Hypothyroidism: Causes, symptoms, and treatment

Thyroid Gland

Thyroid Gland Normal Structure:

• Anatomy Embryologically, the thyroid gland arises from a midline invagination at the root of the tongue and grows downwards in front of the trachea and thyroid cartilage to reach its normal position.
• Failure to descent may produce anomalous lingual thyroid. The thyroglossal duct that connects the gland to the pharyngeal floor normally disappears by 6th week of embryonic life.
• In adults, its proximal end is represented by the foramen caecum at the base of the tongue and the distal end by the pyramidal lobe of the thyroid. Persistence of the remnants of thyroglossal duct in adults may develop into thyroglossal cysts. The C-cells of the thyroid originate from the neuroectoderm.
• The thyroid gland in an adult weighs 15-40 gm and is composed of two lateral lobes connected in the midline by a broad isthmus which may have a pyramidal lobe extending upwards. The cut section of the normal thyroid is yellowish and translucent.

Read And Learn More: Systemic Pathology Notes

• Histology The thyroid is composed of lobules of colloid-filled spherical follicles or acini. The lobules are enclosed by fibrovascular septa.
• The follicles are the main functional units of the thyroid. They are lined by cuboidal epithelium with numerous fine microvilli extending into the follicular colloid that contains the glycoprotein, thyroglobulin.
• The follicles are separated from each other by delicate fibrous tissue that contains blood vessels, lymphatics and nerves. Calcitonin-secreting C-cells or parafollicular cells are dispersed within the follicles and can only be identified by silver stains and immunohistochemical methods.

Thyroid Gland Functions: The major function of the 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).

The thyroid is one of the most labile organs in the body and responds to numerous stimuli such as puberty, pregnancy, physiologic stress and various pathologic states. This functional liability of the thyroid is responsible for transient hyperplasia of the thyroidal epithelium.

Under normal conditions, the epithelial lining of the follicles may show changes in various phases of function as under:

1. The resting phase is characterised by large follicles lined by flattened cells and filled with deeply
   staining homogeneous colloid example in colloid goitre and iodine-treated hyperthyroidism.
2. The secretory phase is in which the follicles are lined by cuboidal epithelium and the colloid is
   moderately dark pink e.g. in normal thyroid.
3. The resorptive phase is characterised by follicles lined by columnar epithelium and containing
   lightly stained vacuolated and scalloped colloid examples in hyperthyroidism.

The synthesis and release of the two main circulating thyroid hormones, T3 and T4 are regulated by hypophyseal thyroid-stimulating hormone (TSH) and involve the following steps:

1. Iodine trapping by thyroidal cells involves absorbing iodine from the blood and
   concentrating it more than twenty-fold.
2. Oxidation of the iodide takes place within the cells by thyroid peroxidase.
3. Iodination occurs next, at the microvilli level between the oxidised iodine and the tyrosine residues of thyroglobulin so as to form mono-iodotyrosine (MIT) and di-iodotyrosine (DIT).
4. Coupling of MIT and DIT in the presence of thyroid peroxidase forms tri-iodothyronine (T3) and thyroxine (T4).

The thyroid hormones so formed are released by endocytosis of colloid and proteolysis of thyroglobulin within the follicular cells resulting in the discharge of T3 and T4 into circulation where they are bound to thyroxine-binding globulin.

A number of thyroid function tests are currently available. These include the following:

1. Determination of serum levels of total and free thyroxine (T3, T4) by radioimmunoassay (RIA).
2. TSH and TRH determination.
3. Determination of calcitonin secreted by parafollicular C cells.
4. Estimation of thyroglobulin secreted by thyroid follicular cells.
5. Anti-thyroid antibodies levels (TPO antibodies)
6. Assessment of thyroid activity by its ability to uptake radioactive iodine (RAIU).
7. An assessment of whether the thyroid lesion is a nonfunctioning (‘cold nodule’) or hyperactive mass (‘hot nodule’).

Diseases of the thyroid include hyperthyroidism, hypothyroidism, thyroiditis, Graves’ disease, goitre and tumours. The relative frequency of some of these diseases varies in different geographic regions according to the iodine content of the diet consumed.

One of the important investigation tools available in current times is the widespread use of FNAC for thyroid lesions which helps in avoiding a large number of unwanted diagnostic biopsies.

Hyperthyroidism (Thyrotoxicosis):

Hyperthyroidism, also called thyrotoxicosis, is a hypermetabolic clinical and biochemical state caused by the excess production of thyroid hormones. The condition is more frequent in females and is associated with a rise in both T3 and T4 levels in the blood, though the increase in T3 is generally greater than that of T4.

Etiopathogenesis: Hyperthyroidism may be caused by many diseases but the three most common causes are Graves’ disease (diffuse toxic goitre), toxic multinodular goitre and a toxic adenoma.

Less frequent causes are hypersecretion of pituitary TSH by a pituitary tumour, hypersecretion of TRH, thyroiditis, metastatic tumours of the thyroid, struma ovarii, congenital hyperthyroidism in the newborn of a mother with Graves’ disease, hCG-secreting tumours due to mild thyrotropic effects of hCG (example hydatidiform mole, choriocarcinoma and testicular tumours), and lastly, by excessive doses of thyroid hormones or iodine called Jod-Basedow phenomenon.

Hyperthyroidism Clinical Features: Patients with hyperthyroidism have a slow and insidious onset, varying in severity from case to case. The usual symptoms are emotional instability, nervousness, palpitation, fatigue, weight loss in spite of a good appetite, heat intolerance, perspiration, menstrual disturbances and fine tremors of the outstretched hands.

• Cardiac manifestations in the form of tachycardia, palpitations and cardiomegaly are invariably present in hyperthyroidism. The skin of these patients is warm, moist and flushed. Weakness of skeletal muscles and osteoporosis are common.
• Typical eye changes in the form of exophthalmos are a common feature in Graves’ disease. Serum levels of T3 and T4 are elevated but TSH secretion is usually inhibited.
• A sudden spurt in the severity of hyperthyroidism termed ‘thyroid storm’ or ‘thyroid crisis’ may occur in patients who have undergone subtotal thyroidectomy before adequate control of the hyperthyroid state, or in a hyperthyroid patient under acute stress, trauma, and with severe infection.
• These patients develop high-grade fever, tachycardia, cardiac arrhythmias and coma and may die of congestive heart failure or hyperpyrexia.

Hypothyroidism:

Hypothyroidism is a hypometabolic clinical state resulting from inadequate production of thyroid hormones for prolonged periods, or rarely, from resistance of the peripheral tissues to the effects of thyroid hormones. The clinical manifestations of hypothyroidism, depending upon the age at onset of the disorder, are divided into 2 forms:

1. Cretinism or congenital hypothyroidism is the development of severe hypothyroidism during infancy and childhood.
2. Myxoedema is adulthood hypothyroidism.

Cretinism:

A cretin is a child with severe hypothyroidism present at birth or develop within the first two years of postnatal life. This is the period when brain development is taking place; in the absence of treatment, the child is both physically and mentally retarded.

The word ‘Cretin’ is derived from the French, meaning Christ-like because these children are so mentally retarded that they are incapable of committing sins.

Etiopathogenesis: The causes of congenital hypothyroidism are as follows:

1. Developmental anomalies e.g. thyroid agenesis and ectopic thyroid.
2. Genetic defects in thyroid hormone synthesis example defects in iodine trapping, oxidation, iodination, coupling and thyroglobulin synthesis.
3. Foetal exposure to iodides and antithyroid drugs.
4. Endemic cretinism in regions with endemic goitre due to dietary lack of iodine (sporadic
   cretinism, on the other hand, is due to developmental anomalies and genetic defects in thyroid
   hormone synthesis described above).

Hypothyroidism Clinical Features: The clinical manifestations usually become evident within a few weeks to months of birth. The presenting features of a cretin are slow to thrive, poor feeding, constipation, dry scaly skin, hoarse cry and bradycardia.

• As the child ages, a clinical picture of fully-developed cretinism emerges characterised by impaired skeletal growth and consequent dwarfism, a round face, a narrow forehead, widely-set eyes, a flat and broad nose, a big protuberant tongue and a protuberant abdomen.
• Neurological features such as deaf-mutism, spasticity and mental deficiency are more evident in sporadic cretinism due to developmental anomalies and dyshormonogenetic defects.
• Characteristic laboratory findings include a rise in TSH levels and a fall in T3 and T4 levels.

Myxoedema:

The adult-onset severe hypothyroidism causes myxoedema. The term myxoedema connotes nonpitting oedema due to the accumulation of hydrophilic mucopolysaccharides in the ground substance of the dermis and other tissues.

Etiopathogenesis: There are several causes of myxoedema listed below but the first two are the most common causes:

1. Ablation of the thyroid by surgery or radiation.
2. Autoimmune (lymphocytic) thyroiditis (termed primary idiopathic myxoedema).
3. Endemic or sporadic goitre.
4. Hypothalamic-pituitary lesions.
5. Thyroid cancer.
6. Prolonged administration of antithyroid drugs.
7. Mild developmental anomalies and dyshormonogenesis.

Myxoedema Clinical Features: The onset of myxoedema is slow and a fully-developed clinical syndrome may appear after several years of hypothyroidism. The striking features are cold intolerance, mental and physical lethargy, constipation, slowing of speech and intellectual function, puffiness of the face, loss of hair and altered texture of the skin.

• The laboratory diagnosis in myxoedema is made by low serum T3 and T4 levels and markedly elevated TSH levels as in the case of cretinism but cases with parathyroid lesions (hypothalamic-pituitary disease) have low TSH levels.
• The clinical appearance of these three major forms of functional disorders of the thyroid gland (hyperthyroidism, cretinism and myxoedema) is shown.

Thyroiditis:

Inflammation of the thyroid, thyroiditis, is more often due to non-infectious causes and is classified on the basis of onset and duration of disease into acute, subacute and chronic as under:

Acute thyroiditis

1. Bacterial infection example Staphylococcus, and Streptococcus.
2. Fungal infection example Aspergillus, Histoplasma, and Pneumocystis.
3. Radiation injury.

Subacute thyroiditis

1. Subacute granulomatous thyroiditis (de Quervain’s thyroiditis, giant cell thyroiditis, viral thyroiditis)
2. Subacute lymphocytic (postpartum, silent) thyroiditis
3. Tuberculous thyroiditis.

Chronic thyroiditis

1. Autoimmune thyroiditis (Hashimoto’s thyroiditis or chronic lymphocytic thyroiditis)
2. Riedel’s thyroiditis (or invasive fibrous thyroiditis)

While acute infectious thyroiditis is uncommon, some of the morphologically important forms of thyroiditis from the above list are discussed below.

Hashimoto’S (Autoimmune, Chronic Lymphocytic) Thyroiditis:

Hashimoto’s thyroiditis, also called diffuse lymphocytic thyroiditis, struma lymphomatous or goitrous autoimmune thyroiditis, is characterised by 3 principal features:

1. Diffuse firm, goitrous enlargement of the thyroid.
2. Lymphocytic infiltration of the thyroid gland.
3. Presence of thyroid autoantibodies.

Hashimoto’s thyroiditis occurs more frequently between the age of 30 and 50 years and shows an approximately ten-fold preponderance among females. Though rare in children, about half the cases of adolescent goitre are owing to autoimmune thyroiditis.

Hashimoto’s thyroiditis is the most common cause of goitrous hypothyroidism in regions with chronic exposure to high iodine diet such as in Japan.

Hashimoto’S Etiopathogenesis: Hashimoto’s thyroiditis is an autoimmune disease that is well-established. Hashimoto, a Japanese surgeon, described it in 1912 as the first autoimmune disease of any organ. The autoimmune pathogenesis of Hashimoto’s thyroiditis is explained by the following observations:

1. Other autoimmune disease association Like many autoimmune diseases, Hashimoto’s disease has been found in associated with other autoimmune diseases such as Graves’ disease, SLE, Sjögren’s syndrome, rheumatoid arthritis, pernicious anaemia and Type 1 diabetes mellitus.
2. Immune destruction of thyroid cells An association of cytotoxic lymphocyte-associated antigen 4 (CTLA4), a T cell regulatory gene, with the autoimmune phenomenon in Hashimoto’s disease has been reported. There is initial activation of CD4+ T helper cells, which then induce infiltration of CD8+ T cytotoxic cells in the thyroid parenchyma.
   • In the process, B cells are also activated to form autoantibodies, which bring about immune destruction of the thyroid parenchyma.
3. Detection of autoantibodies The following autoantibodies against different thyroid cell antigens are detectable in the sera of most patients with Hashimoto’s thyroiditis:
   1. Thyroid microsomal autoantibodies (against the microsomes of the follicular cells).
   2. Thyroglobulin autoantibodies.
   3. TSH receptor autoantibodies.
   4. Less constantly found are thyroid autoantibodies against follicular cell membranes, thyroid hormones themselves, and colloid components other than thyroglobulin.
4. Inhibitory TSH-receptor antibodies TSH-receptor antibody seen on the surface of thyroid cells in Hashimoto’s thyroiditis is inhibitory to TSH, producing hypothyroidism. A similar antibody is observed in Graves’ disease where it causes hyperthyroidism.
   • It appears that TSH receptor antibodies may act both to depress or stimulate the thyroid cells to produce hypo- or hyperthyroidism respectively. Thus, these patients may have alternate episodes of hypo- or hyperthyroidism.
5. Genetic basis The disease has a higher incidence in first-degree relatives of affected patients. Hashimoto’s thyroiditis is seen more often with HLA-DR3, -DR4-DR5 in Caucasians.

Morphologic Features: Pathologically, two varieties of Hashimoto’s thyroiditis are seen: the classic form, the usual and more common, and the fibrosing variant found in only 10% of cases of Hashimoto’s thyroiditis.

Grossly, the classic form is characterised by diffuse, symmetric, firm and rubbery enlargement of the thyroid which may weigh 100-300 gm. The sectioned surface of the thyroid is fleshly with accentuation of normal lobulations but with the retained normal shape of the gland. A fibrosing variant has a firm, enlarged thyroid with compression of the surrounding tissues.

Histologically, the classic form shows the following features:

1. There is extensive infiltration of the gland by lymphocytes, plasma cells, immunoblasts and macrophages, with the formation of lymphoid follicles having germinal centres.
2. There is a decreased number of thyroid follicles which are generally atrophic and are often devoid of colloid.
3. The follicular epithelial cells are transformed into their degenerated state termed Hürthle cells (also called Askanazy cells, oxyphil cells, or oncocytes). These cells have abundant oxyphilic or eosinophilic and granular cytoplasm due to a large number of mitochondria and contain large vesicular nuclei.
4. There is the slight fibrous thickening of the septa separating the thyroid lobules.

The less common fibrosing variant of Hashimoto’s thyroiditis shows considerable fibrous replacement of thyroid parenchyma and a less prominent lymphoid infiltrate.

Hashimoto’S Clinical Features: Presenting feature of Hashimoto’s thyroiditis is a painless, firm and moderate goitrous enlargement of the thyroid gland, usually associated with hypothyroidism, in a middle-aged woman.

• At this stage, serum T3 and T4 levels are decreased and RAIU is also reduced. A few cases, however, develop hyperthyroidism, termed hashitoxicosis, further substantiating the similarities in the autoimmune phenomena between Hashimoto’s thyroiditis and Graves’ thyrotoxicosis.
• There is no increased risk of developing thyroid carcinoma in Hashimoto’s thyroiditis but there is increased frequency of malignant lymphoma in these cases.
• A variant of autoimmune thyroiditis is subacute lymphocytic (or painless or silent or postpartum) thyroiditis seen more often 3-6 months after delivery.

Subacute Granulomatous (De Quervain’S) Thyroiditis:

• Granulomatous thyroiditis, also called de Quervain’s or subacute, or giant cell thyroiditis, is a distinctive form of self-limited inflammation of the thyroid gland.
• The etiology of the condition is not known 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. The condition is self-limiting and shows complete recovery of thyroid function in about 6 months.

Morphologic Features Grossly, there is moderate enlargement of the gland which is often asymmetric or focal. 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 the formation of microabscesses.
• Later, the more characteristic feature of granulomatous appearance is produced. These granulomas consist of central colloid material surrounded by histiocytes and scattered multinucleate giant cells.
• 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.

Riedel’S Thyroiditis:

• Riedel’s thyroiditis, also called Riedel’s struma or invasive fibrous thyroiditis, is a rare chronic disease characterised by stony-hard thyroid that is densely adherent to the adjacent structures in
  the neck.
• The condition is clinically significant due to compressive clinical features (for example dysphagia, dyspnoea, recurrent laryngeal nerve paralysis and stridor) and its resemblance with thyroid cancer. Riedel’s struma is seen more commonly in females in the 4th to 7th decades of life.
• The 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.

Morphologic Features Grossly, the thyroid gland is usually contracted, stony-hard, asymmetric and firmly adherent to the adjacent structures. The Cut section is hard and devoid of lobulations.

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.

Graves’ Disease (Diffuse Toxic Goitre):

Graves’ disease, also known as Basedow’s disease, primary hyperplasia, exophthalmic goitre,
and diffuse toxic goitre, is characterised by a triad of features:

1. Hyperthyroidism (thyrotoxicosis)
2. Diffuse thyroid enlargement
3. Ophthalmopathy

The disease is more frequent between the age of 30 and 40 years and has a five-fold increased prevalence among females.

Etiopathogenesis: Graves’ disease is an autoimmune disease having many immunologic similarities with Hashimoto’s thyroiditis. A combination of environmental and genetic factors contribute to susceptibility to Graves’ disease. These are as follows:

1. Genetic factor association: Like in Hashimoto’s thyroiditis. Graves’ disease too has a genetic predisposition. A familial occurrence has been observed. Susceptibility to develop Graves’ disease has been found associated with HLA-DR3, CTLA-4 and PTPN22 (a T-cell regulatory gene)Hashimoto’s thyroiditis has HLA-DR3, -DR4 and -DR5 association,

2. Autoimmune disease association: Graves’ disease may be found in association with other organ-specific autoimmune diseases. Hashimoto’s thyroiditis and Graves’ disease are frequently present in the same families and the two diseases may coexist in the same patient.

3. Other factors: Besides these two factors, Graves’ disease has a higher prevalence in women (7 to 10 times), and is associated with emotional stress and smoking.

4. Autoantibodies: Autoantibodies against thyroid antigens are detectable in the serum of these patients too but their sites of action are different from that of Hashimoto’s thyroiditis. In Graves’ disease, TSH-receptor autoantigen is the main antigen against which autoantibodies are directed. These are as under:

1. Thyroid-stimulating immunoglobulin (TSI) binds to the TSH receptor and stimulates increased
   release of thyroid hormone.
2. Thyroid growth-stimulating immunoglobulins (TGI) stimulates the proliferation of follicular epithelium.
3. TSH-binding inhibitor immunoglobulins (TBII) It is inhibitory to the binding of TSH to its own receptor. Depending upon its action as inhibitory or stimulatory to the follicular epithelium, it may result in alternate episodes of hypo- and hyperthyroidism.

However, it is not quite clear what stimulates B cells to form these autoantibodies in Graves’ disease. Possibly, intrathyroidal CD4+ helper T cells are responsible for stimulating B cells to secrete autoantibodies.

The pathogenesis of Graves’ infiltrative ophthalmopathy is also based on autoimmune origin. The evidence in support is the intense lymphocytic infiltrate around the ocular muscles and detection of circulating autoantibodies against muscle antigens that cross-react with thyroid microsomes.

Morphologic Features Grossly, the thyroid is moderately, diffusely and symmetrically enlarged and may weigh up to 70-90 gm. On the cut section, the thyroid parenchyma is typically homogeneous, red-brown and meaty and lacks the normal translucency.

Histologically, the following features are found:

1. There is considerable epithelial hyperplasia and hypertrophy as seen by the increased height of the follicular lining cells and formation of papillary infoldings of piled up epithelium into the lumina of follicles which are small.
2. The colloid is markedly diminished and is lightly staining, watery and finely vacuolated.
3. The stroma shows increased vascularity and accumulation of lymphoid cells.

However, the pathologic changes in gross specimens as well as on histologic examination are considerably altered if preoperative medication has been administered. Iodine administration results in the accumulation of colloids in the follicles and a decrease in vascularity and height of follicular cells, while antithyroid drugs such as thiouracil cause marked hyperplasia.

Clinical Features: Graves’ disease generally develops slowly and insidiously.

• Patients are usually young women who present with symmetric, moderate enlargement of the thyroid gland with features of thyrotoxicosis, ophthalmopathy and dermatopathy.
• Ocular abnormalities are lid lag, upper lid retraction, stare, weakness of eye muscles and proptosis. In extreme cases, the lids can no longer close and may produce corneal injuries and ulcerations.
• Dermatopathy in Graves’ disease most often consists of pretibial (localised) myxoedema in the form of firm plaques.

Like in Hashimoto’s thyroiditis, there is no increased risk of development of thyroid cancer in Graves’ disease.

Goitre:

The term goitre is defined as thyroid enlargement caused by compensatory hyperplasia and hypertrophy of the follicular epithelium in response to thyroid hormone deficiency.

The end result of this hyperplasia is generally a euthyroid state (in contrast to thyrotoxicosis occurring in diffuse toxic goitre or Graves’ disease) though at some stages there may be hypo- or hyperthyroidism. Two morphologic forms of goitre are distinguished:

1. Diffuse goitre (simple nontoxic goitre or colloid goitre).
2. Nodular goitre (multinodular goitre or adenomatous goitre).

Pathogenesis Of Goitre:

• The pathogenetic mechanisms of both forms of goitre can be considered together since nodular goitre is generally regarded as the end-stage of a long-standing simple goitre. The fundamental defect is the deficient production of thyroid hormones due to various etiologic factors described below, but the most common is a dietary lack of iodine.
• Deficient thyroid hormone production causes excessive TSH stimulation which leads to hyperplasia of follicular epithelium as well as formation of new thyroid follicles. The cyclical hyperplastic stage followed by the involution stage completes the picture of simple goitre.
• Repeated and prolonged changes of hyperplasia result in the continued growth of thyroid tissue while involuted areas undergo fibrosis, thus completing the picture of nodular goitre.

Diffuse Goitre (Simple Non-Toxic Goitre, Colloid Goitre):

• Diffuse, nontoxic simple or colloid goitre is the name given to diffuse enlargement of the thyroid gland, unaccompanied by hyperthyroidism.
• Most cases are in a state of euthyroid though they may have passed through the preceding stage of hypothyroidism due to an inadequate supply of iodine.
• TSH levels are invariably elevated. In general, goitre is more common in females. Simple goitre
  often appears at puberty or in adolescence, following which it may either regress or may progress
  to nodular goitre.

Aetiology: Epidemiologically, goitre occurs in 2 forms: endemic, and non-endemic or sporadic.

Endemic goitre: The prevalence of goitre in a geographic area in more than 10% of the population is termed endemic goitre. Such endemic areas are several high mountainous regions far from the sea where the iodine content of drinking water and food is low such as in the regions of the Himalayas, the Alps and the Andes. Of late, however, the prevalence in these areas has declined due to the prophylactic use of iodised salt.

Though most endemic goitres are caused by a dietary lack of iodine, 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 roots.

Sporadic (non-endemic) goitre: Non-endemic or sporadic simple goitre is less common than the endemic variety. In most cases, the aetiology of sporadic goitre is unknown. A number of causal influences have been attributed. These include the following:

1. Suboptimal iodine intake in conditions of increased demand example in puberty, pregnancy
2. Genetic factors
3. Dietary goitrogenic
4. Hereditary defect in thyroid hormone synthesis and transport (dyshormonogenesis)
5. Inborn errors in iodine metabolism

Morphologic Features Grossly, the enlargement of the thyroid gland in simple goitre is moderate (weighing up to 100-150 gm), symmetric and diffuse. Cut surface is gelatinous and translucent brown.

Histologically, two stages are distinguished:

1. The hyperplastic stage is the early stage and is characterised by tall columnar follicular epithelium showing papillary infoldings and the formation of small new follicles.
2. The involution stage generally follows the hyperplastic stage after a variable period of time. This stage is characterised by large follicles distended by colloid and lined by flattened follicular epithelium.

Goitre

• As already stated nodular goitre is regarded as the end-stage of long-standing simple goitre. It is
  characterised by the most extreme degree of tumour-like enlargement of the thyroid gland and
  characteristic nodularity.
• The enlargement of the gland may be sufficient to not only cause cosmetic disfigurement but in many cases may cause dysphagia and choking due to compression of the oesophagus and trachea.
• Most cases are in a euthyroid state but about 10% of cases may develop thyrotoxicosis resulting in toxic nodular goitre or Plummer’s disease. However, thyrotoxicosis of Plummer’s disease (toxic nodular goitre) differs from that of Graves’ disease (diffuse toxic goitre) in lacking features of ophthalmopathy and dermatopathy.
• Such ‘hot nodules’ may be picked up by CT scans or by RAIU studies. Since nodular goitre is derived from simple goitre, it has the same female preponderance but affects older individuals because it is a late complication of simple goitre.

Aetiology: Etiologic factors implicated in an endemic and non-endemic or sporadic variety of simple goitre are involved in the aetiology of nodular goitre too. However, how the nodular pattern is produced is not clearly understood.

Possibly, epithelial hyperplasia, generation of new follicles, and irregular accumulation of colloid in the follicles all contribute to producing increased tension and stress in the thyroid gland causing rupture of follicles and vessels.

This is followed by haemorrhages, cystic change, scarring and sometimes calcification, resulting in the development of a nodular pattern.

Morphologic Features Grossly, the thyroid in nodular goitre shows asymmetric and extreme enlargement, weighing 100-500 gm or even more. The five cardinal macroscopic features are as under:

1. Nodularity with poor encapsulation
2. Fibrous scarring
3. Haemorrhages
4. Focal calcification
5. Cystic degeneration

The cut surface generally shows multinodular but occasionally there may be only one or two nodules which are poorly circumscribed (unlike complete encapsulation of thyroid adenoma, described below).

Histologically, the same heterogenicity as seen on gross appearance is seen. Corresponding microscopic features are as follows:

1. Partial or incomplete encapsulation of nodules.
2. The follicles vary from small to large and are lined by flat to high epithelium. A few may show micropapillary formation.
3. Areas of haemorrhages, haemosiderin-laden macrophages and cholesterol crystals.
4. Fibrous scarring with foci of calcification.
5. Micro-macro cystic change.

Non-neoplastic Diseases of the Thyroid Gland:

• Hyperthyroidism or thyrotoxicosis is a hypermetabolic clinical and biochemical state caused by the excess production of thyroid hormones.
• Hypothyroidism is a hypometabolic state resulting from inadequate production of thyroid hormones for prolonged periods. It has 2 forms: cretinism or congenital hypothyroidism is the development of severe hypothyroidism during infancy and childhood, and myxoedema is adulthood hypothyroidism.
• Thyroiditis may be due to infections but is more often noninfectious. It includes acute (bacterial or fungal infection and radiation injury), subacute (granulomatous thyroiditis) and chronic (for example autoimmune thyroiditis or Hashimoto’s thyroiditis, Riedel’s thyroiditis).
• Graves’ disease is a combination of 3 features: diffuse thyroid enlargement, hyperthyroidism, and ophthalmopathy. It has autoimmune pathogenesis in a genetically susceptible individual with exposure to environmental factors.
• Goitre is an enlargement of the thyroid due to compensatory hyperplasia in response to thyroid hormone deficiency. It may be diffuse or nodular goitre.

Thyroid Tumours:

Most primary tumours of the thyroid are of follicular epithelial origin; a few arise from parafollicular C-cells. Besides clearly benign and clearly malignant tumours, the 2017 WHO classification of thyroid tumours has added a borderline group too. Common examples are discussed below.