A Brief Review on Thyroid Disease

Thyroid diseases are, arguably, among the commonest endocrine disorders worldwide. India too, is no exception. According to a projection from various studies on thyroid disease, it has been estimated that about 42 million people in India suffer from thyroid diseases. (1) Thyroid diseases are different from other diseases in terms of their ease of diagnosis, accessibility of medical treatment, and the relative visibility that even a small swelling of the thyroid offers to the treating physician. Early this diagnosis and treatment remains the cornerstone of management. Thyroid disorders affect a substantial proportion of the general population, but most have a remarkably higher incidence in women. Worldwide, the most common cause of thyroid disorders is iodine deficiency. Although eradicated in many parts of the world, it is still a major health problem affecting almost a third of the world's population. About twenty million people are believed to be significantly mentally handicapped as a result of iodine deficiency. In iodine-sufficient regions, the autoimmune thyroid diseases, Hashimoto's thyroiditis and Graves’ disease are the most common clinical entities affecting the thyroid. The prevalence of thyroid disorders depends on the diagnostic criteria used and the surveyed population's age and sex. The prevalence of overt hypothyroidism is ∼ 3–20 per 1000 females and ∼ 1–7 per 1000 males. The most common cause of hypothyroidism is Hashimoto's thyroiditis. The prevalence of hyperthyroidism is ∼ 2–19 per 1000 females and ∼ 1–2 per 1000 males. Graves’ disease is its most frequent cause. The differences in the prevalence of hypo- and hyperthyroidism in men and women are most commonly explained by influences of sex steroids on immune regulatory mechanisms. Thyroid carcinomas are relatively rare neoplasms that account for 0.6–1.6% of all malignancies. The annual incidence of papillary, follicular, and differentiated thyroid carcinomas cancer is 1–10 per 100,000 people. They are about three times more common in women than men. (2) The thyroid hormone axis is an endocrine system with many important actions, including growth and development. As a result, the thyroid hormone axis is also a potential cause of myriad signs and symptoms. Thyroid function is routinely checked as part of the annual physical examination despite the lack of clinical evidence for this practice and the resultant increase in health-care costs. Concern for thyroid dysfunction is one of the most common reasons for referral to apediatric endocrinologist. As with other endocrine measures, age and clinical status strongly influence what are considered normal values with testing .Although thyroid dysfunction. (2) Problems with the thyroid gland are extremely common. It has been estimated that as many as one and a half billion people in the world are at risk for thyroid problems. Hypo-thyroidism the most common thyroid malfuntion but it is possible to have hyperactive thyroid gland. Subclinical hypo-thyroidism is also an important condition, affecting upto20 % of persons beyond 60 years of age. (3).

Literature Review:

• Introduction to thyroid gland and their functions:

The thyroid gland consists of two lobe connected by a thin isthmus, usually located below and anterior to the larynx. Each lobe is divided into lobules, each containing 20 to 40 evenly dispersed follicles. The follicles are lined by cuboidal to low columnar epithelial cells that synthesize thyroglobulin, the iodinated precursor protein active thyroid hormone. Thyroglobulin is stored in the lumen of follicles as a homogeneous suspension called colloid. In response to trophic factors from the hypothalamus, TSH (also called thyrotropin) is released by thyrotrophs in the anterior pituitary into the circulation. TSH binds to its receptor on thyroid follicular epithelial cells, activating a stimulatory G-protein, and this signaling pathway induces the synthesis and release of thyroid hormone. (4)

• Anatomy of thyroid gland

The thyroid is a butterfly-shaped gland located in the front of the neck just above the trachea. It weighs approximately 15 to 20 grams in the adult human. The thyroid gland is divided into two lobes connected by the isthmus, which crosses the midline of the upper trachea at the second and third tracheal rings. In its anatomic position, the thyroid gland lies posterior to the sternothyroid and sternohyoid muscles, wrapping around the cricoid cartilage and tracheal rings.  It is located inferior to the laryngeal thyroid cartilage, typically corresponding to the vertebral levels C5-T1. The thyroid attaches to the trachea via a consolidation of connective tissue, referred to as the lateral suspensory ligament or Berry’s ligament. This ligament connects each of the thyroid lobes to the trachea. The thyroid gland, along with the esophagus, pharynx, and trachea, is found within the visceral compartment of the neck, which is bound by pre tracheal fascia^.(5) The thyroid gland, anterior pituitary gland, and hypothalamus comprise a self-regulatory circuit called the hypothalamic-pituitary-thyroid axis. The main hormones produced by the thyroid gland are thyroxine or tetraiodothyronine (T4) and triiodothyronine (T3). Thyrotropin-releasing hormone (TRH) from the hypothalamus, thyroid-stimulating hormone (TSH) from the anterior pituitary gland, and T4 work in synchronous harmony to maintain proper feedback mechanisms and homeostasis. Hypothyroidism, caused by an underactive thyroid gland, typically manifests as bradycardia, cold intolerance, constipation, fatigue, and weight gain. In contrast, hyperthyroidism caused by increased thyroid gland function manifests as weight loss, heat intolerance, diarrhea, fine tremor, and muscle weakness^{. (6)} Regulation of thyroid hormone starts at the hypothalamus. The hypothalamus releases thyrotropin-releasing hormone (TRH) into the hypothalamic-hypophyseal portal system to the anterior pituitary gland. TRH stimulates thyrotropin cells in the anterior pituitary to release thyroid-stimulating hormone (TSH). TRH is a peptide hormone created by the cell bodies in the periventricular nucleus (PVN) of the hypothalamus. These cell bodies project their neurosecretory neurons down to the hypophyseal portal circulation, where TRH can concentrate before reaching the anterior pituitary. ⁽⁶⁾

Fig (1). Anatomy of thyroid gland (7)

• Synthesis, storage and secretion of thyroid hormone ⁽⁸⁾

The thyroid hormoes are synthesized and stored in the thyroid follicles as part of thyroglobulin molecule—which is a glycoprotein synthesized by thyroid cells, MW 660 KDa, contains 10% sugar. The synthesis, storage and release of T4 and T3 is summarized in Fig. (2) and involves the following processes.

(1) Inorganic iodide is transported into the gland

(2) Intra thyroidal iodide is oxidized to iodine under the influence of h2o2 and peroxidase

(3) Iodine is bound in thyroglobulin to tyrosine, forming monoiodotyrosine and diiodotyrosine

(4) Iodotyrosines are enzymatically coupled to form thyroxine (t4) and triiodothyronine (t3)

(5) Iodothyronines, t4 and t3, are stored in thyroglobulin until released into the circulation; and

(6) Unused iodotyrosines are deiodinated and the iodide is recycled.

1. Iodide Uptake

The total body content of I2, obtained from food and water, is 30–50 mg, out of which about 1/5 is present in the thyroid. Concentration of iodide in blood is low (0.2–0.4 μg/dl) but thyroid cells have an active transport process (Na+: I¯ symporter or NIS) to concentrate this anion; this trapping is stimulated by TSH to exceed a gradient of more than 100 fold. The I2 content of thyroid gland somehow regulates the uptake mechanism: meagre store activating and large store inhibiting it. The iodide concentrating mechanism is not peculiar to thyroid; skin, salivary glands, gastric mucosa, intestine, mammary glands and placenta also possess it, but uptake in these organs is not stimulated by TSH.

2. Oxidation And Iodination          

Iodide trapped by follicular cells is carried across the apical membrane by another transporter termed ‘pendrin’ and oxidized by the membrane bound thyroid peroxidase enzyme to iodinium (I+) ions or hypoiodous acid (HOI) or enzyme linked hypoiodate (EOI) with the help of H2O2. These forms of iodine combine avidly with tyrosil residues of thyroglobulin, apparently without any enzymatic intervention, to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) while the residues are still attached to the thyroglobulin chains.

Fig. (2) Synthesis, storage and secretion of thyroid hormone ⁽⁹⁾

3. Coupling

Pairs of iodinated tyrosil residues couple together (Fig. 18.2) to form T3 and T4. Normally much more T4 than T3 is formed, but during I2 deficiency relatively more MIT is available and a greater proportion of T3 is formed. Thus, more active hormone is generated with lesser amount of I2.Coupling is an oxidative reaction and is catalysed by the same thyroid peroxidase. Thyroglobulin is the most efficient protein in supporting coupling by providing favourable spatial configuration to facilitate the reaction. Oxidation of iodide and coupling are both stimulated by TSH.

4. Storage and Release        

Thyroglobulin containing iodinated tyrosil and thyronil residues is transported to the interior of the follicles and remains stored as thyroid colloid till it is taken back into the cells by endocytosis and broken down by lysosomal proteases. The T4 and T3 so released is secreted into circulation while MIT and DIT residues are de-iodinated and the iodide released is reutilized. The uptake of colloid and proteolysis are stimulated by TSH: the quiscent gland has follicles distended with colloid and cells are flat or cubical, while the TSH stimulated gland has columnar cells and colloid virtually disappears. Normal human thyroid secretes 60-90 µg of T4 and 10-30 µg of T3 daily.

5. Peripheral Conversion of T4 To T3

Peripheral tissues, especially liver and kidney, convert T4 to T3. About 1/3 of T4 secreted by thyroid undergoes this change and most of the T3 in plasma is derived from liver. Target tissues take up T3 from circulation for their metabolic need, except brain and pituitary which take up T4 and convert it to T3 within their own cells. Almost equal amounts of 3, 5, 3' triiodothyronine (normal T3: active) and 3, 3?, 5′ triiodothyronine (reverse T3: inactive) are produced in the periphery. Propylthiouracil (but not carbimazole), propranolol (high doses), amiodarone and glucocorticoids inhibit peripheral conversion of T4 to T3 (except in brain and pituitary).

• Normal ranges for thyroid functioning test

Fig. (3) Normal Ranges of thyroid functioning test ⁽⁹⁾

Flow chart (1) of Pathophysiology of Thyroid ⁽¹⁰⁾

5. Types of thyroid disease

Fig. (4) Types of thyroid diseases ⁽¹¹⁾

Hypothyroidism is a disorder that occurs when the thyroid gland does not make enough thyroid hormone to meet the body’s needs. Thyroid hormone regulates metabolism—the way the body uses energy and affects nearly every organ in the body. Without enough thyroid hormone, many of the body’s functions slow down. About 4.6 percent of the U.S. population age 12 and older has hypothyroidism. ⁽¹²⁾ Among the various varieties of hypothyroidism, congenital hypothyroidism is probably the most important, as it is requires an early diagnosis, which is usually followed by appropriate therapy that can prevent the onset of brain damage. Studies from Mumbai have suggested that congenital hypothyroidism is common in India, the disease occurring in 1 out of 2640 neonates, when compared with the worldwide average value of 1 in 3800 subjects. There is often a delay in the diagnosis of congenital hypothyroidism in the country. This delay is attributable to the lack of awareness about the illness, as well as the lack of facilities available or screening program in placeto comprehensively screen and test newborns for this illness. In childhood too, hypothyroidism can occur. In a clinic-based study from Mumbai, out of 800 children with thyroid disease, 79% had hypothyroidism. Common causes of hypothyroidism in these children were thyroid dysgenesis, dyshormonogenesis, and thyroiditis.  ⁽¹⁾ Among adult people in India, the prevalence of hypothyroidism has been recently studied. In this population base study done in Cochin on 971 adult subjects, the prevalence of hypothyroidism was 3.9%. The prevalence of subclinical hypothyroidism was also high in this study, the value being 9.4%. In women, the prevalence was higher, at 11.4%, when compared with men, in whom the prevalence was 6.2%. The prevalence of subclinical hypothyroidism increased with age. About 53% of subjects with subclinical hypothyroidism were positive for anti-TPO antibodies. This was a population-based study, which used cluster sampling strategy. In this study, Urinary Iodine Status was studied in 954 subjects from the same population sampled, and the median value was 211μg/l. ⁽¹⁾

• Hyperthyroidism

Hyperthyroidism, also called overactive thyroid, is when the thyroid gland makes more thyroid hormones than your body needs. The thyroid is a small, butterfly-shaped gland in the front of our neck. Thyroid hormones control the way the body uses energy, so they affect nearly every organ in our body, even the way your heart beats. With too much thyroid hormone, many of your body’s functions speed up. ^(1). The prevalence of hyperthyroidism has been studied in several studies. In an epidemiological study from Cochin, subclinical and overt hyperthyroidism were present in 1.6% and 1.3% of subjects participating in a community survey. In a hospital-based study of women from Pondicherry, subclinical and overt hyperthyroidism were present in 0.6% and 1.2% of subjects.[4] More than a third of community-detected hyperthyroid cases have positive anti-TPO antibodies, and about39% of these subjects are goiter. (1).

Fig. (5) Hyperthyroidism and Hypothyroidism ⁽¹³⁾

• Goiter ⁽¹⁴⁾

Goiter means enlargement of the thyroid gland and is a general term that conveys the information that the volume of the thyroid gland is larger than normal. The presence of goiter can be determined by inspection, palpation, or by an imaging study. Normal thyroid gland measures 4 to 4.8 cm in sagittal, 1 to 1.8 cm in transverse, and 0.8 to 1.6 cm in anteroposterior dimensions. This corresponds to a volume of 7 to 10 mL on ultrasonography calculations and 10-20 grams in weight. Thyroid size increases with age and body size. It is larger in males as opposed to females. The size decreases with higher iodine intake.

• Thyroid Nodule ⁽¹⁴⁾

A thyroid nodule is a lump in or on the thyroid gland. Thyroid nodules are detected in about 6 percent of women and 1-2 percent of men; they occur 10 times as often in older individuals, but are usually not diagnosed. Any time a lump is discovered in thyroid tissue, the possibility of malignancy (cancer) must be considered. More than 95 percent of thyroid nodules are benign (noncancerous), but tests are needed to determine if a nodule is cancerous^{. (15)}

• Thyroid Cancer ⁽¹⁴⁾

Most thyroid cancers are differentiated cancers. The cells in these cancers look a lot like normal thyroid tissue when seen in the lab. These cancers develop from thyroid follicular cells.

1. Papillary cancer (also called papillary carcinomas or papillary adenocarcinomas)
2. Follicular cancer (also called follicular carcinoma or follicular adenocarcinoma)
3. Hürthle (Hurthle) cell cancer (also called oxyphil cell carcinoma)
4. Medullary thyroid carcinoma
5. Anaplastic (undifferentiated) thyroid cancer
6. Parathyroid cancer

• Causes and symptoms

Conditions that can cause hypothyroidism include:

1. Thyroiditis: This condition is an inflammation (swelling) of the thyroid gland. Thyroiditis can lower the amount of hormones your thyroid produces.
2. Hashimoto’s thyroditis: A painless disease, Hashimoto’s thyroiditis is an autoimmune condition where the body’s cells attack and a magete thyroid. This is an inherited condition.
3. Postpartumthyroiditis: This condition occurs in 5%to9% of women after childbirth. It’s usually a temporary condition.
4. Iodine deficiency: Iodine is used by the thyroid to produce hormones. An iodine deficiency is an issue that affects several million people around the world.
5. A non-functioning thyroid gland:

Sometimes, the thyroid gland doesn’t work correctly from birth. This affects about 1 in 4,000 newborns. If left untreated, the child could have both physical and mental issues in the future. All newborns are given a screening blood test in the hospital to check their thyroid function ^(16).

Conditions that can cause hyperthyroidism include:

1. Graves’ Disease: In this condition the entire thyroid gland might be overactive and produce too much hormone .This problem is also called diffuse toxic goiter (enlarged thyroid gland).

2. Nodules: Hyperthyroidism can be caused by nodules that are overactive within the thyroid. A single nodule is called toxic autonomously functioning thyroid nodule, while a gland with several nodules is called a toxic multi-nodular goiter.

3. Thyroiditis: This disorder can be either painfull or not felt at all .In thyroiditis ,the thyroid releases hormones that were stored there .This can last for a few weeks or onths.

4. Excessive Iodine: When you have too much iodine (the mineral that is used to make thyroid hormones) in your body, the thyroid makes more thyroid hormones than it needs. Excessive iodine can be found in some medications (amiodarone, a heart medication) (15)

Fig. (6) Symptoms of Hyperthyroidism ⁽¹⁵⁾

Fig. (7) Symptoms ofHypothyroidism ⁽¹⁵⁾

• Diagnosis of Hypothyroidism

Hypothyroidism is a hypo-metabolic state that results from a deficiency in T4 and T3. Its major clinical manifestations are fatigue, lethargy, cold intolerance, slowed speech and intellectual function, slowed reflexes, hair loss, dry skin, weight gain, and constipation. It is more prevalent in women than men. The most common cause of hypothyroidism is disease of the thyroid itself primary hypothyroidism. The most common cause of primary hypothyroidism is chronic autoimmune thyroiditis (Hashimoto's disease), in which the thyroid is destroyed by antibodies or lymphocytes that attack the gland. Other causes are radioactive iodine and surgical therapy for hyperthyroidism or thyroid cancer, thyroid inflammatory disease, iodine deficiency, and several drugs that interfere with the synthesis or availability of thyroid hormone. Hypothyroidism may also occur rarely (<1percent of cases) as a result of deficiency of TRH or impaired TSH secretion due to hypothalamic or pituitary disease, respectively.

• Diagnosis of Hyperthyroidism

The most common cause of hyperthyroidism is Graves' disease, an autoimmune disease characterized by the production of antibodies that activate the TSH receptor, resulting in stimulation of T4 and T3 production and enlargement of the thyroid. Other caused of hyperthyroidism area multinodular goiter, solitary thyroid adenoma, thyroiditis, iodide-or drug-induced hyperthyroidism, and, very rarely, a TSH secreting pituitary tumor. The diagnosis of hyperthyroidism is based on the findings of a high serum free T4 level and a low serum TSH concentration. Occasionally, people with hyperthyroidism have a normal serum free T4 and high serum free T3 concentrations. These patients have what is called T3-hyperthyroidism. An increase in serum thyroid hormone binding protein will raise the serum total T4 level but not free T4 concentrations. In these patients the serum TSH remains normal. Patients with a low serum TSH concentration and normal serum free T4 and free T3 levels have, by definition, subclinical hyperthyroidism. ^{(13-13/01/2024)}

• Screening Methods:

Screening can be defined as “the application of a test to detect a potential disease or condition in a person who has no known signs or symptoms of that condition at the time the test is done.” By this definition, screening with thyroid function tests may identify asymptomatic individuals as well as patients who have mild, nonspecific symptoms such as cold intolerance or feeling. When many of these symptoms and signs occur together, the clinician may have a strong suspicion that the patient has thyroid disease. However, patients who complain of one or two of the symptoms in may be no more likely to have abnormal thyroid function tests than those who have no complaints. In older patients 7and in pregnant women, such symptoms are so common that it becomes meaningless to try to distinguish between “asymptomatic” patients and those who have symptoms that may or may not be related to thyroid state. ⁽¹⁶⁾

• Thyroid function test ⁽¹⁷⁾

A. Blood test

Tests for thyroid include blood tests to assess thyroid function. They primarily include the       following:

1. 1. TSH
   2. SerumT3, andT4
   3. Thyroglobulin
   4. Auto immunemarkers.

1) TSH: It is one of the most useful tests for assessing thyroid function. Over past few years, three generation of assay tests have come up. All the 3 generation assays can pick up elevated levels of TSH and hence aid in diagnosing primary hypothyroidism (low thyroid hormones due to thyroid gland disease).Second generation immunemetric assays for TSH have detection limits of 0.1mU/Landarehelpfulinscreeningforhyperthyroidism.Thirdgenerationchemiluminescentassays (with detection limits of0.01 m U/L) can distinguish more accurately between hyperthyroidism and hypothyroidism. Normal level so TSH are* 0.4- 4.2mu*U /L.

2) Serum T3, and T4 levels are estimated by radioimmunoassay (RIA), or immunometric techniques like chemiluminescence. Normal levels of T3:70-204ng/dl     Normal levels of T4:6-11µg/dl More than 99.9% of thyroid hormones are bound to proteins but it is only the free hormone that is the active form. Hence assays have been developed to measure free T_{y} and free T, hormones.

The normal levels of free T.: 210 - 440pg / d l The normal levels of free T?: 0.8 - 2.7ng / dl

3) Thyroglobulin:

Thyroglobulin levels can be estimated as part of thyroid function tests along with T y 'T_{4} and TSH levels. It is synthesised by the follicular cells thyroid gland and its levels increase in the blood benign or malignant tumors of the thyroid gland.

4)  Autoimmune markers:

Tests for TSH receptor antibodies (TRAB, TSH-Ab) can detect both types of antibodies-stimulatory as well as those blocking the TSH receptor. In Graves' disease both stimulating and blocking antibody assays will be positive in more than 70% patients. Chronic lymphocytic thyroiditis (Hashimoto's thyroiditis) is characterized by production of antibodies which lead to decreased production of thyroid hormone by the gland. The thyroidperoxidase (TPO) antibody is seen in more than 80% of these patients. Another test involves the measurement of antibodies produced against thyroglobuline

B. Tests-based on use of Nuclear Medicine

Radioactive iodine (RAI) uptake studies by the thyroid gland are assessed along with measurement of TSH levels. In Graves' disease, the uptake is high in spite of very low or undetectable TSH levels. In cases of subacute thyroiditis, the RAI uptake is low along with undetectableTSH.Technetiumpertechnetateorradioactiveiodinescanningcanbeusedtodetect"hot" nodules (not likely to be cancerous) or "cold" nodules which can be cancerous though some dare benign . Radioactive scanning also helps to detect thyroid metastasis or ectopic thyroid tissue. The perchlorate discharge test can be used to pick up defective iodide oxidation or defects in iodination of thyroglobuline.

C. Thyroid Ultrasound

This can pick up very small nodules that may not be picked up clinically.

D. Fine Needle Aspiration Biopsy

This is helpful in assessment of thyroid nodules. It can help in diagnosing and early treatment of thyroid malignancies, while at the same time helps avoid unnecessary surgery in patients with Benign nodules Ultrasound imaging can be used to assist biopsy in cases of nodules that are not palpable.

Fig (7). Thyroid Ultrasound ⁽¹⁷⁾

E. Thyrotropin Releasing Hormone (TRH) Response Test

The patient if administered with thyrotropin releasing hormone, and the variation in secretion of TSH, T3, and T4 is observed (the normal response is increased TSH, TyT1 secretion with increased T3, T4, levels). In patients of hypopituitarism in which pituitary response to TRH is deranged, it leads to abnormal 'thyrotropin releasing hormone test' results. Similarly, the physiological response of TRH (i.e. increased TSH and thereby Ty T?) does not occur and is attributed to the fact that the negative feedback effect of high levels of T, overrides the stimulatory physiological response of TRH.

Classification of thyroid inhibitors

Fig. (8) Classification of Antithyroid Drugs ⁽¹⁸⁾