. Phenyl ketonuria
4. Loss of feed back mechanism Eg. Lesch- Nyhan syndrome

I. The absence of an end product – eg. Albinism
In this condition the person lacks the enzyme TYROSINASE, which is involved in converting L-Tyrosine into DihydrOxy PhenylAlanine ( DOPA). Dopa is subsequently converted into quinone and then to melanin. The deficiency of melanin manifests as a hypomelanotic syndrome, which can be classified into the ocular form and the oculocutaneous form, the former is a rare condition and it affects only the eyes, where as the latter is the more common variety which affects both the eyes and the skin.

II. Accumulation of intermediate compounds
the storage diseases
The lysosomes are the normal constituents of the cell. These contain hydrolytic enzymes, which help the hydrolytic division of the various metabolites entering the cell. In the presence of these enzymes the metabolite is converted into various components by utilizing the hydrogen radical and the hydroxyl radical obtained by splitting a water molecule. The hydrogen radical attaches to one end of the molecule and the hydroxyl to the other end of the molecule. This highly unstable compound is split into its constituents like water, carbon dioxide etc.
In the absence of these specific enzymes, or in presence of abnormal, nonfunctioning enzymes, the corresponding metabolite fails to be converted into its components and hence gets collected in the cell interior. Lysosomal storage diseases result from the abnormal accumulation of cytoplasmic materials. Depending upon the organ, which is involved in the metabolic process, the clinical features are produced.

This defect can be because of multiple causes including,

  • Lack of synthesis of a particular enzyme.
  • Synthesis of abnormal enzyme
  • Inability to transport the enzyme to the lysosome
  • Synthesis of enzymes, which are inactive when inside the lysosomes
  • Absence or inactivity of activator enzymes, which activate the precursor of the enzyme.

There are four different types of lysosomal storage diseases:

  • Sphingolipidoses
  • Mucopolysaccharidoses
  • Mucolipidoses
  • Glycogen storage diseases

III. Loss of feed back mechanism   Eg. Lesch-nyhann syndrome
Lesch- Nyhan syndrome is a rare X-linked recessive inborn error of metabolism which is due to the deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase. The syndrome is characterized by gout and severe overproduction of uric acid, associated with choreoathetosis, spasticity, variable degree of mental deficiency and compulsive self mutilation. The prenatal detection can be undertaken using amniotic fluid cells.

IV. Increased use of a minor pathway with detrimental consequences eg. Phenyl ketonuria
All defects causing persistent hyperphenylalanemia are inherited as autosomal recessives. The importance of the study on Phenyl ketonuria lies in the fact that prompt recognition of the condition in the first days of life helps the infant to be grown under strict dietary regulations so that one can prevent early death, or even worse, survival with mental retardation. Another inborn error of metabolism that has a similar prognosis is Galactosemia.

Phenyl alanine is an essential aminoacid. Dietary phenylalanine, which is not used for protein synthesis, is normally degraded by the tyrosine pathway. Deficiency of the enzyme, phenyl alanine hydroxylase, or of its cofactor tetrahydrobiopterin, causes accumulation of phenylalanine in the body fluids. Several clinically and biochemically distinct forms of phenyl alanemia exist.
Classic phenyl ketonuria
PKU due to deficiency of cofactor tetrahydrobiopterin
Persistent hyperphenylalanemia
Transient phenylalanemia

Classic phenyl ketonuria
This condition is characterized by complete or near complete absence of the enzyme phenylalanine hydroxylase. Hence excess phenylalanine is converted into phenyl pyruvic acid or decarboxylated to phenyl ethylamine. These products along with their byproducts and the excess phenylalanine disrupt the normal metabolism and cause brain damage.

Clinical features

  • The affected infant is normal at birth.
  • Mental retardation may develop gradually and need not be detected soon after birth (Untreated infants loose about 50 points in IQ by the end of the first year)
  • Vomiting some times misdiagnosed, as pyloric stenosis may be an early symptom.
  • Older children become hyperactive with purposeless movements, rhythmic movements and athetosis.
  • Clinical findings
  • Infants are blonder than their siblings; they have fair skin and blue eyes.
  • Some have seborrheic or eczemoid rash, which usually disappears when the child becomes older.
  • Children have an unusual odor of phenyl acetic acid, described as musty, mousy or wolf like.
  • Infants are hypotonic, with hyperactive deep tendon reflexes.
  • About one fourth have seizures, and EEG changes.
  • Microcephaly with widely spaced teeth, enamel hypoplasia and growth retardation.


  • Plasma levels of phenyl alanine above 20 mg / dl
  • Normal tyrosine level
  • Increased urinary levels of metabolites of phenylalanine like phenyl pyruvic acid and o-hydroxy phenyl acetic acids.
  • Inability to tolerate an oral challenge of phenylalanine.
  • Normal concentration of cofactor tetrahydrobiopterin.


  • Diet low in phenylalanine
  • The optimum serum level of phenylalanine should be maintained at 2-9 mg /dl
  • Reduced amount of phenylalanine in the blood may cause features like lethargy, anorexia, anemia, rashes, diarrhea, and even death.
  • Pregnant mothers with PKU have a higher risk of spontaneous abortion. Infants born to such mothers are generally mentally retarded and may have microcephaly and/or congenital heart anomaly. In affected mothers care should be taken to maintain the blood value of phenyl alanine at 10 mg/dl.
  • Phenyl ketonuria due to deficiency of cofactor tetrahydrobiopterin -BH4
  • In about 2% of cases presenting with phenylalanemia, the defect lies in one of the enzymes necessary for the production of BH4. There is neurological deterioration in the infant.

Persistent hyperphenylalanemia
Occasionally identified are children whose blood levels of phenylalanine are only slightly elevated. These concentrations are insufficient to result in the excretion of phenyl pyruvic acid. The infants are asymptomatic and may develop normally without special dietary treatment.
Transient hyperphenylalanemia –Moderately elevated levels of phenylalanine occur in transient hyperphenylalanemia

Complement system- active transport

Dr Smitha Madhavan   BHMS,MD(Hom)

Active transport
Definition : Movement of solute molecules against a concentration gradient by an energy dependent mechanism.

Two basic forms:
1. Primary active transport
2. Secondary active transport

Substances that are usually actively transported are sodium , potassium, calcium, urate ions , hydrogen ions , chloride ions & most of the aminoacids. Carrier proteins have a major role in active transport .

Primary active transport

  • Here energy is produced by direct hydrolysis of ATP . e.g. ; Sodium- potassium pump
  • Calcium pump
  • Hydrogen ion transport
  • Sodium – potassium pump

Function :
1. It is the basis of nerve function for transmitting nerve impulses.
2. Keeping the interior of cell negatively charged & exteroir positively charged.
3. Control of the volume of the cell : Proteins & other organic compounds present in the interior of the cell is negatively charged . So they have a tendency to attract positively charged particles from outside along with water molecules. Once the cell swells , it activate the sodium – potassium pump & which help in maintaining the volume of cell intact .

Through the sodium – potassium pump sodium ion is transported to the exterior of the cell & potassium ions to the interior with the help of carrier protein . This carrier protein has three sodium ion binding sites , two potassium ion binding sites & ATPase activity which help in splitting up of ATP to ADP & inorganic phosphate , inturn release energy .

Calcium pump
Calcium is transported from ICF to ECF .
Hydrogen ion transport
Occurs in,
1. Gastric glands of the stomach especially with parietal cells & is the basis of HCl secretion in stomach
2. In late distal tubule & cortical collecting tubules of the kidney by excreting H+ ion in urine & to maintain the appropriate H+ concentration in blood .

Applied physiology
1. Na/ K ATPase is inhibited by cardiac glycoside , digitalis which causes Na+ accumulation inside the cell , inturn causes Ca2+ accumulation in the myocardial cells & this increases myocardial contractility So digitalis is used in a failing heart.
2. Refrigeration of blood at 40C suppresses Na/ K ATPase activity . At 450C – denaturation of enzyme , Optimum activity is at normal body temperature

Secondary active transport

Energy is produced by movement of one solute down concentration gradient is used for the transport of another solute against concentration gradient. ( energy is produced by maintaining an ionic concentratoin gradient by primary active transport )

It is of two types
1. Co- transport
2. Counter transport

Co – transport
e.g.; Glucose & aminoacid co – transport with Na.
Concentration gradient produced by primary active transport represents a store house of energy . There is always a tendency to move Na+ down the concentration gradient to the cell .Under appropriate condition this energy pull certain substance along with Na ions with the help of carrier protein to the interior of cell .

Counter transport
Substance to be transported is inside the membrane . Na+ binds to carrier protein at its exterior surface & the other substance to the interior of carrier protein . Confirmational change occure in the carrier protein & Na+ is transported to the interior of the cell & other substance is transported to the exterior .
e.g.; Na+ / Ca2+ counter transport
Na+ / H+ counter transport

Applied physiology
1. Heriditory disorders associated with aminoacid & glucose co transport
2. Glucose galactose malabsorption by intestine
3. Malabsorption of neutral aminoacids ( Hartnup’s disease )
4. Cystinuria : Defective reabsorption of filtered cystine , ornithine, arginine & lysine. High concentration of cystine in urine leads to cystine stone formation.
5. Diabetic aminoaciduria : Defect in reabsorption of lysine, arginine , ornithine in proximal renal tubule & jejunal mucosa. Autosomal recessive disease. Manifested as protein intolerance .
6. Lysinuria : Defect in lysine transport in proximal renal tubule – seizures , physical & mental retardation , Autosomal recessive.
7. Hartnup’s disease: Malabsorption of neutral aminoacids in proximal renal tubule & jejunal mucosa . Constant neutral aminoaciduria. Intermittent symptoms of pellagra.
8. Tryptophan malabsorption: Autosomal recessive. Defect in absorption of tryptophan in jejunal mucosa due to mutation of tryptophan transport protein. Clinical features are indol urea, hypercalcemia and nephrocalcinosis.
9. Methionine malabsorption : Autosomal recessive , white hair . mental retardation , convulsions, oedema
10. Histidinuria
11. Renal glycosuria : Autosomal recessive , Defect in glucose transport in proximal renal tubule . There is glycosuria with normal blood glucose.
12. Bartter’s syndrome & Gitelman’s syndrome : Defect in sodium & chloride ion co transport system , autosomal recessive.Associated with hypokalemic metabolic alkalosis, hypermagnesuria, hypomagnesemia& low calcium excretion.
13. Pendred syndrome : Defect in iodine & chloride ion co transport system . Goitre with deafness, Autosomal recessive.
14. Wilson;s disease : Defect in copper transporting ATPase . Liver and kidney is affected . Motor and psychiatric disturbances . Hepatolenticular degeneration .
15. Congenital chloridorrhea: autosomal recessive. Defect in chloride absorption due to mutation of chloride-hydrogen uptake pump in the ileal and colonic mucosa. Clinical features are watery diarrhoea, elevated faecal chloride, metabolic alkalosis and hyperaldosteronism.
16. Menke’s disease: X-linked recessive. Defect in copper transport due to mutation of copper transporting ATPase. Clinical features mental retardation, kinky hair( pili torti), typical facies and arterial tortuosity.

Text book of medical physiology – Guyton
Physiology – Ganong
Harrison’ s principle of internal medicine
Best and Taylor’s physiological basis of Medical practice


Intra cranial space occupying lesions

brainDr Bindu K   BHMS,MD(HOM)
These are lesions which expand in volume to displace normal neural structures & lead to increase in intra – cranial pressure.


Symptoms are produced due to,
1. Irritation & destruction of brain tissue causing neurological phenomena,eg. epilepsy, paralysis.

2. Raised intra cranial pressure:- The rate of increase of tension depend on the nature of the lesion and its location. Posterior fossa lesions lead to more rapid rise in tension than supratentorial lesions.

3. False localizing signs :-

  • Neurological phenomena arising from the secondary effects of lesion like herniation of neural tissue under the falx-cerebri or downward herniation through tentorium cerebelli or foramen magnum, pressure effects on other parts of brain develop.
  • Countre – coup effect:- This is pressure effect caused on the side opposite to the side of lesion when a space occupying lesion expands. The midline structures such as brainstem may be pushed towards the opposite free margin of tentorium cerebelli to give rise to compression of normal side also.
  • In addition to this , different lesions may produce symptoms specific to their nature like fever in case of brain abscess, signs of meningeal irritation in subarachnoid haemorrhage

Classification of intra cranial space occupying lesions :-

  • I. Congenital :- Dermoid, Epidermoid, Teratoma.
  • II. Traumatic :- Subdural & Extradural haematoma
  • III. Inflammatory :- Abscess, Tuberculoma, Syphilitic gumma,fungal Granulomas.
  • IV. Parasitic :- Cysticercosis, Hydratid cyst, Amebic abscess, Schistosoma japonicum.
  • V. Neoplasms 

a) Tumors arising from neural structures: Gliomas – astrocytoma, ependymoma, oligodendroglioma, germinoma, medulloblastoma.
b) Tumors arising from appendages: Meningioma, schwannoma, chondroma, osteoma.
c) Pituitary lesions : Pituitary adenoma, Craniopharyngioma.
d) Vascular lesions : Angioma, Hemangioblastoma, Papilloma of choroid plexus.
e) Secondary neoplasms.

Clinical features :-
1. Persistent headache not due to any other detectable cause and unresponsive to medication. This may be due to focal irritation, displacement of pain sensitive structures or due to increased intra- cranial tension. If due to increased intra- cranial tension headache develop rapidly over several minutes persist for 20-40 minutes and subside quickly. May awaken the patient from sound sleep 60-70 mts after retiring and also precipitated by coughing, sneezing, vomiting etc.
2. Vomiting & visual loss :- projectile vomiting unassociated with nausea.
3. Papilledema in increased intra- cranial tension.
4. Recent onset behaviour changes.
5. Late onset seizures :- Any type of seizure occuring for the first time after the age of 15 years should suggest the possibility of intra cranial space occupying lesions. It is due to disruption of cortical circuits by tumours that invade or compress cerebral cortex.
6. Sudden onset of neurological deficits like dementia, personality changes, gait disorders etc.

Intracranial haematomas
I. Extra dural haematomas :-
Collection of blood between the dura & the skull due to injury to the middle meningeal vein, middle meningeal artery, diploic vein, dural venous sinuses or small vessels lying between dura and skull. Common site is temporal fossa.

Pathogenesis :-
Initial collection of blood in the extradural space causes stripping of the dura from bone. Symptoms are produced when symptoms exceed 25 ml in volume. Extent and location of haematomas are determined by the ease of stripping of the dura, site of injury, its severity, and presence of depressed fractures of the skull.

Clinical features :-
1. 1 – 2% persons suffering from head injury develop extra dural haematoma.
2. Uncommon in children below 3 yrs and in old age – adherance of dura
To the skull prevents its easy stripping.
3. Progressive deterioration of level of consciousness :- there may be a period of immediate loss of consciousness, after that a period of apparent normalcy with clear consciousness followed by deterioration of mental state.
4. Pupillary changes :- called Hutchinson’s pupillary reaction – pupil on the side of lesion constricts initially then it dilates and as intra cranial tension increases the opposite pupil also dilates.

Investigation :-

  • CT scan 
  • MRI
  • Cerebral angiography.

II. Subdural haematomas :-
Collection of blood between the dura and the arachnoid. Usually follow injuries which may be apparently trivial or even unnoticed. Common causes are bleeding from superficial veins or venous sinuses. Anticoagulant treatment predispose to intracranial bleeding and subdural haematoma. Usual sites are frontal, anterior temporal,& parietal.

Pathology :-
Haematoma consists of fluid blood covered on inner and outer aspects by layers of fibrin. Blood is defibrinated due to the constant pulsation of the brain. High protein content of fluid makes it hyperosmotic. So it absorbs fluid from the surrounding and enlarges leading to increase in intra cranial tension.

Clinical features :– Manifestation may be acute or chronic in nature.
Acute : Clinical features are similar to extra dural hematoma.
Chronic : Dementia, altered behaviour, psychiatric manifestations or
focal neurological deficits may develop.
In middle aged headache, contralateral hemiplegia, papilledema and in children vomiting, restlessness. Irritability, refusal to feed, anaemia, seizures and failure to thrive are common presenting symptoms.

Investigation :-
CT scan
Cerebral angiography.

Neoplasms of brain
About 50 % of intracranial tumors are primary neoplasms and the rest secondary. Out of this 50 – 60 % of primary brain tumors are gliomas, 25% – meningiomas, 10% – schwannoma and the remainder others.

1. Exposure to ionizing radiations is the only well documented enviornmental risk factor.
2. A number of heriditary factors are associated with an increased risk of brain tumours, eg. Neurofibromatosis type – I and type – II, Multiple endocrine neoplasia type –I.
3. Genes also contribute to the development of brain tumours and other malignancies. There are two classes of genes namely, tumour suppressor genes and proto oncogenes. There is over – expression of proto oncogenes in brain tumours.
Clinical course of brain tumours :-

There are four stages of development of tumour.

  • Stage I : Initial period of silent growth.
  • Stage II : Stage of focal syndromes like epilepsy.
  • Stage III : Increased intracranial tension.
  • Stage IV : Brain displacement and false localizing signs.

Primary neoplasmas of brain :
I. Astrocytomas :

Derived from astrocytes. Common sites are cerebrum, cerebellum, thalamus, pons and optic chiasma. Slow growing tumour. Most commonly used grading system is WHO four tired grading system.

WHO grading,

  • Grade I – Least malignant with excellent prognosis after surgical excision, eg. pilocytic astrocytoma.
  • Grade II – Astroblastoma
  • Grade III – Anaplastic astrocytoma
  • Grade IV – Glioblastoma multiforme – clinically aggressive

Astrocytomas occur in three forms namely, diffuse or infiltrating, solid and cystic.

Prognosis :-
Poor prognosis in age over 65 years, poor functional status in grade III and grade IV astrocytomas.
Low grade astrocytoma :- usually in children, spindle shaped cell (pilocytic astrocytoma), occurs from cerebellum, well demarcated, cystic. Complete surgical excision usually produces long term survival.
High grade astrocytoma :- seen in adults, usually supra – tentorial, no clearly defined margins, infiltration to white matter and metastasis to spine through CSF called drop metastasis occurs. Usually fatal and total surgical excision is not possible.
Gliomatosis cerebri :-Rare form with diffuse infiltration of the brain by malignant astrocytes without a focal enhancing mass.
Treatment :-whole brain radiation therapy in selected patients with chemotherapy.

II. Oligodendrogliomas :-
Slow growing tumour compared to astrocytoma. They contain mixture of cells with astrocytic and oligodendroglial features called mixed glioma. Usually supratentorial. 50% of patients with 5 year survival.
25– 34% with 10 year survival. Less infiltrative and complete surgical excision possible.

III. Ependymoma :-
Arise from spinal cord especially from lumbo-sacral region in adults and from ventricles especially fourthventricle in children.
Histologically myxopapillary that is, papillary arrangement of cells and mucin production. Usually relatively demarcated from adjucent neural tissue. Metastasis through CSF occurs.
Gross total excision provides 5 year disease free survival in 80% cases.

IV. Germinoma :-
A variety of germ cell tumor arising in midline structures.Common site within or adjacent to 3rd ventricle. Due to their location causes features of hypothalamic dysfunction like diabetes incipedus, visual field defects, disturbances of memory and hydrocephalus.
Radiosensitive and chemosensitive. 5 year survival in 80% patients.

V. Medulloblastoma :-
Arise from neural precurssor cells. The most frequent malignancy of children. Rapidly growing tumours affecting vermis of the cerebellum and giving rise to wide spread metastasis.

VI. Meningioma :-
Arise from arachnoid cells particularly seen in sites having arachnoid granulations. Those are usually benign and attached to dura. More common in women. Invades skull rarely invades brain.
Common sites are along sagital sinus, c-p angle and along the dorsum of spinal cord.
Treatment : Surgical resection and post – operartive radiation.

VII. Schwannoma :-
Arise from Schwann cells of nerve roots. Commonly from 8th cranial nerve and less commonly 5th cranial nerve is affected. It can arise from any cranial nerve except optic and olfactory (myelinated by oligodendroglia). Neurofibromatosis type – II predisposes to vestibular schwannoma. Neurofibromatosis type – I predisposes to schwannoma of spinal nerve roots.
Clinical features are progressive unilateral hearing loss, tinitis, vertigo.
Treatment : Surgical excision.

VIII. Craniopharyngioma :-
Arise from remnants of the pituitary stalk called Rathke’s pouch
(mesodermal structures from which anterior pituitary gland is derived). Cystic supracellar tumour and in adults usually calcified.
Clinical features are growth failure in children, endocrinal disturbances due to pressure on hypothalamus like diabetes incipedus, somnolence, obesity, hyperphagia and visual loss.

Metastatic tumors of brain :-
Common route is through haematogenous.Primary site is lung in most of the cases. Usually from carcinoma breast metastasis occurs to cerebellum and posterior pituitary gland. Others are GIT malignancies, melanoma, thyroid cancer, Hodgkin’s lymphoma. In brain the usual site of metastasis is the grey matter – white matter junction and border zone between middle cerebral and posterior cerebral artery distribution. Usually incurable. Palliative therapy and radiotherapy are the treatment of choice.

Investigations :-

In primary brain tumour no increase in ESR and tumor specific antigen.
In metastatic tumours associated with systemic signs of malignancy.
Lumbar puncture – Should not be performed in patients with mass lesion it may precipitatebrain herniation.
CSF : increase opening pressure, elevated protein level, mild lymphocytic pleocytosis and rarely contains malignant cells.
EEG : to distinguish epileptic seizures produced by focal lesions and idiopathic epilepsy.

Hypersensitivity – applied aspects

When adaptive immune response occurs in an exaggerated or inappropriate form, the term hypersensitivity is applied. Hypersensitivity reactions are the result of normally beneficial immune responses acting inappropriately and sometimes cause inflammatory reactions and tissue damage.
Many antigens can provoke hypersensitivity. The causes of hypersensitivity reactions vary from one individual to the next. Hypersensitivity is not manifested on the first contact with the antigen but appears on subsequent contact.

Coombs & Gell classified four types of Hypersensitivity i.e., Types I,II,III,&IV., But in practice these types do not necessarily occur in isolation. The first three are antibody mediated; T cells & macrophages mediate the fourth.

–Anaphylactic type
Prototype disorder – Anaphylaxis, some forms of bronchial asthma, hay fever, eczema.
Immune mechanism – Formation of Ig E ( Cytotrophic antibody) leads to release of vaso active amines and other mediators from basophils and mast cells followed by the recruitment of other inflammatory cells.

– Cytotoxic type
Prototype disorder- Autoimmune haemolytic anaemia, Erythroblastosis foetalis, Good Pasteur’s syndrome, Pemphigus vulgaris.
Immune mechanism – Formation of Ig G , Ig M, which binds to the antigen on target cell surfaces, leading to phagocytosis of target cells or lysis of target cells by C 8 , C 9 fraction of the activated compliment.

I – Immune complex disease
Prototype disorder – Arthus reaction, Serum sickness, SLE, Certain forms of acute glomerulonephrites.
Immune mechanism – Antigen –antibody complexes lead to activation of compliment. Attracted neutrophils results in release of lysosomal enzymes & other toxic substances.

– Cell mediated ( delayed) H
Prototype disorder – Tuberculosis, Contact dermatitis, Transplant rejection.
Immune mechanism – Sensitised T lymphocytes produce release of lymphokines and T Cell mediated cyto toxicity.

Type I hypersensitivity is characterized by an allergic reaction that occurs immediately following contact with the antigen, referred to as the allergen.
Atopy is the umbrella term covering asthma, eczema, hay fever, & food allergy.
Coca & Cooke in 1923, described atopy as the clinical presentation of type I hypersensitivity, which include asthma, eczema, urticaria,& food allergy. These usually occur in subjects with a family history of these or similar conditions, & who also show immediate wheal & flare skin reactions to common environmental allergens.

Mechanism:- The initial contact of an allergen with the mucosa is followed by a complex series of events, leading to the production of Ig E. The IgE response is a local event occurring at the site of the allergen’s entry into the body, i.e., at the mucosal surface or the local lymph nodes. Ig E production by the B Cells depends upon allergen presentation by the antigen presenting cells ( A P Cs), & cooperation between the B cells & the TH2 cells. Locally produced IgE first sensitizes local mast cells. Spill over IgE then enters the circulation& binds to specific receptors on both circulating basophils and tissue fixed mast cells throughout the body.

Another important characteristic of IgE is its ability to bind the mast cells & basophils with high affinity through its Fc portion. Thus although the serum half life of free IgE is only a few days, mast cells may remain sensitized by IgE for many months due to the high affinity of binding to the IgE receptor, which protect IgE from destruction by serum proteases

Clinical manifestations:-
A type I reaction may occur as a systemic disorder or as a local reaction. Often the route of antigen exposure determines this. Systemic (parenteral) administration of protein antigens like antisera and drugs like penicillin results in systemic anaphylaxis. Within minutes after re exposure, itching, hives, and skin erythema appear, followed thereafter by striking respiratory difficulty, resulting presumably from the constriction of respiratory bronchioles. Thus the principal organ affected is the lung, more specifically the smooth musculature of the pulmonary blood vessels and the respiratory passages. Pulmonary obstruction is accentuated by hypersecretion of mucus. Laryngeal oedema may cause obstruction of the upper airway. In addition the musculature of the entire gastro intestinal tract may be affected, with resulting diarrhoea, vomiting and abdominal cramps. The patient may go into shock and die within minutes.
Local reactions:- Generally occur on the skin or mucosal surfaces, when these are sites of antigenic exposure. In the skin they may produce urticaria (hives). The common forms of food allergy, hay fever, and certain forms of asthma are examples of localized anaphylactic reactions.

Ig G and Ig M antibodies binding to specific cells or tissues mediate the type II hypersensitivity reactions. The damage caused is thus restricted to the specific cells or tissues bearing the antigens. In general, those antibodies which are directed against the cell surface antigens are usually pathogenetic while those against internal antigens are not so.

:-In type II hypersensitivity, antibody directed against cell surface or tissue antigens interacts with complement and a variety of effector cells to bring about damage to the target cells.
Once the antibody has attached itself to the surface of the cell or tissue, it can bind and activate compliment component C1. The consequence of this activation are as follows:-
1. Compliment fragments ( C3a and C5a ) generated by activation of compliment attract macrophages and polymorphs to the site, and also stimulate mast cells and basophils to produce molecules that attract and activate other effector cells.
2. The classical compliment pathway and activation loop leads to the deposition of C3b, C3bi, and C3d on the target cell membrane.
3. The classical compliment pathway and lytic pathway result in the production of C5b-9 membrane attack complex and insertion of the complex into the target cell membrane.

Effector cells, in this case the macrophages, neutrophils, eosinophils, and killer cells ( K cells), bind either to the complexed antibody, via their Fc receptors, or to the membrane – bound C3b, C3bi, C3d via their C3 receptors. Antibodies binding to Fc receptors stimulate phagocytes to produce more leucotrienes and prostaglandins, which are molecules involved in the inflammatory response. Chemokines and chemotactic molecules including C5a, leucotrine B4 ( LTB4) and fibrin peptides may also activate incoming cells. The effector cells firmly bound to the target cells and fully activated, can cause considerable damage.

Examples for type II hypersensitivity reaction:-

  • Reaction in response to erythrocytes-
  • Incompatible blood transfusion where the recipient becomes sensitized to the antigens on the surface of the donors erythrocytes.
  • Haemolytic disease of the newborn where the pregnant woman has become sensitized to the fetal erythrocytes.
  • Reaction to platelets –Can cause thrombocytopenia
  • Reactions to neutrophils and lymphocytes are associated with systemic lupus erythematosus.
  • Reactions against tissue antigens-
  • A number of autoimmune conditions occur in which antibodies to tissue antigens cause immunopathological damage by activation of type II hypersensitivity mechanisms. Eg. Good Pasteurs Syndrome, Pemphigus and Myesthenia gravis.

Good Pasteur’s Syndrome:-
A number of patients with nephritis are found to have antibodies to a glycoprotein of the glomerular basement membrane. The antibody is usually IgG and in atleast 50% of patients it appears to fix the compliment. The condition usually results in severe necrosis of the glomerulus with fibrin deposition.The assosciation of this type of nephritis with lung haemorrhage was originally noticed by Good Pasture, hence the name.

Pemphigus vulgaris is a serious blistering disease of the skin and mucus membranes. Patients have autoantibodies against desmoglobin-3 a component of desmosomes, which form junctions between epidermal cells. The antibodies disrupt cellular adhesion leading to breakdown of the epidermis.

Myesthenia Gravis:-

A condition in which there is extreme muscular weakness, is associated with antibodies to the acetyl choline receptors present on the surface of muscle membranes.


Immune complexes are formed every time the antibody meets the antigen, and generally they are removed effectively by the mononuclear phagocyte system, but occasionally they persist and eventually deposit in a range of tissues and organs. The compliment and effector cell mediated damage that follows is known as the type iii hypersensitivity reaction, or immune complex disease.


Diseases resulting from immune complex formation can be divided into three groups :-
1. Those due to persistent infection.
2. Those due autoimmune disease.
3. Those caused by inhalation of antigenic material.

Persistent infection
– The combined effects of low-grade persistent infection and a weak antibody response lead to chronic immune complex formation, and eventual deposition of complexes in the tissues. Diseases with this etiology include leprosy, malaria, dengue hemorrhagic fever, viral hepatitis and staphylococcal infective endocarditis.

Autoimmune diseases – Immune complex disease is a frequent complication of autoimmune disease, where the continued production of autoantibody to a self-antigen leads to a prolonged immune complex formation. As the number of complexes in the blood increases, the systems that are responsible for the removal of complexes become overloaded, and the complexes are deposited in the tissues. Diseases with this aetiology include rheumatoid arthritis, systemic lupus erythematosis and polymyositis.

Inhalation of antigenic material
– Immune complexes may be formed at body surfaces following exposure to extrinsic antigens. Such reactions are seen in the lungs following repeated inhalation of antigenic materials from moulds, plants or animals. This is exemplified in farmer’s lung and pigeon fancier’s lung, where there are circulating antibodies against actinomycetic fungi found in mouldy hay or to pigeon antigens. Both diseases are forms of extrinsic allergic alveolitis, and only occur after repeated exposure to the antigens.


1. Immune complexes are capable of triggering a wide variety of inflammatory processes. They interact with the compliment system to generate C3a and C5a ( anaphylatoxins ). These compliment fragments stimulate the release of vasoactive amines, (including histamine and 5- hydroxy tryptamine) and chemotactic factors from mast cells and basophils.
2. Macrophages are stimulated to release cytokines.
3. Complexes interact directly with basophils and platelets to induce
4. the release of vasoactive amines.
5. The vaso active amines released by basophils, platelets and mast cells cause endothelial cell retraction and thus increase vascular permeability, allowing the deposition of immune complexes on the blood vessel wall.


There are two patterns of immune complex mediated injury. In the first type, the complexes are deposited in various tissues of the body, thus causing a systematic pattern of injury. In the other, the injury is localized to the site of formation, within a tissue or organ, of the complexes.

Serum sickness type:– ( systemic immune complex disease) :- Induced by injections of foreign antigens, mimics the effect of a persistent infection. Here circulating immune complexes deposit in the blood vessel wall and tissues, leading to increased vascular permeability and thus to inflammatory diseases such as glomerulonephritis and arthritis.

Local immune complex disease (Arthus reaction) :- The arthus reaction may be defined as a localized area of tissue necrosis resulting from acute immune complex vasculitis. The reaction can be produced experimentally by infecting an antigen into the skin of a previously immunized animal. Antibodies against the antigen are therefore already present in the circulation. Because of the large excess of antibodies immune complexes are formed, these are precipitated at the site of injection, especially within vessel walls, where the injected antigen is immediately bound to the circulating antibodies. Intrapulmonary Arthus type reactions seem to be responsible for a number of diseases in humans, including farmer’s lung.

Type IV hypersensitivity is mediated by Tcells rather than by antibodies. Two types of reactions mediated by different T cells subsets are involved in type IV hypersensitivity
1. Delayed type hypersensitivity initiated by CD 4 T cells
2. Cellular cytotoxicity, mediated by CD 8 + T cells
In both cases, the reaction is initiated by exposure of sensitized T cells to specific antigenic peptides bound to self-MHC molecules, but the subsequent events are different. In delayed H T4 1 type CD4+ T Cells secrete cytokines, leading to recruitment of other cells, especially macrophages, which are the major effector cells. In cell mediated cytotoxicity, on the other hand, cytotoxic CD8+ T cells themselves assume the effector function.

Variants of type IV hypersensitivity reactions
1. Contact H
2. Tuberculin type H .Both occur within 72 hours of antigen challenge
3. Granulomatous H
Develop over a period of 21-28 days. The granulomas are formed by the aggregation and proliferation of macrophages and may persist for weeks. In terms of its clinical consequences, this is by far the most serious type of type IV hypersensitivity response.

Contact H : This is characterized by an eczematous reaction at the point of contact with an allergen. It is often seen following contact with agents such as nickel, chromate, rubber accelerators, penta deca catechol ( found in poison ivy). Langerhans cells and keratinocytes have key roles in contact hypersensitivity. The Langerhans cells are the principal antigen presenting cells. A contact hypersensitivity reaction has two stages, i.e., a sensitization phase and an elicitation phase.
Sensitization takes 10 – 14 days in humans. Once the hapten is absorbed, it combines with a protein and is internalized by epidermal Langerhans cells which leave the epidermis and migrate as veiled cells, afferent lymphatics, to the paracortical areas of regional lymphnodes. Here they present these cells to CD4+ lymphocytes, producing a population of memory CD4+ T cells.
Elicitation phase: Degranulation and cytokine release by mast cells follow soon after contact with an allergen. The earliest histological change, seen after 4-8 hours is the appearance of mononuclear cells around adnexae and blood vessels, with subsequent epidermal infiltration. Macrophages invade the dermis and epidermis by 48 hours. The number of cells infiltrating the epidermis and the dermis reaches the peak in 48-72 hours. Most infiltrating lymphocytes are CD4+ with a few CD8+.

Tuberculin type H : This type of hypersensitivity was originally described by Koch. The tuberculin skin test is an example of the recall response to soluble antigen previously encountered during an infection. Following an intradermal tuberculin challenge in a sensitized individual, antigen specific T cells are activated to secrete cytokines that mediate the hypersensitivity reaction. Macrophages are the main APCs in the tuberculin hypersensitivity reaction. The tuberculin lesion normally resolves within 5-7 days, but if there is persistence of antigen in the tissues, it may develop into a granulomatous reaction.

Granulomatous Hypersensitivity: This is clinically the most important form of type IV hypersensitivity and causes many of the pathological effects in diseases that involve T cell mediated immunity. It usually results from the persistence within macrophages or other particles that the cell is unable to destroy. On occasion it may also be caused by persistent immune complexes, for eg. In allergic alveolitis. Epitheloid cells and giant cells are typical of granulomatous H

Epitheloid cells: These cells are large and flattened with increased endoplasmic rerticulam. They are derived from activated macrophages under the chronic stimulation of cytokines. They continue to secrete TNF and thus potentiate continuing inflammation.

Giant cells : Epitheloid cells may fuse together to form multinucleated giant cells, sometimes referred to as Langerhans giant cells. They have central nuclei but not at the center. There is little endoplasmic retinaculam and the mitochondria and lysosomes appear to be undergoing degeneration.

Granuloma: An immunological granuloma typically has a core of epitheloid cells and macrophages, sometimes with giant cells. In some diseases such as tuberculosis, this central area may have a zone of necrosis, with complete destruction of all the cellular architecture. A cuff of lymphocytes surrounds the macrophage or epitheloid core, and there may also be considerable fibrosis caused by proliferation of fibroblasts and increased collagen synthesis.
Eg . Mitsuda reaction to M. leprae antigens or the Kveim test, where the patients suffering from sarcoidosis react to (unknown) splenic antigens derived from other sarcoid patients.

Immunology – Roitt- Brostoff-Male
Basic pathology by Kumar , Cotran, Robbins
Text book of Microbiology by Jayaram Panikkar
Boyd’s text book of pathology

Transport Across the plasma membrane

Dr Sreekumar A

Transport across the plasma membrane is essential to the life of a cell.
Certain substances must move into the cell to support metabolic reactions.
Certain substances produced by the cell for export and cellular waste materials must move out.

Two types of transport processes are 

Passive transport

  • Substances move down its concentration or electrical gradient to cross the membrane using its own kinetic energy.
  • Kinetic energy is intrinsic to the particles that are moving.
  • No input of energy from the cell.
  • Eg: Diffusion ,Osmosis.
  • In facilitated diffusion substances must bind to specific proteins to cross a cellular membrane.

Active transport

  • Cellular energy is used to drive the substance uphill against its concentration or electrical gradient.
  • Cellular energy in the form of ATP is used here.

Passive Transport


Diffusion is the net movement of material from an area of high concentration of that material to an area with lower concentration. The difference of concentration between the two areas is often termed as the concentration gradient, and diffusion will continue until this gradient has been eliminated. Since diffusion moves material from area of higher concentration to the lower, it is described as moving solutes “down the concentration gradient” (compared with active transport which often moves material from area of low concentration to area of higher concentration, and therefore referred to as moving the material “against the concentration gradient”).

If and when the concentration gradient has been eliminated, no net exchange of material occurs. Although material may move forth from one area to the other, it will be balanced by movement of the same amount of material to the opposite direction.

Diffusion is biologically important because it enables the abolishment of concentration gradients in the body. For example, metabolic activity will consume oxygen  which will reduce its concentration in the bloodstream; diffusion of oxygen in the alveoli of the lungs allows it to be replenished.

Is a passive process in which the random mixing of particles in a solution occurs because of particles own kinetic energy.

Here both the solutes(dissolved substance) and the solvent(Liquid that does the dissolving) undergo diffusion.

If  a particular solute is present in high concentration in one area of a solution and in low concentration in another area,solute molecules will diffuse toward the area of lower they move down their concentration gradient.Later partilcles become evenly distributed throughout the solution and the solution is said  to be at equilibrium.The particles will continue to move about randomly due to their kinetic energy but without change in concentration.

  • Substance may also diffuse through a membrane if the membrane is permeable to them.
  • Factors which influence the rate of diffusion across plasma membrane
  • Steepness of the concentration gradient.
  • The greater the difference between the two sides of the membrane,the higher the rate of diffusion.
  • Temperature.
  • The higher the temperature,the faster the rate of diffusion.
  • Mass of the diffusing substance.
  • The larger the mass of the diffusing particle,the slower its diffusion rate.
  • Surface area : The larger the membrane surface area available for diffusion the faster the diffusion rate.

Eg: Air sacs of the lungs have a large surface area available for diffusion of oxygen from the air into the blood.Some lung diseases,such as emphysema,reduce the surface area. This slows the rate of oxygen diffusion and makes breathing more difficult.

  • Diffusion distance : The greater the distance over which diffusion must occur,the longer it takes.

Diffusion across a plasma membrane takes only a fraction of second because the membrane is so thin.In pneumonia fluid collects in lung;the additional fluid increases the diffusion distance because oxygen must move through both the built-up fluid and the membrane to reach the blood stream.

Diffusion through the lipid bilayer

  • The basic structural framework of the plasma membrane is the lipid bilayer.
  • Non polar,hydrophobic molecules diffuse freely through the lipid bilayer of the plasma membrane of cells without the help of  membrane transport proteins.Eg: O2,CO 2,Nitrogen gases,fatty acids,steroids,fat soluble vitamins.
  • Eg: Movement of oxygen and carbon dioxide between blood and body cells.Movement of oxygen and carbondioxide between blood and air during breathing.

Diffusion through membrane ion channels.

  • Most membrane channels are ion channels.
  • Each ion can diffuse across the membrane only at certain sites.
  • In plasma membrane the most numerous ion channels are selective for Potassium or Chloride ions.Fewer channels are available for Sodium and Calcium ions.
  • Diffusion of ions through channels is generally slower than free diffusion through the lipid bilayer.However more than a million potassium ions can flow through a K channel in one second!
  • A channel is said to be gated when part of the channel protein acts as a “plug” or “gate”,changing shape in one way to open the pore and in another way to close it.
  • When the gates of a channel are open,ions diffuse into or out of cells,down their electrochemical gradients.
  • The plasma membranes of different types of cells have diffeent numbers of ion channels and thus display different permeabilities to various ions.

Osmosis is the diffusion of a solvent across a membrane to a region of higher solute concentration. (In biological processes then, it usually is diffusion of water molecules). Most cell membranes are permeable to water, and since the diffusion of water plays such an important role in the biological functioning of any living being, a special term has been coined for it — osmosis.

  • Is a net movement of solvent through a selectively permeable membrane.
  • In living systems, the solvent is water, wich moves by osmosis across plasma membranes from an area of higher water concentration to lower concentration.
  • In other words water move through a selectively permeable membrane from an area of lower solute concentration to an area og higher solute concentration.
  • Water molecules pass through a plasma membrane in two ways
  • By moving through the lipid bilayer
  • By moving through aquaporins(integral membrane proteins that function as water channels)

Osmosis occurs only when a membrane is permeable to water but not to certain solutes.

  • Osmotic pressure
  • Hydrostatic pressure
  • Solution’s tonicity

A solution’s tonicity is a measure of the solution’s ability to change the volume of cells by altering its water content.

  • Isotonic
  • Hypertonic
  • Hypotonic

Medical uses of Isotonic,Hypertonic and Hypotonic solutions.

Isotonic solution

RBC’s and other body cells may be damaged or destroyed if exposed to hypertonic or hypotonic solutions.So most IV fluds are isotonic.

    Eg: isotonic saline (0.9% NaCl)

    D5W (dextrose 5% in water)

Hypertonic solution
Mannitol is useful to treat patients with cerebral oedema where there is excess interstitial fluid in the brain.This causes osmosis of water from interstitial fluid to blood.kidneys excrete the excess of water from blood into urine.

Hypotonic solution
Given either orally or intravenously can be used to treat people who are dehydrated.The water in the hypotonic solution moves from the blood into the interstitial fluid and then into the body cells to rehydrate them.

Facilitated diffusion
Facilitated diffusion is movement of molecules across the cell membrane via special transport proteins that are embedded within the cellular membrane. Many large molecules, such as glucose, are insoluble in lipids and too large to fit through the membrane pores. Therefore, it will bind with its specific carrier proteins, and the complex will then be bonded to a receptor site and moved through the cellular membrane. Bear in mind, however, that facilitated diffusion is a passive process, and the solutes still move down the concentration gradient. The alveoli are tiny grapelike sacs located at the end of the bronchial tubes. This is where oxygen diffuses into the alveoli and is exchanged for carbon dioxide.

  • Is done by solutes that are too polar or highly charged to diffuse through the lipid bilayer and are too big to diffuse through membrane channels.
  • Here a solute binds to a specific transporter on one side of the membrane and is released to the other side after the transporter undergoes a change in shape.
  • The solute binds more often to the transporter on the side of the membrane with a higher concentration of solute.
  • The rate of facilitated diffusion is determined by the steepness of the concentration gradient across the membrane.
  • The number of transporters available in a plasma membrane places an upper limit known as the transport maximum.Once all the transporters are occupied,the transport maximum is reached, and a further increase in the concentration gradient doesnot increase the rate of facilitated diffusion.
    Eg: Hormone Insulin promotes the insertion of many copies of a specific type of glucose transporter into the plasma membranes of certain cells.Thus the effect of insulin to elevate the transport maximum for facilitated diffusion of glucose into cells.With more transporters available.body cells can pick up glucose from the blood rapidly.

Filtration is movement of water and solute molecules across the cell membrane due to hydrostatic pressure generated by the cardiovascular system. Depending on the size of the membrane pores, only solutes of a certain size may pass through it. For example, the membrane pores of the Bowman’s capsule in the kidneys are very small, and only albumin, the smallest of the proteins, have any chance of being filtered through. On the other hand, the membrane pores of liver cells are extremely large, to allow a variety of solutes to pass through and be metabolized

Passive transport – diffusion & osmosis
The fluid inside the cells of the body ( intracellular fluid ) is very different from that outside the cells ( extracellular fluid ) .

The extracellular fluid includes the interstitial fluid which circulates in the spaces between the cells and also  the fluid of the blood plasma that mixes freely with the interstitial fluid through the capillary walls. Extracellular fluid supplies the cells with the nutrients and other substances needed for cellular functions.
ECF contains large quantities of Na+ , Cl- & HCO3- while intracellular fluid contains K+ , Mg 2+ & phosphates. Proteins are found in greater amount in ICF.  These differences between the components of  icf & ecf  are important to the life of the cell which is brought about by different transport mechanisms.

Mainly substances are transported through  the cell membrane by 2 major processes—DIFFUSION ( passive transport ) & active transport.

Diffusion means free movement of substances in a random fashion caused by the normal kinetic motion of substances. Motion of these particles is called heat, the greater the motion higher the temperature, and motion never ceases at any condition, except absolute zero temperature.

When a moving molecule A approaches at a stationary molecule B, the electrostatic and internuclear forces of A repel B , adding some of the energy  of motion to molecule B . Consequently molecule B gains kinetic energy of motion while molecule A slows down, losing some of its kinetic energy.

This continual movement of molecules among each other in liquid or in gas is called diffusion. 

Kinetics of diffusion- The Concentration difference
When a large amount of dissolved substance is placed in a sovent at one end of a chamber, it immediately begins to diffuse towards the opposite end of the chamber. If the same amount of substance is placed in the opposite end of the chamber it begins to diffuse towards the first end, the same amount diffusing in each direction. As a result the net rate of diffusion from one end to other is zero. If the concentration of the substance is greater at one end of the chamber than at the other end the net rate of diffusion from the area of higher concentration to the lower concentration is directly proportional to the larger concentration minus the lower concentration. The total concentration change along the axis of chamber is called concentration difference and the concentration difference divided by the distance is called concentration or diffusion gradient.

When the molecular size is greater, rapidity  with which molecule diffuse from one point to another is less. The rate of diffusion is approximately inversely proportional to square root of molecular weight but is affected by shape of the molecule as well.

Different factors which affect the rate of diffusion are 

  • The greater the concentration difference, greater is the rate of diffusion.
  • The less the square root of molecular weight, the grater is the rate of diffusion
  • The shorter the distance, the greater the rate
  • The greater the cross section of the chamber in which diffusion takes place, the greater is the rate of diffusion.
  • The greater the temperature, greater the molecular motion and greater the diffusion

The time for equilibriation by diffusion is proportional to square of diffusion distance. This aspect has biological importance. It limits the size of individual cells since cellular metabolism depends upon the rapid diffusion of O2 & substrates from membrane to metabolic sites. In human body no metabolically active cell is more than 20 micro meters from a capillary. The rate of diffusion of molecules down a concentration gradient is given by the FICKE’S EQUATION  dv/dt =J= – DA (dc/dx ) , where dv/dt= rate of diffusion in moles /sec. dc/dx is the concentration gradient down which diffusion is occurring in mol cm-3 cm-1. – sign indicates that diffusion is occurring in direction of decreasing concentration, A is the area of plane of solution at right angles to movement. D is the diffusion coefficient . Value of D depends on size of molecule & viscosity of solution.

The importance of area of surface A across which diffusion takes place is illustrated by enormous surface area of capillary bed; the capillary surface area in 1gm of brain tissue is 250 cm2. Individual cells may have their surface area increased by the development of microvilli. These are conspicuous features of epithelial cells in the small intestine and kidney tubules. The rate of diffusion can also be regulated by varyng the area of surface available.

Eg: In lung tissue , at rest only a fraction of total lung surface is used for gas exchange and while at exercise total surface area of 75 m2 becomes available for diffusion.

Diffusion across cell membrane  

It is divided into 2 —– Simple diffusion &  Facilitated  diffusion.

In simple diffusion molecular kinetic movement occurs while in fecilitated diffusion , there is interaction of carrier protein with molecules and ions.

The carrier protein aids passage of molecules or ions through them by binding chemically with them.

Simple diffusion can take place in 2 ways

  •   through the interstices of lipid bilayer
  •   through water channels that penetrate all the way through some of the large transport proteins.

Diffusion through protein channels 

  • Protein channels provide watery pathway through the interstices of protein molecule. They have 2 important properties
  • They are selectively permeable
  • Many of the channels can be opened and closed by gates, which are a means of controlling the ion permeability of the channel

The opening and closing of gates are controlled in 2 principal ways

1. Voltage gating—Here the molecular confirmation of the gate respond to electrical potential across the cell membrane. This gate is the basic cause of action potential in the nerves that are responsible for signals.

2. Chemical gating ( ligand gating ) —- Here a chemical substance binds with the protein which helps in opening and closing of a gate.

Eg : Acetyl choline in acetyl choline channel. This gating is important for the transmission of nerve signals from one nerve  to another.

Facilitated diffusion
Also called a carrier mediated diffusion because a substance transported in this manner diffuses through the membrane with a specific carrier protein helping it to do so. Facilitated diffusion differs from simple diffusion through an open channel in the foll important way;

When the rate of diffusion approaches a maximum called Vmax, as the concentration of substance increases, in simple diffusion rate increases with the concentration of diffusing substance.

What is that limits the rate of facilitated diffusion ?
The carrier protein has a channel large enough to transport a specific molecule pathway through the membrane. Also there is a binding receptor on the inside of the protein carrier, the molecule to be transported enters channel and gets bound. Then in a fraction of second, a conformational change occurs in the carrier protein, so that the channel now opens on the opposite side of the membrane. Because of the binding force of the receptor is weak, the thermal motion of the attached molecules causes it to break away and to be released to the opposite side.

  • The most important substance that cross cell membrane by facilitated diffusion is glucose and most of aminoacids.
  • In glucose the carrier molecule has a molecular weight of 45, 000. 

Factors that affect the net rate of diffusion
Effects of concentration difference on net diffusion through a membrane is proportional to the concentration on outside to     concentration on inside.

Effect of membrane electric potential on diffusion of ions—the NEST EQUATION– At normal body temperature the electric difference that will balance a given concentration difference of univalent ions is determined by NEST EQUATION: EMF(mV) = + or – 61 log c1/c2, where EMF is electromotive force between sides 1 & 2 , C1 is the concentration on side 1 & C2 is concentration on side 2. The polarity of the voltage on side 1 in equation above is +  for –ve ions & -ve for +ve ions. This equation is helpful for understanding nerve impulses.

Effect of pressure difference across the membrane
Pressure effect is mostly seen in blood capillary membrane in all tissues of the body. The pressure is 20 mm Hg greater inside the capillary than outside. Fecilitated diffusion is believed to depend upon the pressure in the cell  membrane of a relatively small number of carrier molecules. These ferry the glucose across the membrane by first binding to the sugar at the border of the membrane at which the glucose concentration is higher. The sugar carrier complex then transfers the glucose to the other border of the membrane when it dissociates to deliver the sugar into the fluid on that side.

Facilitated diffusion displays considerable substrate specificity.
Eg : Glucose entry is a stereospecific process. Physiological isomer D-glucose is rapidly transported into the cell, the optical isomer L glucose is not rapidly transported.

Physiological importance of DIFFUSION

  • Admixture of food stuff with digestive juices.
  • Absorption from the intestine.
  • Exchange between plasma and red cells.
  • Exchange in the capillary bed. Eg : Food stuff, oxygen etc. pass out from the blood stream to the tissue fluids and then to the tissue cells where they are used up. The metabolites including CO2 comes out of the cell, to the tissue fluids and to the blood stream.
  • Exchange in lung capillaries
  • Admixture of gases in the lungs.


The diffusion of water through a semipermeable membrane is called osmosis.

If a layer of water be separated from  sugar solution by a semipermeable membrane, it will be seen that the sugar solution gradually increases in volume for some time and then there will be no further change. Here the sugar molecules being impermeable the water molecules will pass from the water molecules to the sugar solution, than will pass from the latter to the  former. Due to this the volume and level of sugar solution will rise. This will raise the hydrostatic pressure of the sugar solution and this increased pressure will force more and more water molecules to pass out of sugar solution. Thus a time will come when the movement of water molecules on either  side will be the same , so that no further alteration in volume takes place . At this stage the hydrostatic pressure of the sugar solution exactly neutralizes the attractive force of the solution for water molecules.

This force under which a solvent moves from a solution of lower solute concentration to a solution of higher solute concentration when a selectively permeable membrane separates these solutions is called osmotic pressure.

Osmotic pressure does not depend on the size of the molecules but the total number of discrete particles per unit volume. If the solution be ionizable, the osmotic pressure will be proportionally more.

  • The passage of water against concentration gradient is called ultrafiltration.
  • If the two solutions separated by a membrane have same OP, they are called isotonic. One having less OP is called hypotonic.
  • 0.9%  NaCl  solution is isotonic with blood plasma commonly known as normal saline or physiological saline.
  • Two solutions having same number of particles per unit volume are called isosmotic.

Physiological importance of osmosis   

  • Absorption from intestine.
  • Exchange in capillary bed—continuous osmotic exchange is going on between blood, tissue fluids, tissue cells and lymph.
  • Regulation of urine formation.
  • Reabsorption of CSF.
  • Continuous osmotic exchange between plasma and red cells.

CLINICAL — USE : Injection of hypertonic, hypotonic and isotonic saline and other solutions are given in suitable cases by this method. Saline purgatives and saline diuretics also work on osmotic principle.

Methods of measurement

  • Mechanical methods
  • By putting weights – The simplest way is to apply adequate pressure upon the stronger solution to prevent any rise of pressure
  • Biological methods

Hamburger’s red corpuscle method—Red  cells are kept in unknown solution for sometime after which the cell volume is noted. If the cell volume be reduced the solution is hypertonic than plasma & if the cell swells up then the solution is hypotonic.

De vri”s plant cell method —- Here plant cells are used instead of red cells.

Physical method

  • By noting the depression of freezing point — higher the concentration lower will be the freezing point and higher the OP.
  • By  noting the vapour tension – higher the concentration lower will be the rate of evaporation.

Hill’s method
Using the thermopile—higher the rate of evaporation more will be the fall of temperature and less will be the OP

Immediate hypersensitivity (Type1 hypersensitivity)

The Immune Sysyem is made up of a complex network of

Lymphoid organs
Humoral factors and

Which enable us to recognize self from nonself or altered self and thereby protection against disease.
Although Vital to survival, immune system is similar to proverbial double edged sword.

· Underactivity causes immunodefeciency states which make us a easy prey to infections and possibly tumours.
· Overactivity leads to allergic and autoimmune diseases.

Disorders of the Immune system.
Pathology related to the immune system falls into four broad general categories.

1)  Hypersensitivty reactions.  e.g:Anaphylaxis.
2)  Autoimmunity – immune responses to self.
3)  Deficiency states. – congenital or acquired.
4)  Amyloidosis.- a disorder of extracellular protein accumulation.

Hypersensitivity Reactions.
Allergy or hypersensitivity was initially defined by Von Pirquet in 1906, as ‘specifically changed reactivity of an host to an agent on a second or subsequent occasion’.

Allergy is now taken to mean a damaging reaction.
Word allergy is derived  from two Greek words.
–   allos (meaning ‘other’).
–   and ergon (meaning ‘action’).

Exogenous antigens occur in dust,pollens,foods,drugs,microbiological agents,chemicals,blood products etc.

Contact with these antigens lead not only to induction of a protective immune response but also to reactions that can be damaging to tissues.

These hypersensitivity reactions are divided into four general catogories based on the underlying mechanism of immune injury.

They are

  •  Type I hypersensitivity  – Immediate hypersensitivity.
  •  Type II hypersensitivity – Antibody mediated disorders.
  •  Type III hypersensitivity –Immune complex mediated disorders.
  •  Type IV hypersensitivity – Cell mediated immune disorders.

In Immediate hypersensitivity ( Type 1 hypersensitivity) the immune response releases
Vasoactive and spasmogenic substances that act on vessels and smooth muscles.
Pro inflammatory cytokines that recruit inflammatory cells.

In antibody mediated disorders (type II hypersensitivity)

  • Antibodies participate directly
  • In injury to cells promoting their phagocytosis or lysis
  • In injury to tissues by inducing  inflammations.
  • May also interfere with cellular functions and cause disease without tissue injury.

In Immune complex mediated disorders (type III )

  • Antibodies bind antigens and then induce inflammations directly or by activating compliment.
  • The leucocytes that are recruited (neutrophils and monocytes) produce tissue damage by release of lysosomal enzymes and generation of toxic free radicals.

In cell mediated immune disorders (type IV )
Sensitized T lymphocytes are the cause of the cellular and tissue injury.

Immediate (Type I ) Hypersensitivity 
Immediate or type I,Hypersensitivty is a rapidly developing immunologic reaction occurring within minutes after the combination of an antigen with antibody bound to mast cells in individuals previously sensitized to the antigen.
These reactions are often called allergy and the antigens are called allergens.It may occur as a local reaction.

Common antigens which cause Type I Hypersensitivity reaction
–   Birch tree,Rag weed,Oil seed rape.
–   Eggs,Nuts,Sea food.
–   Pencillin,Salicylates.
Insect Products
–   Bee venom,House dust mite.
Animal Hair
–   Cat hair,Dander.

Immediate (Type I ) HypersensitivityIs mediated by immunglobulin E (IgE) antibodies directed against specific antigens(allergens).

Incidence and genetic susceptibility
Some 20-30% of the population exhibit type I hypersensitivity or atopic allergy to common environmental substances.
There is a genetic component to atopic allergy such that if both your parents exhibit this susceptibility you are more than 2 × more likely to do so and if neither parent has manifest allergies you are less than half as likely to when compared to the population as a whole.
Some individuals have multiple and severe allergies, typically both hayfever and eczema; these individuals are termed atopic and frequently have raised total serum IgE levels (10 -100 × normal).
There is a correlation between total [IgE] and atopy.

IgE is produced by B-cells that have previously been stimulated by the antigen.
IgE then attaches to mast cells and basophils, which release primary and secondary mediators upon combination with the antigen.
Type I immediate hypersensitivity occurs within minutes of combination of an antigen with an antibody bound to previously sensitized cell.
Many of these hyper sensitivity reactions have two well defined phases.

The immediate or rapid or  initial response characterized by

  • Vasodilatation
  • Vascular leakage
  • Smooth muscle spasm
  • Glandular secretion

These changes become evident by 5 to 30 minutes after exposure and tend to subside within 60 minutes.

§  Primary mast cell mediators that induce the initial rapid response include
–   Biogenic amines.Eg: Histamine
–   Chemotactic mediators.
–   Enzymes.Eg: Chymase,Tryptase.
–   Proteoglycans.Eg: Heparin

Second or Delayed Phase charecterised by

§  Infiltration of tissues with
–   Eosinophils,neutrophils,basophils,monocytes,CD4 +T cells.

§  Tissue destruction in the form of mucosal epithelial cell damage.

The second phase reaction sets in 2 to 24 hours later without additional exposure and may last for several days.
· Driven by
–   Lipid mediators.
Platelet-activating factors.
–   Cytokine mediators recruit and activate inflammatory cells

Systemic anaphylaxis 
Systemic reaction follows injection of an antigen to which the host has become sensitized.
Typically follows parentral or oral administration of an allergen.
–   Eg :-  Drugs – pencillin.
–   Food – peanuts.
Severity reflects the level of sensitization.
Even a minute doses may induce shock in an appropriate host.
·         Pruritus,urticaria and erythema occur minutes after exposure,followed by bronchoconstriction and laryngeal oedema.This can escalate into laryngeal obstruction,hypotensive shock and death within minutes.

 Local Immediate Hypersensitivity Reactions.
· Exemplified by atopic allergies
· Hereditary predisposition
· Vary depending on portal of entry of the allergen and may take the form of
–   localized cutaneous swelling – hives.
–   nasal and conjuctival discharge.
–   hay fever,bronchial asthma.
–   allergic gastroenteritis.

Diseases due to type 1 Hypersensitivity

  • Extrinsic asthma
  • Atopic ezcema
  • Allergic rhinitis/conjunctivitis
  • Food allergies
  • Anaphylaxis
  • Angio-oedema


  • Typical clinical history.
  • Skin-prick test.(wheal and flare reaction).
  • Measuring specific IgE in the serum.

Patient Care:  
–  A history of allergic reactions, particularly to drugs, blood, or contrast media, is obtained.
–  The at- risk patient is observed for reaction during and immediately after administration of any of these agents.
–  The patient is taught to identify and avoid common allergens and to recognize an allergic reaction

Leucocytes and its applied Physiology


Leucocytes -Its Development, Functions, Normal Values, Variations.
Leucocytes or white blood cells have an important function in defending the body cells against the microbes and other foreign materials. Leucocytes are the largest blood cells and they account for about 1% of the blood volume. Most of the leucocytes are outside the circulation, and few in the bloodstream are in transit from one site to another. They are of two types.

1) Granulocytes
The term granulocyte is due to the presence of granules in the cytoplasm of these cells. In the different types of granulocytes, the granules are different which help us to distinguish them. In fact, these granules have a different affinity towards neutral, acid or basic stains and give the cytoplasm different colors. So, granulocytes distinguish themselves into Europhile (purple as they take both dyes), eosinophil or acidophil (take red in acid dye eosin) and basophil (alkaline dye methyelene blue).

2) Lymphoid cells or agranulocytes
The lymphoid cells are lymphocytes and monocytes. They have a large nucleus and have no granules in their cytoplasm.

Formation of White blood Cells

  • Haemopoetic cells are seen in yolk sac of a 2 week embryo. By 8 weeks haemopoesis gets established in liver. By 12-16 weeks, liver becomes the major site and continues to be active until a few weeks before birth.
  • During this period spleen is also active in lymphoid cell production. Also foetal thymus is a transient site for few lymphocytes in this period. By 20 weeks of gestation bone marrow becomes active. 
  • At birth red marrow occupies the entire capacity of bone. and continues so for 2-3 years 
  • Within 10 weeks of birth marrow becomes the major site of haemopoesis.Gradually red marrow is replaced by inactive, fatty, yellow lymphoid marrow. 
  • By 20-22 years red marrow is present only in the flat bones and upper ends of femur and humerus. 
  • However, because of the growth in body and bone size that has occurred during this period, the total amount of active red marrow (approximately 1000-1500 g) is nearly identical in the child and the adult.
  • About two-thirds of the marrow mass, functions in white cell production (leucopoiesis), and one-third in red cell production (erythropoiesis). However there are approximately 700 times as many red cells as white cells in peripheral blood. This apparent anomaly reflects the shorter life span and hence greater turnover of the white blood cells in comparison with the red blood cells.

It is now generally accepted that all blood cells are made from a relatively few ‘uncommitted’ cells which are capable of mitosis and of differentiation into ‘committed’ precursors of each of the main types of blood cell.  


Unlike red cells, leukocytes have a nucleus. It is easily visible under the microscope, but only after having stained the smear. The nucleus of these cells can show multiple lobes, or be indented or kidney-shaped (reniform). Usually, the shape of the nucleus of various kinds of leukocytes is different. Together with the different colors of granules, the shape of nucleus helps us to recognize these cells. Leukocytes are divided into granulocytes and lymphoid cells. In the drawings which follow, besides nuclei and granules, you can see even mitochondria, Golgi apparatus, endoplasmic reticula and ribosomes.

The neutrophil are the more common leukocytes. They have a diameter of 12-15 µm. You can recognize them as their nucleus is divided into 2 – 5 lobes connected by a fine nuclear strand or filament. The cytoplasm is transparent because its granules are small and purple as they take both dyes. In the nucleus of the neutrophil of cells from females, you may see an appendage like a little drumstick. It is the second X chromosome, inactivated.

Normally the eosinophils are quite rare in the blood and have the same size as the neutrophils.Generally nucleus is bi-lobed. But even nuclei with three or four lobes have been observed. The cytoplasm is full of large angular granules which assume a characteristic pink-orange color as they take acid stain-eosin.

Basophils are the rarest leukocytes: less than 1 %. They are quite small: 9-10 µm in diameter. Cytoplasm is very rich in large granules which take a dark purple color due to the alkaline dye methylene blue. The granules contain histamine and heparin. The nucleus is bi- or tri-lobed, but it is hard to see because of the number of granules which hide it.

LYMPHOID CELLS (or agranulocytes)

 They have a compact nucleus and a transparent cytoplasm.

Lymphocytes are quite common in the blood: 20-40%, 8-10 µm in diameter and generally they are smaller than the other leukocytes but they are still a few larger than red cells. The cytoplasm is transparent. The nucleus is round and large in comparison to the cell and it occupies most of it. In any case, some of the cytoplasm remains visible, generally in a lateral position. According to the quantity of cytoplasm, lymphocytes are divided into small, medium and large.

Monocytes are the biggest leukocytes: 16-20 µm. They have a great reniform or horseshoe-shaped nucleus, in some cases even bi-lobed. The cytoplasm is transparent, but with an appearance of “ground glass”. 


NeutrophilsPrime function of which is to ingest and kill bacteria, fungi and damaged cells.Neutrophils are attracted to sites of infection or inflammation by chemotaxins.Recognition of foreign or dead material is aided by coating of particles with immunoglobulin and compliment as neutrophils have their receptors. The material is ingested into vacuoles where it is subjected to enzymic destruction.

EosinophilsPlay an important role in allergic responses and in the defense against infections with helminthes and protozoa.

Basophil secretes anti-coagulant and vasodilatory substances as histamines and serotonin. Even if they have a phagocytory capability, their main function is secreting substances which mediate the hypersensitivity reaction.

Lymphocytes are cells which, besides being present in the blood, populate the lymphoid tissues and organs too, as well as the lymph circulating in the lymphatic vessel. The lymphoid organs include thymus, bone marrow (in bird’s bursa), spleen, lymphoid nodules, palatine tonsils, Peyer’s patches and lymphoid tissue of respiratory and gastrointestinal tracts.

Most lymphocytes circulating in the blood is in a resting state. They look like little cells with a compact round nucleus which occupies nearly all the cellular volume. As a consequence, the cytoplasm is much reduced. The lymphocytes of the lymphoid tissues and organs can be activated in a different amount following antigenic stimulation.

The cells of the immune system, chiefly lymphocytes, cooperate amongst themselves to activate, boost or make more precise the immune response. To attain this scope, there exist different types of lymphocytes, with different functions: T and B lymphocytes.

T-Lymphocytes processed by the thymus gland provide cell-mediated immunity. It is programmed to recognize only one type of antigen. In their turn, the T cells are divided into three categories: Tc (cytotoxic), Th (helpers), Ts (suppressors).

 Cytotoxic lymphocytes breed quickly when they are activated. They do not release antibodies in the bloodstream, but they keep the antibodies on their membrane and use them to recognize cells. The cytotoxic lymphocytes kill cells by means of osmotic lysis (cell-mediated response).

The helper lymphocytes are needed to activate both B and Tc lymphocytes which, even though they recognize extraneous agents, seldom enter into direct action.

Suppressor lymphocytes reduce the intensity of the immune response.

B-Lymphocytes are processed in the bone marrow. They produce anti bodies or immunoglobulin which are proteins designed to bind and cause the destruction of of antigen. They thus provide antibody mediated or humoral immunity. When the B cells are activated, they breed quickly (clonal selection) and they become plasma cells which secrete a great deal of antibodies in the blood stream (humoral response).

Monocytes are the precursors of macrophages. The monocytes – Macrophage system is sometimes called the reticuloendothelial system. They are larger blood cells, which after attaining maturity in the bone marrow, enter the blood circulation where they stay for 24-36 hours. Then they migrate into the connective tissue, where they become macrophages and move within the tissues. In the presence of an inflammation site, monocytes quickly migrate from the blood vessel and start an intense phagocytory activity. The role of these cells is not solely in phagocytosis because they have also had an intense secretory activity. They produce substances which have defensive functions such as lysozyme, interferons, cytokines and other substances which modulate the functionality of other cells. Macrophages cooperate in the immune defense. They expose molecules of digested bodies on the membrane and present them to more specialized cells, such as B and Th lymphocytes. 

Normal Values:

Total count –        4,000 to 11,000 per mm3

                                             4.0 to 11.0 x 109 /l

Each type of leukocyte is present in the blood in different proportions. In the child up to the age of 7years, Lymphocytes are the predominant white cell type but after the age of 7 neutrophils is the most predominant type.

Neutrophil     50 – 70 %          (2.5 to 7.5 x 109/l)
Eosinophil     2 – 4 %              (0.04 to 0.44 x 109/l)
Basophil        0.5 – 1 %           (0.015 to 0.1 x 109/l)
Lymphocyte 20 – 40 %            (1.5     to 3.5 x 109/l)
Monocytes      3 – 8 %             (0.2 to 0.8 x 109/l)

Absolute Eosinophil Count – The number of eosinophil cells in a given area per 100 cells is counted. The percentage of eosinophil is multiplied by the wbc count   give the absolute eosinophil count. – Less than 350 cells/mol. 


1) Leucopenia – When total leukocyte count is less than 4000/

a.     Granulocytopenia – General term used to indicate an abnormal reduction in the number of circulating granulocytes commonly called Neutropenia because 40  to 75% of granulocytes are neutrophils.Neutrophils less than 1500/ml.

Causes –

  • Congenital -(Kostmann’s syndrome)
  • Racial – common in Black races
  • Infection –  viral, bacterial(typhoid)
  • Felty’s syndrome
  • Auto immune Neutropenia
  • Pancytopenia – marrow aplasia
  • Genetic cyclic Neutropenia every 2-3 weeks

b. Agranulocytosis – Extreme shortage or absence of granulocytes.

2) Leucocytosis – When total leucocyte count is more than   11,000/ any tissue necrosis there is a release of various soluble factors, causing leucocytosis.

Neutrophil leucocytosis – greater than 10,000/

  • Bacterial infections
  • Tissue necrosis
  • Myocardial infarction
  • Trauma
  • Drugs
  • Corticosteroids
  • Lithium


  • Myeloproliferative disease
  • Leukaemoid reaction
  • Leucoerythroblastic anaemia


  • Pregnancy
  • Exercise
  • Malignant diseases
  • Metabolic
  • Renal failure, acidosis.

Eosinophilia – greater than 4,000/

· Parasitic infestations

o   Ascaris,Hookworm,Strongyloides

· Allergic disorders

o   Hay fever,Hypersensitivity reactions

· Skin disorders

o   Pemphigus,Eczema,Urticaria

· Pulmonary disorders

o   Bronchial asthma

o   Tropical pulmonary eosinophilia

o   Allergic bronchopulmonary aspergillosis

·        Malignant disorders

o   Hodgkin’s disease

o   Carcinoma

o   Eosinophilic leukemia

·   Miscellaneous

o   Sarcoidosis

o   Hypoadrenalism

o   Eosinophilic gastroenteritis

Basophils – Usually few but are significantly increased in myeloproliferative disorders like PV,CML,ET.

 Lymphocytosis – greater than 5,000/ occurs in response to

· Viral infections


· Chronic infections

o   TB,Toxoplasmosis

· Chronic lymphocytic leukemia

· Lymphomas

Monocytosis – greater than 800/ may be seen in

·  chronic bacterial infections such as

o   tuberculosis

o   infective endocarditis

· Chronic neutropenia

· Patients with myelodysplasia

Other variations-

  • Toxic granulation – When granule staining becomes more intense in response to infection.
  • Right shift – In megaloblastic or iron deficiency anemia six or more nuclear segments appear in neutrophils.
  • Immature neutrophils have a band-shaped or horse shoe-shaped nucleus and are known as band cells.
  • Leucoerythroblastic picture – Appearance of more primitive myeloid precursors in blood associated with presence of nucleated red cells.
  • Leukemia – Is a malignant proliferation of white blood cell precursors by the bone marrow which results in uncontrolled increase in the production of leucocytes and/or their precursors.

Homoeopathic Actions 

1) IODUM (William Boericke)
Iodine arouses the defensive apparatus of the system by assembling the mononuclear leucocytes whose phagocytic action is marked, at a given point.

2) Natr sulph (Clarke) :Nat.sul. withdraws water from the superannuated leucocytes, and thus causes their destruction.  The latter salt is, therefore a remedy for leukemia.

3) X-RAY :A general suppression of all cellular elements of blood except the heterophile leucocytes which increases.

4) ARSENICUM ALBUM (Neatby) :The red corpuscles and leucocytes of the blood are decreased in numbers.

5) CINCHONA : PATHOGENESIS the leucocytes soon become spheroidal and motionless in contact with a solution of quinine.

6) COLCHICUM (Neatby) : The polynuclear leucocytes are first collected in the marrow and tissues, but later they are greatly increased in the blood


RBC – Applied Physiology

bloodDr Sunila BHMS,MD(Hom)

RBC (Normal Red Cell) – Erythrocyte
Human red cell is normally a circular, non-nucleated, biconcave disc; it is very elastic and can undergo astonishing deformation when passing through narrow capillaries. Normal diameter is 7.2 µm. The surface area of the cell is about 140 µm², much greater than its volume when contained in a sphere. Thus O2 and CO2 exchanges are maximized with the biconcave configuration.

The process of red cell production or erythropoiesis begins in the embryonic sac and is continued in the liver, spleen and lymph nodes in the maturing foetus. By the end of pregnancy and after birth, however, the process is restricted to the bone marrow. As time progresses the contribution from long bones decreases and in adult life, only the marrow of membranous bones such as vertebrae, ribs and pelvis is involved.

Pluripotential or uncommitted stem cells which have the potential to produce any type of blood cell divide and develop into erythroid stem cells committed to form erythrocytes. These divide and mature, synthesizing hemoglobin and eventually forming normoblasts.

Cytology of erythroid cells
Stage I: Pronormoblast (Proerythroblast)
This early cells which is derived from stem cells, is large; the cytoplasm is a deep violet- blue and there is a small crescent, showing a paler staining, around the nucleus, the cell is devoid of haemoglobin. The nucleus is large and the chromatin forms a fine stripped reticulum and contains several nucleoli.

Stage II: Early normoblast (Early erythroblast)
This cell is some what smaller, the nucleoli have disappeared and the chromatin network is fine and shows a few nodes of condensation.

Stage III: Intermediate normoblast (Late erythroblast)
The cell is smaller and shows acute mitosis; the resting nucleus shows further condensation of the chromatin; haemoglobin increases; its eosinophil staining gives the cytoplasm a poly chromatic appearance.

Stage IV: Late normoblast (Normoblast)
This cell represents a maturation of the previous stage; the condensed chromatins assuming a ‘cart-wheel’ appearance and finally becoming uniformly deeply stained (pyknotic). There is a decrease in the size of the cell; increased condensation and finally pyknosis of the nucleus.

Nuclear material is extruded and the endoplasmic reticulum reabsorbed, producing first a reticulocyte, containing a few remnants of endoplasmic reticulum, and then an erythrocyte. Normally only these two cell types are found in the circulation, with reticulocytes making up less than 2% of the total. This percentage rises during periods of rapid erythrocyte synthesis, when more immature cells enter the circulation. Mature red cells take the form of biconcave discs which deform easily within the narrow capillaries. The normal red cell count in blood is 4x 1012 to 6x 1012/ L.

Erythrocyte Destruction
Ageing erythrocytes are destroyed, often in the spleen, after an average life span of 120 days. The phagocytic cells of reticulo endothelial system degrade the haemoglobin released, with iron from the haem and amino acids from the globulin molecules being recycled. The porphyrin ring is converted into bilurubin, which is further metabolized by the liver and then excreted in the bile.

Control of Erythrocyte Production
Erythropoiesis is controlled by the kidney, which releases a hormone known as erythropoietin if the delivery of O2 to renal cells falls below normal. This will occur if the concentration of circulating haemoglobin is reduced. i.e. during anaemia. The bone marrow responds by increasing the red cell production, thus increasing the haemoglobin content back to normal. Since this control loop is sensitive to tissue O2 levels rather than the actual haemoglobin concentration; other conditions which reduce the O2 content of blood will also stimulate erythropoiesis, even if haemoglobin concentration is normal. This is seen at high altitudes, where the partial pressures of O2 in the lungs and blood are reduced. Over a period of weeks at high altitudes, erythropoietin stimulates an increase in the haemoglobin concentration, with a rise in haematocrit and red cell count (compensatory polycythemia). It is for this reason that athletes wishing to increase the O2 carrying capacity of their blood often train at altitude.

Nutritional Requirement for Red cell Production
Erythropoiesis and haemoglobin synthesis require adequate supplies of the V-B12 (cyanocobalamine) and folic acid. As well as the mineral iron. Deficiencies of these may cause anaemia.

V-B12 and folic acid deficiency: producing macrocytic or megaloblastic anaemia. Abnormal erythrocytes precursors (abnormally large erythrocytes) are found in the marrow.

Iron deficiency:  microcytic, hypochromic anaemia. Erythrocytes smaller than normal and contain less haemoglobin than normal.

Other substances essential to erythropoiesis

  • An adequate protein intake.
  • Vitamin (B6) – pyridoxine: – required as a co-enzyme in the synthesis of aminolaevulic acid which is the first and rate limiting step in the synthesis of haem.
  • Vitamin C: – acts as a reducing agent and increases iron absorption and preserves folates during food preparation.
  • Vitamin E: – acts as an antioxidant and prevents per oxidation of membrane lipids and red cell lysis.
  • Minerals
  • Iron
  • Copper- deficiency interferes with iron metabolism

Other factors

  • Age and sex
  • Environment- at altitudes above 2000 m there is hypoxic stimulation of erythropoiesis.
  • Endocrines: Thyroxine, cortisol, androgens and prolactin promote erythropoiesis.

A thin and well stained blood smear is essential for a proper study of the morphology of normal and abnormal red cells. The cells are studied the best in the area between the tail and the thicker head of the smear, away from the edges. i.e. where the cells lie just near their neighbors without overlapping.

The points to be noted regarding normal mature cells are:

Size and shape: There is moderate variation in the diameter of RBC (average 7.2 mm). Most cells are round, but a small percentage may be slightly oval.

Staining: Cells of normal subjects are stained a pink colour with Leishman’s stain. The staining is deeper at the periphery and gradually lessens towards the centre of the cell; this area of central pallor occupies less than 1/3 of the cell diameter and is due to the biconcave shape of the red cell.

These are juvenile red cells and contain the remnants of basophilic ribonucleoprotein which was present in greater amounts in the cytoplasm of the nucleated precursors. This material appears either as a precipitate of granules, or in the form of interlacing filaments. Reticulocytes do not contain nuclei.

Venous Drainage of Lower Limbs

Dr Meera Narendran BHMS,MD(Hom)
The lower limbs has superficial and deep veins; the superficial veins are in subcutaneous tissue, and the deep veins are in to the deep fasica and accompany all major arteries. The veins of lowerlimb act as a complex pumping meachanism capable of returning venous blood to the heart against the force of gravity in the upright position.

Superficial veins of the lower limb
The two major superficial veins in the lower limb are the great and small saphenous veins.

The great saphenous veins is formed by the union of the dorsal vein of the great toe and the dorsal venus arch of the foot. The great saphenous vein.

  • Ascends anterior to the medical malleolus.
  • Passes posterior to the medical condyl of the femur.
  • Anastamoses freely with the small saphenous vein.
  • Transverses the saphenous opening in the fascia lata.
  • Empties in to the femoral vein.
  • The great saphenous vein has 10 to 12 valves. These valves are usually located just inferior to the perforating veins. The perforating veins also have valves. This valvular mechanism enables the blood in the saphenous vein to overcome the force gravity as it passes to the heart.

As it ascends in the leg and thigh, the great saphenous vein recieves numerous tributaries and communicates in several locations with the small saphenous vein. Tributaries from the medical and posterior aspects of the thigh frequently unite to from an accessory saphenous vein.
The lateral and anterior cutaneous vein arises from networks of veins in the inferior part of the thigh and enter the great saphenous vein superiorly, just before it enters the femoral vein. Near its termination the great saphanous vein also receives the superficial circumflex iliac, superficial epigastric, and external pudendal veins.
The small saphenous vein arises on the lateral side of the foot from the union of the dorsal vein of the small toe with the dorsal venous arch.

The small Saphenous vein.

  • Ascends posterior to the lateral malleolus as a continuation of the lateral marginal vein.
  • Passes along the lateral border of the calcaneal tendon.
  • Inclines to the midline of the fibula and penetrates the deep fascia.
  • Ascends between the heads of the gastronemus muscle.
  • Empties into the politeal vein in the popliteal fossa.

Although many tributaries are received by the saphenous veins, their diameter remains remarkably uniform as they descend the limb. This is possible because the blood they received is continuously shunted from these superficial veins in the subcutaneous tissue to the deep veins by means of the many perforating veins.
The perforating veins, penetrate the deep fasia close to their origin from the superficial veins and contains valves that when functioning normally, only allow blood to flow from the superficial veins to the deep veins. The perforating veins pass through the deep fascia at an oblique angle so that when muscle the deep fascia, the perforating veins are compressed. This also prevents blood from flowing from the deep to the superficial veins.

Deep veins of the lower limb
Deep veins contained within the vascular sheath with the artery, whose pulsations also help to compress and move blood in the veins.
The dorsal digital veins of the foot receive tributaries from the plantar venous arch and join to form common dorsal digital veins that terminate in the dorsal venous arch.
Medial and lateral plantar veins pass close to the arteries and after communicating with the great and small suphenous veins, form the posterior fibial veins posterior to the medical malleolus. The deep veins communicate with the superficial veins through perforating veins. Because of the effect of gravity, bloodflow is markedly reduced when a person stands quietly. During exercise blood received is propelled by muscular contraction to the femoral and then the internal iliac veins, flow in the reverse direction away from the heart or from the deep to the superficial veins is prevented if venous valves are competent.

Creation of flow within veins
Only three forces create movement of venous blood in the limbs.
1. Aretrial pressure across the capillary beds
2. Musculovenous pumps.
3. Gravity :- If the limb is elevated above the horizontal flow towards the heart occurs by simple gravitational downflow.

Disorderd venous function
Venous insufficiency, a state of inadequate venous return in the upright position and accompanied by venous hypertension, may occur in the following circumstances.
1. Deficient or defective valves in superficial veins, causing massive downflow:- See in simple varices veins.
2. Active venous thrombosis (acute deep vein thrombosis) with imapairment of musculovenous pumping mechanism.
3. Post-thrombotic Syndrome
Venous thrombosis causing obstruction or deformity in the venous circuits.
4. Loss of deep vein valve competence or replacement of the deep veins by enlarged, valves, collateral veins as occurs in post thrombotic states.
5. Valveless and abak vein Syndrome.
In born deficiency of deep vein valves or inherent weakness in the vein wall with valve failure.
6. Prolonged in activity of the muscles with the limbs in a dependent position, as in paralysis or disease states innibiting use of muscles.
Arteriovenous fistula by direct arterial in flow to the venous side can cause venous hypertension and the characteristic venotensive changes resulting from it.

Signs of venous abnormality in the lower limb with patient standing
1. Tortuosity
This is the most significiant visible sign of abnormality. This is mostly seen in superficial valve incompetence, where strong gravitational downflow occurs. High flow in a normal direction at increased pressure, intermiftently or continuously, will cause enlargement but seldom accompanied by tortousity.

2. Saccules on the veins
Since saphenous vein is too robust, seldom become tortous, instead one or more saccules may be seen or palpated along its length. Usually a saccule is immediately below valve cusps and which are leaking heavily and the gross turbulence this causes on coughing give rise to a characteristic, palpable thrill, readily confirmed by Doppler flowmetry and functional phelebography. The presence of a saccules is a clear indication of a incompetent valve.

3. Inky-blue-black veins
Varicose commonly become adherent to overlying skin and may so stretch it that the dark blue venous blood shows through very clearly. This fragile covering will be vulnerable to minor trauma which may cause heavy haemarrhage.

4. Distended Subdermal and intradermal venules
Extensive patterns of radiating venules are commonly seen around the ankle and on the foot (corona phlebectatica). These flares of veins indicate venous congestion with increased venous pressure. They occur more readily in the weakened tissues of the elderly and are not necessarly the precursons of ulceration. (These veins must be distingushed from small elustens of intradermal venules (thread or spider veins). Seen on the thigh or upper leg increasingly as middle age approaches these may signify underlying venous disorder.

5. Cough impulse
Varicose veins give a palpable impulse when the patient coughs, because of the absence of functioning valve between the abdomen and the vein, and it confirms incompetence in the valves of deep and superficial veins leading to this point.

6. Increased warmth in veins
Veins carrying a strong reversed flow of blood that has just emerged from a deep vein at true body temparature, as in simple varicose veins. This is valuable confirmation of the vein’s abnormal state. This sign is also seen in Arteriovenous fistula.
With the patient lying
Hollows and grooves in the elevated limb.
When the limb is elevated the veins wil empty and space occupied by large varicose veins becomes a hollow or a groove readly palpable or even visible.
The nature of varicose veins

Varicose veins, arise in 3 circumstances of unnatural flow.
I. Simple (or primary)
II. Secondary
III. Arteriovenous fistula

1. Simple (or primary) varicose veins
These occur only in the superficial veins of the lower limbs and are by far the most common variety of varicose veins. Such veins have no competent valves and are subject to substantial upright and moving. Due to inadequate valves.
2. Secondary varicose veins
Tortuisty is often seen in superficial veins carrying reversed flow as a part of collateral mechanism compensating for obstruction in a neighbouring deep vein. Tortousity is seen in normal veins.
Eg:- Suprapubic veins acting as collaterials to iliac vein oesophageal varices in portal hyperation.
3. Arteriovenous fistula
Tortuosity is often present in lesser veins inthe vicinity of an A.V. fistula but major veins leading from it enlarge without totuosity.

Signs of venous hypertension
Venous hypertension is a common consequence of venous disorder. Raised venous pressure cause an increase in capillary pressure & will cause characteristic changes in skin and subcuteneous tissues. These are mainly the result of excess capillary transudation carrying with it protein molecules and leading to deposition of fibrin which forms a barrier to nutritional exchange between capillaries and the surrounding tissues. Other substances are also extravasated including haemosiderin which eventually gives the characteristic brown skin pigmenation of venous hypertension.

Venotensive change
1. Swelling
Mainly due to oedema
2. Induration
A characteristic diffuse fibrosis in the subcutaneous tissues. These changes may be accentuated by fat necrosis and chronic inflammatory changes. The term “lipodermatosclerosis or liposclerosis are often used to describe induration due to venous disorder.
3. Pigmentation
Most characterstic change, due to accumulation of haemosiderin in the skin.
4. Ulceration
If the condition remain untreated, prograssive deterioration in skin nutrition leads to small areas of tissue death, to form an ulcer.
An venous ulcer will be surrounded by pigmented skin and atleast induration. In long standing ulcers the neibouring skin may also show a characteristic white scarring known as “atrophie blache”.
5. Eczema and dermatitis.
Skin is prone to eczema especially the pigmented area. Pruritus will be prominent.

Symptoms of venous disorder
(When venotensive changes are not present)
1. Distress and aching after prolonged standing. In women discomfort is most marked over a few days before menstruration.
2. Nocturnal cramps
Additional Symptoms when venotensive changes are present include

1. Pruritus – May be the early change
2. Increased discomfort
3. Venous claudication

By clinical history and clinical examination
Clinical Tests
1. Brodie – Trendelenburg test
2. Tourniquet test
3. Perthe’s test
4. Modified Perths test
5. Scwartz test
6. Pralt’s test
7. Morrisey’s Cough impulse test
8. Fegan’s method
(to indicate the sites of perforators)

Special investigations
1. Phlebography
2. Ascending fuctional cinephiebography
3. Doppler ultrasonogram
4. Duplex imaging
5. Ultrasound and CT scan

1. Reassurance
2. Use of elastic compression stockings (creep bandage)
3. Injection Sclerotherapy
4. Surgical treatment

Homoeopathic Medicines
Sulphur, Pulsatilla, Graphitis, Fluric acid, Millifolium, Hammamelis, Cale flur, Ambragrisea Vipera, Lycopodium, Bothrops, Lachesis, Carbo veg, Arnica.