Applied physiology of thyroid gland

Dr Smitha Madavan  BHMS,MD(Hom)

It is highly vascular , largest endocrine ductless gland lies deep to the sternothyroid and sternohyoid muscles from the level of C5-T1 vertebrae.It consists of two lobes right and left anterolateral to the trachea and larynx. An isthmus unites the lobes over the trachea usually to the 2nd -3rd tracheal rings. The thyroid is surrounded by a thin fibrous capsule. External to the capsule is a loose sheath found by a visceral layer of the pretracheal deep cervical layer. Dense connective tissue attaches the capsule of the thyroid gland to the cricoid cartilage and the superficial tracheal rings.

The thyroid is divided into lobules composed of about 20-40 evenly disperse follicles. The follicles range from uniform to variable in size and lined by cuboidal to low columnar which is filled with thyroglobulin. In response to trophic factors from the hypothalamus, TSH is released by thyrotrophs in the anterior pituitary into the circulation. TSH act on the thyroid and convert thyroglobulin into thyroxine – T4 & lesser amounts of triodothyroidin – T3 and are released into the systemic circulation. The binding proteins serve to maintain the serum free T3 & T4 concentration in narrow limits yet ensure that the hormones are readily available to the tissues. In the interfollicular stroma the thyroid gland also contains a population of parafollicular cells or C cells which synthesis and secrete the hormone calcitonin. This hormone promotes the absorption of calcium by the skeletal system and inhibits the reabsorption of bone by osteoclasts.

Arterial supply:superior and inferior thyroidal arteries.
Venous drainage: Three pairs of veins drain the thyroid gland; superior, middle and inferior thyroidal veins.
Nervous supply: nerve fibres from the cervical sympathetic ganglion indirectly influence thyroid secretion by acting on blood vessels.

The functional liability is reflected in transcient hyperplasia of the thyroidal epithelium. At this time thyroglobulin is resorted and the follicular cells become tall & columnar, sometimes forming small unfolded buds or papillae. When the stress abates involution occurs, ie, the height of the epithelium falls, colloid accumulates and the follicular cells resume their normal size and architecture. Failure of this balance between hyperplasia and involution may produce major or minor deviations from the usual histologic pattern. Thyroid abnormalities are relatively common in the general population.

Clinical conditions related to Thyroid
1. Hyperthyroidism–Toxic goitre
2. Hypothyroidism
• 1o—-defect in the thyroid gland
• 2o— defect in the thyroid hormone synthesis
• 3o— defect in the hypothalamus / pituitary

3.Thyroiditis

  •  acute thyroiditis
  •  riedel’s thyroiditis
  •  hashimoto’s thyroiditis
  •  subacute granulomatous thyroiditis
  •  subacute lymphocytic thyroiditis

4.Goitre

  • non-toxic— parenchymatous goitre

— diffuse colloid goitre
— nodular goitre

  • toxic–1— diffuse toxic goiter—Grave’s disease

         2— nodular goitre—Multinodular goitre

5.Neoplasms
• adenoma
• carcinoma—papillary
— follicular
— medullary
— anaplastic

6.Congenital anomaly—thyroglossal cyst

Investigations
1) TFT
2) BMR
3) ECG
4) FNAB & Cytology
5) USG
6) Serum creatinine
7) Serum Cholesterol level
8) Serum Colloidal gold test
9) Iodine uptake
10) Urinary excreation of radioactive iodine
11) Radioiodine scan / scintiscan
12) Radiography
13) Laryngeoscopy
14) Tendon reflex
15) Thyroid antibodies
16) Protein bind plasma activity
17) Precipitin test
18) Tumour marker

Manifestations of the thyroid disease
I)Hyperthyroidism:it is a hypermetabolic state caused by increased levels of circulating tri-iodothyronine (T3) and thyroxine(T4). When the elevated levels arise from hyperfunction of the thyroid gland–Hyperthyroidism. If it is due to excessive leakage of hormone out of non-hyperactive gland-thyrotoxicosis.

Causes:
• diffuse hyperplasia of the thyroid gland
• ingestion of exogenous thyroid hormone
• swellings hyperfunctional mononodular goiter
adenoma of thyroid
thyroiditis

Primary—Hyperthyroidism arising from an intrinsic thyroid abnormality.
Secondary—Hyperthyroidism arising from a process outside the thyroid eg., pituitary tumour.

Manifestations:

  • Nervousness 
  • Palpitations
  • Rapid pulse
  • Fatigue
  • Muscular weakness
  • Weight loss with good appetite
  • Diarrhea
  • Heat intolerance
  • Warm skin
  • Excessive perspiration
  • Emotional liability
  • Menstrual changes
  • Tremor
  • Eye changes:
  • Wide eyed gaze
  • Lid lag-von graefe’s sign
  • Graves disease
  • Ophthalmopathy
  • Lid retraction 

Neuromuscular:

  • Fine tremor
  • Emotional liability
  • Anxiety
  • Inability to concentrate
  • Insomnia
  • Proximal muscle weakness
  • Skin:warm moist and flushed
  • Increased sweating
  • Absence of wrinkling of skin of forehead—joffrey’s sign

GIT:

  • Increased mobility
  • Increase in appetite but weight loss
  • Skeletal :osteoporosis
  • ardiac:tachycardia
  • Palpitation
  • Atrial arrhythmias
  • Cardiomegaly
  • CCF
  • Sleeping pulse rate is increased 

Lab diagnosis:
serum T3 ↑
serum T4 ↑ –primary hyperthyroidism

serum TSH ↓–primary /secondary hyperthyroidism. To differentiate primary /secondary hyperthyroidism TSH levels after the injection of TRH (TRH stimulation test) is used in the evaluation of cases of suspected hyperthyroidism with equivocal changes in the baseline serum TSH level. A normal rise in TSH after administration of TRH excludes secondary hyperthyroidism ie.,the defect is in thyroid.
Measurement of radioactive iodine uptake level provides an additional direct indication. Weyne’s diagnostic index

II) Hypothyroidism: it is a hypometabolic state caused by deficiency of circulating thyroid hormones.
Causes:
• insufficient thyroid parenchyma due to non goitrous
goitrous—dyshormogenesis
drug induced
deficiency of iodine
postablative—after surgery
radioactive
developmental defect
• Interference with thyroid hormone synthesis due to enzyme deficiency
• Suprathyroidal lesions—vascular damage to anterior pituitary gland

Aetiology:
Hereditary influence
Predominance in females
Usually after the age of 35

Manifestations—1)cretinism 2)myxoedema

Cretinism: the severity of the mental impairment appears to be directly influenced by the time at which thyroid deficiency occurs in utero impaired development of skeletal system and CNS.

Manifestations:

  • Mental retardation
  • Short stature
  • Dry rough skin 
  • Wide set eyes 
  • periorbital puffiness 
  • enlarged protruded tongue
  • Umbilical hernia 
  • cold intolerance 
  • pot belly
  • Delayed bone age
  • New born 
  • Lethargic 
  • Flaccid
  • seldom crying

Myxoedema –hypothyroidism developing in the older child or adult. In longstanding cases it is characterised by the deposition of mucinous material causing swelling of the skin and subcutaneous tissues.

Manifestations

  • Decreased physical and mental activities
  • Fatigue
  • Cold intolerance
  • Apathy
  • Speech and intellectual functions slowed listless
  • Overweight
  • Constipated
  • ↓sweating
  • carpal tunnel syndrome
  • skin cool pale
  • dull expression 
  • bloated look 
  • pouting lips
  • signs
  • periorbital oedema
  • coarsening of skin
  • facial features
  • cardiomegaly
  • pericardial effusion
  • hair loss
  • vitiligo
  • cold extremeties
  • malar flush
  • yellowish tint to the skin

Lab diagnosis:
1)serumT3↓
serum T4↓ — primary hyperthyroidism
serum TSH↑

2) serumT3↓
serum T4↓ —secondary hyperthyroidism
serum TSH (WNL /<(N)

3)serum cholesterol— primary thyroid failure
4)ECG—bradycardia
low voltage complexes
flattened or inverted T waves
5)tendon reflex—prolonged duration
6)thyroid antibodies–+ in hashimoto’s disease

III) Thyroiditis:
inflammation of the thyroid gland
a)acute infectious disease:caused by infectious agents like staphylococcus aureus, streptococci, salmonella, enterobacteria, mycobacteria, fungi, haematogenous in origin, manifests as hot , painful enlargement of gland.

b)Riedel’s thyroiditis:progressively increasing sclerosis, replacing thyroid parenchyma by dense fibrous tissue penetrating the capsule extend beyond trachea,stony hardness of the gland. Usually males are affected. Manifestations include glandular atrophy and hypothyroidism. Iodine uptake studies (N) thyroid scan no uptake of the hormones.

c)Hashimoto’s thyroiditis: :exclusively in females. It is the most common cause of goitrous hypothyroidism in regions where dietary iodine is adequate. Manifests as symmetrical diffuse, painless enlargement of the gland with well defined margin and of rubbery consistency.

Pathogenesis:R elated to the defect in function of thyroid specific suppressor T cells, resulting in the emergence of CD4 + helper T cells directed at thyroid and the production of autoantibodies to various components of the thyroid.
It is associated with other autoimmune disease.

Genetic component: goitrous form is associated with HLA-DR5. Atrophic form is associated with HLA-DR3.

Morphology: goitrous form characterised by the enlarged asymmetric gland with intact capsule, the parenchyma is generally paler than normal microscopic changes include exuberant infiltrate of lymphocytes plasma cells and macrophages often with germinal centres abundant eosinophilic granular cytoplasm in residual follicular cells and delicate fibrosis. Atrophic form with extreme fibrosis and less inflammation size of the gland is reduced.

Lab diagnosis:
serum T3 ↑
serum T4 ↑
serum TSH ↓
radioactive iodine uptake↓

d) subacute lymphocytic thyroiditis: : common in females especially in the post partum family history of autoimmune disease often seen along with viral infection. Antibodies to viruses demonstrable in half of the cases. Self limited form.
Manifestations:
Palpitation tachycardia
Tremor weakness
Fatigue
Lab diagnosis:
serum T3 ↑
serum T4 ↑
serum TSH ↓
radioactive iodine uptake↓

e) subacute granulomatous thyroiditis: self limiting form female of second fifth decade, after viral infection with HLAB35 antigen is formed from virus induced host tissue damage. This antigen stimulates the form of cytotoxic T lymphocytes with then damage thyroid follicular cells. the immune response is limited. This transcient hyperthyroidism usually diminish in 2-6 weeks which results in release of excessive thyroid hormones in 6-8 weeks thyroid function returns to normal. Clinical features:
painful enlargement of thyroid ,upper jaw, throat , pain in ears while swallowing
acute fever illness with raised ESR. Fatigue, malaise, myalgia
Lab diagnosis:
serum T3 ↑
serum T4 ↑
serum TSH ↓
radioactive iodine uptake↓
thyroid antibodies ↑

Grave’s disease:previously healthy gland is now characterized by hyperthyroidism due to a hyperfunctioning diffuse goiter, infiltrative ophthalmopathy, oedematous dermopathy (localized myxoedma) female predominance, history of stress and strain.
Pathogenesis: autoimmune process initiated by IgG antibodies against portions of the TSH receptor.
Morphology: mildly & symmetrically enlarged with an intact capsule and soft parenchyma. Microscopic changes include wide spread hypertrophy & hyperplasia of follicular epithelium manifested by crowding of columnar cells into irregular pappilary folds-colloid is substantially decreased ,interfollicular parenchyma contains hyperplastic lympjhoid tissue & increased number of blood vessels.

Manifestations:
Ophthalmopathy
Dermopathy,
Diffuse hyperplasia

Characteristics:
exophthalmos, goiter, tachycardia, tremor,the volume of the pretibial myxoedema –minority both retro-orbital of patients –orange peel texture and connective tissue and extra ocular muscles and is increased due to inflammation of extracellular matrix components including proteoglycans and hyaluronic acid.

Lab diagnosis:
serum T3 ↑
serum T4 ↑
serum TSH ↓
radioactive iodine uptake↓

IV) Goiter: most often caused by dietary Iodine deficiency or goitrogens. It decrease the thyroid hormone production. Compensatory increase in the TSH with resultant hyperplasia and hypertrophy of the gland. Female predominance. Usually those around puberty, during pregnancy, at menopause which subsides itself or with iodine therapy.
Diffusely enlarged, no evidence of hyper or hypothyroidism sporadically it caused by biosynthetic defects .
Morphology—massive enlargement of gland secondary to accumulation of colloid and variable atrophy of follicular epithelium. Palpable smooth , painless move with deglutition due to persistently fluctuating TSH stimulation.
Nodular goiter:sporadic form seen as single nodule at the junction of the isthmus and one lateral lobe. Complication—haemorrhage, calcification, secondary toxicosis and carcinoma.Sudden haemorrhage will lead to tracheal compression leading to dyspnoea demanding immediate tracheostomy.

Multinodular goiter : endemic nontoxic with hyper irregular nodular with focal haemorrhage, fibrosis, calcification and cystic changes include a variable degree of colloid accumulation follicular epithelial hyperplasia and follicular involution massively enlarged. >2000gm and extend behind sternum (retrosternal goiter)—substernal, plunging type,purely intrathoracic
Clinical features:
Dyspnoea
Dysphagia
Cough
Stridor
Engorgement of the neck veins
Recurrent laryngeal nerve paralysis
Lab diagnosis:
serum T3 ↑
serum T4 ↑
radioactive iodine uptake uneven

V) Neoplasms :
characterized by fixity to the underlying structures. More than
90 % are prone to be adenomas. There are certain clinical features helps in evaluation.Solitary nodule may be neoplastic.Functioning hot nodules on scintiscans are more likely benign than malignant. Nodules in younger patients < 40 and in males. FNAC is useful in evaluation of thyroid nodules.

Benign adenoma: multiple histologic variant.
Gross appearance : well demarcated solitary lesion occasionally accompanying fibrosis, haemorrhage or calcification 1)papillary type 11)follicular type
Microscopic:sharp demarcation from adjacent parenchyma by a fibrous capsule. Architecture distinct from that of adjacent compression of the surrounding gland by adenoma absence of multinodularity in the remaining gland.
Histologic:hurthle cell adenomas feature granular eosinophilic cells contain abundant mitochondria .
Clinical features:
Focal mass must be differentiated from carcinoma. Haemorrhage into adenoma may produce rapid painful enlargement of the gland .TSH dependent tumour. Most are cold on scans rarely with hyperthyroidism.

Malignant nodule:papillary-75-85%

  • Follicular: 90% are well differentiated lesions. Pathogenesis related to head and neck irradiation during the first two decades of life.
  • Papillary carcinoma —common form in 3rd % 5th decades.
  • Gross features :infiltrative lesion with calcification or cystic change.
  • Microscopic —papillary with predominance of follicular elements.
  • Hypocromatic empty nuclei devoid of nucleoli—(orphan annie eyes)nuclear grooves, Eosinophilic intranuclear lesions.inclusions-psamoma bodies
  • Histologic variants include encapsulated follicular tall cell
  • Clinical features:
  • First mass in cervical node
  • Dyspnoea
  • Dysphagia
  • Cough
  • cold mass on scitiscans
  • Prognosis :generally excellent 90% survival rate if >20 years
  • Favourable factors include
  • Well differentiated histology
  • Female sex
  • Age less than 20 years
  • Confinement of lesion to thyroid

Follicular carcinoma
Female predominance in fifth, sixth decade, Multinodular goiter predispose to follicular carcinoma ,Apparent encapsulation, Colloid filled follicles, Metastases by haematogenous spread.Prognosis depend upon
-Size of the lesion
-Presence or absence of capsular invasion
-Presence of metastasis
-Degree of histologic anaplasia

Medullary carcinoma

  • Represent neuroendocrine tumours originating from the parafollicular or C cells of the thyroid. Distinctive features include secreation of calcitonin, prostaglandin
  • Clinical features:
  • Dysphagia 
  • Hoarseness 
  • cough
  • Prognosis variable
  • Malignant lymphoma:very rare and very difficult to differentiate from anaplastic CA

VI) Congenital anomaly

  • Thyroglossal cyst
  • Cyst developing from thyroglossal tract
  • common sites: beneath hyoid
  • In the region of thyroid
  • Above thyroid
  • Located in middle or just lateral to it involves on deglutition and moves upward when the tongue is protruded due to attachment of foramen caecum
  • Histolgy
  • Squamous epithelium

Specific investigations

  • BMR

This is estimated by determining the Oxygen consumption of the patient in the basal state.The reading obtained is compared with a normal standard and the difference is recorded as a % .Normally the rate varies from –20% — +20%
In thyrotoxicosis 80—90 % myxoedema –45 %

  • Serum creatinineà0.6mg / 100ml—thyrotoxicosis
  • Diagnosis is confirmed if the level falls after thyouracil therapy.
  • Blood cholesterol level decreased in hyperthyroidism increased in hypothyroidism
  • Serum colloid gold test +in hashimotos disease
  • Precipitin test-when the antibodies produced in hashimotos disease are mixed with thyroglobulin or saline extract of the thyroid gland precipitation occurs.
  • Iodine uptake

The functions of the thyroid gland is better understood by its capacity to concentrate iodine(10000 times more than the normal tissue.The patient who has not received any medication for at least 1 month is given a tracer quantity of radioactive iodine(ie., 25 microcuries in 100 ml of water for a normal sized gland the dose should be increased when the gland is larger than normal and the uptake is directly measured by Gieger muller counter 24 hours after the dose induced. In healthy subjects the iodine uptake is about 20- 40% , ie., this amount is retained by the thyroid gland and rest is excreted. An uptake of 55% or more indicates hyperthyroid and uptake of 20% or less indicates hypothyroidism.

Protein bound plasma activity: the patient who has not taken iodine for at least 2 weeks is given a dose of 10 -20 microcuries of radioactive iodine and 10 ml of blood is taken 48 hours later. Normal range—0—0.4 % dose found in 1 litre of plasma.Thyrotoxicosisà >0.4%

Urinary excretion of radioactive iodine-urine samples in next 48 hours is collected in 3 samples .
Normal range—35-70% of the dose.
Hyperthyroidism—5-35%
Hypothyroidism—70-97% of the dose.
Laryngioscopy
Involvement of recurrent laryngeal nerve
Radiography—determining the position of trachea which may be displaced or depressed.

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