Essay: Hypothyroidism

Hypothyroidism is a familiar endocrine disease which is a consequent from insufficiency of thyroid hormone or, more rarely, from their retarded function at tissue level. Prevalence is 1.9% in women, and it increases with age. It may be a primary process in which the thyroid gland produces inadequate amounts of thyroid hormone, but can also be secondary, that is, paucity of thyroid hormone secretion due to inadequate secretion of either thyrotropin (that is, thyroid-stimulating hormone [TSH]) from the pituitary gland or thyrotropin-releasing hormone (TRH) from the hypothalamus (secondary or tertiary hypothyroidism). The patient’s inducement may vary from asymptomatic to rarely, coma with multisystem organ failure (myxedema coma). Hypothyroidism is characterized by an overall reduction in metabolic function that most often manifests as a slowing of physical and mental alertness. Subclinical hypothyroidism, referred to as mild hypothyroidism, is defined as normal serum free thyroxine (T4) levels with slightly high serum TSH concentration. The clinical appearance of hypothyroidism are dependent on the patient’s age, the presence of other disease, and the rate at which hypothyroidism develops.

Congenital hypothyroidism (CH) is defined as thyroid hormone deficiency existing at birth. Thyroid hormone deficiency at birth is most usually caused by an issue with thyroid gland development (dysgenesis) or a disability of thyroid hormone biosynthesis (dyshormonogenesis). These disorders result in primary hypothyroidism. Secondary or central hypothyroidism at birth outcome from a deficiency of thyroid stimulating hormone (TSH). Congenital TSH deficiency may rarely be an isolated problem, but most commonly it is associated with other pituitary hormone deficiencies, as part of congenital hypopituitarism. Peripheral hypothyroidism is a separate class resulting from defects of thyroid hormone transport, metabolism, or action. Congenital hypothyroidism is differentiated into permanent and transient congenital hypothyroidism. Permanent congenital hypothyroidism refers to a continuing paucity of thyroid hormone that requires life-long treatment. Transient CH is known as short lived deficiency of thyroid hormone, discovered in neonates, but then recovering to normal thyroid hormone production. Amelioration to euthyroidism usually occurs in the first few months or years of life. Permanent CH can be again classified into permanent primary and secondary (or central) CH; transient primary CH has also been reported. Moreover, some forms of CH are affiliated with defects in other organ systems; these are classified as syndromic hypothyroidism.

Environmental agents intervene with thyroid function at multiple sites, additionally thyroid hormone synthesis, thyroid hormone metabolism and excretion, and thyroid hormone action (1–4). Most of these agents reduce circulating thyroid hormone levels or alter thyroid hormone action, nonetheless some may influence the pituitary and thyrotropin (TSH) secretion, or even be partial thyroid hormone receptor agonists. A number of environmental agents interfere with iodine uptake. For these agents, low iodine nutriment increases frailty and satisfactory iodine intake is advisable to reduce their effect (3, 5). A noteworthy focusing in clinical thyroid disease is to find out and scrutinize thyroid disease at the earliest stages (6). Latest efforts in assessing the impact of environmental agents that interrupt thyroid function have focused on identifying the earliest and astucious effects (7). A less often documented impact of environmental agents that influence the thyroid is triggering autoimmune thyroid disease. The etiology of most functional disorders of the thyroid is autoimmunity. Unnatural thyroid function detected in combination with an environmental exposure is generally thought to be a direct effect of the factors. These facts are best interpreted with familiarity with the factors that can influence thyroid function, including thyroid autoantibody level, iodine intake, smoking history, family history of autoimmune thyroid disease, pregnancy, and medicament usage. In most studies, these details are not all available.

However, the current review has been made to highlight the congenital and environmental factors affecting the hypothyroidism and current status of Bangladesh in thyroid disorders so that it might be helpful in the future to diagnose and pinpoint the actual key factors behind the disease-hypothyroidism and other thyroid disorders in Bangladesh perspective.

Thyroid physiology:

Thyroid hormones are the only iodine-containing substances of physiologic importance in vertebrates. Thyroid cells actively extract and pertain iodide from plasma. T4, a prohormone, is converted to triiodo-thyronine (T3), the efficacious form of thyroid hormone, in the peripheral tissues by 5’-deiodination. Prematurely in the disease mechanism, mandatory mechanisms maintain T3 levels. Regular thyroid hormones produces all of the circulating T4 and T3 (about 20%) (8) and most cellular activity of thyroid hormones are resultant of T3 which has greater affinity (4 to 10 times) for receptors than T4 (9, 10). 80% of serum T3 is obtained from the deiodination of T4 in tissues such as the liver and kidney.

Once T4 and T3 are secreted into the blood flow, they are bound by thyroxine-binding globulin (TBG), transthyretin (thyroxine-binding prealbumin), and albumin. Only the free (unbound) flowing T4 and T3 is capable of binding to specific thyroid hormone receptors in peripheral tissues and possesses biologic activity. Normally, nearly 0.03% of T4 and 0.5% of T3 is free (11, 12).

Changes in the binding ability of thyroid hormone transport proteins may notably affect the calculation of total thyroid hormone concentration and thereby create complication in the diagnosis of hypothyroidism. The accurate diagnosis of thyroid disease is more difficult in patients with multiple abnormalities in thyroid hormone-binding proteins (13).

Pathophysiology: [14]

Most common cause of hypothyroidism is the localized disorder of the thyroid gland that results in decreased thyroid hormone production. Under normal conditions, the thyroid releases 100 to 125 mol of T4 daily and only small amounts of T3. Reduced production of T4 causes an increase in the secretion of TSH by the pituitary gland. TSH stimulates hypertrophy and hyperplasia of the thyroid gland and thyroid T4-5′- deiodinase action. This in turn causes the thyroid to release more T3. Deficiency of the hormone has a wide range of effects, because all metabolically active cells require thyroid hormone. Systemic effects are cause of either derangements in metabolic processes or direct effects by myxedematous infiltration (that is, aggregation of glucosaminoglycans in the tissues).

Congenital factors affecting hypothyroidism:

Prior to the onset of newborn screening programs, the incidence of congenital hypothyroidism, as diagnosed after clinical manifestations, was in the range of 1;7,000 to 1:10,000 [15]. With the advent of screening of newborn populations, the incidence was initially reported to be in the range of 1:3,000 to 1:4,000 [16]. With more experience from state, regional, and national screening programs, it has become apparent that the incidence varies by geographic location. A report from the French newborn screening program summarizing a 20 year period found the incidence of permanent hypothyroidism to be 1:10,000 [17], whereas a report from the Greek Cypriot population over an 11 year period found the incidence in newborns to be 1:800 [18].

A recent report showed that the incidence in the United States increased from 1:4,094 in 1987 to 1:2,372 in 2002 [19]. The reason(s) for the increased incidence is not clear, but one possible explanation may be a change in testing strategy. With increased sensitivity and accuracy of TSH methods, many U.S. and other programs around the world have switched from a primary T4-followup TSH approach to a primary TSH test. If the TSH cutoff is lowered, more infants with milder congenital hypothyroidism will be detected. In addition, there is some variation in the incidence among different racial and ethnic groups, and the mix of these groups has changed. A summary of the New York State program during the years 2000 to 2003 showed some interesting demographic variations in the incidence of congenital hypothyroidism (see Table 1).

Table 1: Incidence of congenital hypothyroidism: Selected demographics from New York State (2000-2003) [20]

Demographic Incidence

Overall 1:1681

Gender

Male 1:1763

Female 1:1601

Ethnicity

White 1:1815

Black 1:1902

Asian 1:1016

Hispanic 1:1559

Birth weight

<1500g 1:1396

1500-2500g 1:815

>2500g 1:1843

Single vs Multiple Birth

Single 1:1765

Twin 1:876

Multiple 1:575

Mother’s age

<20 1:1703

20-29 1:1608

30-39 1:1677

>39 1:1328

As compared to the overall incidence of congenital hypothyroidism, the incidence was somewhat lower in Whites (1:1815) and Blacks (1:1902), somewhat higher in Hispanics (1:1559), and highest in the Asian population (1:1016). In addition, New York found the incidence nearly double in twin births (1:876) as compared to singletons (1:1765), and even higher with multiple births (1:575). Older mothers (> 39 years) had a higher incidence (1:1,328) compared to younger mothers (< 20 years, 1:1,703). The incidence was higher in preterm vs. term infants [19]. It is not clear whether that the congenital hypothyroidism in preterm infants is transient or permanent. However, as the incidence of preterm births has increased by approximately 20 percent over the last 20 years, this may contribute to the reported overall increased incidence. Nearly all screening programs report a female preponderance, approaching 2:1 female to male ratio [21]. A report from Quebec shows this female preponderance occurs mostly with thyroid ectopy, and less so with agenesis [22].

Clinical description:

The clinical features of congenital hypothyroidism are often subtle and many newborn infants remain undiagnosed at birth [23, 24]. This is due in part to passage of maternal thyroid hormone across the placenta. This is measured in umbilical cord serum to be 25-50 percent of normal [25]. This provides a protective effect, especially to the fetal brain [26]. Also, the most common form of congenital hypothyroidism has some moderately functioning thyroid tissue [27]. The slow development of obvious clinical symptoms [28], coupled with the importance of early treatment led to the implementation of widespread newborn screening for this condition [16]. However, newborn screening for hypothyroidism is not done in many third world countries. Only an estimated 1/3 of the worldwide birth population is screened. It is therefore important that clinicians are able to recognize and treat the disorder.

Symptoms [29]:

Over half the babies born with CHT look entirely normal and have no obvious symptoms at all. That is why it is so important that all children are tested at birth. CHT can often be diagnosed before the baby shows any definite signs of the condition. Some babies with hypothyroidism are sleepy and difficult to feed, although lots of babies have these symptoms without being hypothyroid! This really highlights the importance of screening for CHT in all newborn babies. Other symptoms may include constipation, low muscle tone (floppiness), cold extremities, and poor growth. Some hypothyroid babies have prolonged jaundice (with an associated yellow skin) after birth. Although some children with CHT have development problems, the likelihood of a significant long-lasting effect is low as long as appropriate treatment is started promptly. If your child is diagnosed with CHT the doctor will examine them very carefully to check for any other problems.

Signs:

The physical findings of hypothyroidism may or may not be present at birth. Signs include the following: coarse facial features, macroglossia, large fontanelles, umbilical hernia, mottled, cool, and dry skin, developmental delay, pallor, myxedema, Goiter etc. [30]. The typical appearance of a hypothyroid infant before the advent of newborn screening is shown in the infant in Figure 1. Features include jaundice, a puffy face and wide posterior fontanelle with open sutures. The nasal bridge is flat and the eyes exhibit pseudo hypertelorism. The mouth may be slightly open revealing macroglossia. Further examination would reveal a protuberant abdomen with a large umbilical hernia. Skin may be cool to touch and mottled in appearance reflecting circulatory compromise [23].

Figure 1: Infant with congenital hypothyroidism. A – 3 month old infant with untreated CH; picture demonstrates hypotonic posture, myxedematous facies, macroglossia, and umbilical hernia. B – Same infant, close up of face, showing myxedematous facies, macroglossia, and skin mottling. C – Same infant, close up showing abdominal distension and umbilical hernia. [20]

Congenital malformations

Congenital hypothyroidism appears to be associated with an increased risk of congenital malformations. In one study of 1420 infants with congenital hypothyroidism, extra thyroidal congenital malformations had a prevalence of 8.4%. Of these, the majority were cardiac [31]. Other associated malformations include spiky hair, cleft palate, neurologic abnormalities and genitourinary malformations [31-33]. Also, the incidence of congenital hypothyroidism is increased in patients with Down’s syndrome [34]. Gene mutations causing congenital hypothyroidism can be a rare cause of distinct clinical phenotypes. Most well-known is Pendred’s syndrome. Affected patients have sensorineural deafness, hypothyroidism and goiter. This syndrome is due to a defect in pendrin, which is a transmembrane chloride-iodide transporter expressed in both the thyroid gland and the inner ear [35]. A mutation in thyroid transcription factor 2 (TTF-2) causes a syndrome of thyroid dysgenesis, choanal atresia, cleft palate and spiky hair also known as Bamforth-Lazarus syndrome [36] (Figure 2). Mutations in NKX 2.1 causes congenital hypothyroidism associated with respiratory distress and neurologic problems such as benign hereditary chorea and ataxia [37-39]. One clinical manifestation of long standing congenital hypothyroidism is the Kocher-Debre-Semelaigne syndrome. This presents as promixal muscle weakness associated with calf hypertrophy and resolves with thyroid hormone treatment [40]. Other clinical syndromes that include congenital hypothyroidism are included under “Syndromic hypothyroidism” in Table 2.

Figure 2: Bamforth- Lazarus syndrome. An 8 month old infant with a homozygous mutation in the TTF-2 gene locus leading to congenital hypothyroidism. Phenotypic features include, low set ears, extensive cleft palate, hypertelorism, spiky hair and low posterior hairline. (Taken from; A novel loss-of-function mutation in TTF-2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate; Human Molecular Genetics, 2002, Vol. 11, No. 17. Courtesy Dr. Michel Polak and the Oxford University Press.) [20]

Etiology

Permanent congenital hypothyroidism may be due to primary or secondary (central) causes. Primary causes include defects of thyroid gland development, deficiencies in thyroid hormone production, and hypothyroidism resulting from defects of TSH binding or signal transduction. Peripheral hypothyroidism results from defects in thyroid hormone transport, metabolism, or resistance to thyroid hormone action. Secondary or central causes include defects of thyrotropin releasing hormone (TRH) formation or binding and TSH production. These are covered briefly in this review and are listed in Table 2.

Table 2 Classification and etiology of congenital hypothyroidism [20]

1. Primary hypothyroidism

Thyroid dysgenesis: hypothyroidism due to a developmental anomaly

(Thyroid ectopia, athyreosis, hypoplasia, hemiagenesis)

Associated mutations: (these account for only 2% of thyroid dysgenesis cases; 98% unknown)

TTF-2,

NKX2.1,

NKX2.5

PAX-9

Thyroid dyshormonogenesis: hypothyroidism due to impaired hormone production

Associated mutations:

Sodium-iodide symporter defect

Thyroid peroxidase defects

Hydrogen peroxide generation defects (DUOX2, DUOXA2 gene mutations)

Pendrin defect (Pendred syndrome)

Thyroglobulin defect

Iodotyrosine deiododinase defect (DEHAL1, SECISBP2 gene mutations)

Resistance to TSH binding or signaling

Associated mutations:

TSH receptor defect

G-protein mutation: pseudohypoparathyroidism type 1a

2. Central hypothyroidism ( secondary hypothyroidism)

Isolated TSH deficiency (TSH b subunit gene mutation)

Thyrotropin-releasing hormone deficiency

Isolated, pituitary stalk interruption syndrome (PSIS), hypothalamic lesion, e.g. hamartoma

Thyrotropin-releasing hormone resistance

TRH receptor gene mutation

Hypothyroidism due to deficient transcription factors involved in pituitary development or function

HESX1, LHX3, LHX4, PIT1, PROP1 gene mutations

3. Peripheral hypothyroidism

Resistance to thyroid hormone

Thyroid receptor b mutation

Abnormalities of thyroid hormone transport

Allan-Herndon-Dudley syndrome (monocarboxylase transporter 8 [MCT8] gene mutation)

4. Syndromic Hypothyroidism

Pendred syndrome – (hypothyroidism- deafness – goiter) Pendrin mutation

Bamforth-Lazarus syndrome – (hypothyroidism – cleft palate – spiky hair) TTF-2 mutation

Ectodermal dysplasia – (hypohidrotic – hypothyroidism – ciliary dyskinesia)

Hypothyroidism – (dysmorphism – postaxial polydactyly – intellectual deficit)

Kocher – Deber – Semilange syndrome – (muscular pseudohypertrophy- hypothyroidism)

Benign chorea – hypothyroidism

Choreoathetosis – (hypothyroidism – neonatal respiratory distress) NKX2.1 /TTF-1 mutation

Obesity – colitis – (hypothyroidism – cardiac hypertrophy – developmental delay)

5. Transient Congenital Hypothyroidism

Maternal intake of antithyroid drugs

Transplacental passage of maternal TSH receptor blocking antibodies

Maternal and neonatal iodine deficiency or excess

Heterozygous mutations of THOX2 or DUOXA2

Congenital hepatic hemangioma/hemangioendothelioma

Transient hypothyroidism may be caused by maternal or neonatal factors. Maternal factors include antithyroid medications, transplacental thyrotropin receptor blocking antibodies and exposure to iodine deficiency or excess. Neonatal factors include, neonatal iodine deficiency or excess, congenital liver hemangiomas and mutations in the genes encoding for DUOX and DUOXA2 (see Table 2).

Permanent congenital hypothyroidism

In iodine sufficient countries, 85% of congenital hypothyroidism is due to thyroid dysgenesis. This term refers to an aberration of the embryological development of the thyroid gland. The remaining 10-15% of cases can be attributed to the inborn errors of thyroid hormone synthesis, also called dyshormonogenesis, or to defects in peripheral thyroid hormone transport, metabolism, or action [41].

Thyroid dysgenesis

Thyroid dysgenesis presents in three major forms: thyroid ectopy, athyreosis and thyroid hypoplasia. Thyroid ectopy refers to an ectopic location of the thyroid gland. This accounts for two-thirds of congenital hypothyroidism due to thyroid dysgenesis and is twice as common in females. Athyreosis refers to the complete absence of thyroid tissue. Athyreosis and thyroid hypoplasia account for the remaining one third of thyroid dysgenesis.

Some genes have been implicated as a cause of thyroid dysgenesis. However, these generally account for a small number of cases [42]. These include paired box gene eight (PAX8), TTF-2, NKX2.1 and NXK2.5 [36-39] [43-46]. These encode for transcription factors which are expressed both during thyroid embryogenesis and in the normal functioning gland. Transcription factors are also expressed in other tissues of the developing fetus. Mutations in genes coding for these transcription factors lead to distinct phenotypic syndromes which are linked to their tissue expression [47]. Transcription factors are-

• TTF-2 – a homozygous missense mutation in TTF-2 causes a genetic syndrome of thyroid dysgenesis, choanal atresia, cleft palate and spiky hair [36]. This syndrome has been recently referred to as Bamforth- Lazarus Syndrome [42].

• NKX2.1 – mutations in NKX2.1, also known as TTF-1, have been associated with congenital hypothyroidism, respiratory distress and ataxia [37, 38]. Also, recent reports describe an NKX2.1 mutation with congenital hypothyroidism and benign chorea [39, 45].

• NKX2.5 has been expressed in cardiac tissues; the recent finding of NKX2.5 mutations in patients with thyroid dysgenesis suggest a genetic cause for the increased incidence of cardiac malformations in congenital hypothyroidism [46].

In contrast, PAX8 mutations seem to cause thyroid dysgenesis in the absence of other congenital anomalies [42-44]. However, given that PAX8 is also expressed in the mesonephros and ureteric buds [47], this may explain the increased incidence of genitourinary malformations in patients with congenital hypothyroidism [33].

TSH resistance

There are several forms of TSH resistance. Mutations in the TSH receptor gene leading to thyroid hypoplasia have been found [48]. Another form of TSH resistance is dominantly inherited and has been linked to the long arm of chromosome 15 [49]. Resistance occurs in the absence of a TSH receptor mutation and can again cause thyroid hypoplasia [50]. Pseudohypoparathyroidism type 1a, caused by mutations in the alpha subunit of the stimulatory guanine nucleotide binding protein (Gs alpha), results in defective TSH signaling [51].

Thyroid dyshormonogenesis

Thyroid dyshormonogenesis (or dyshormogenetic goiter) is a rare condition due to genetic defects in the synthesis of thyroid hormones. Hereditary defects in virtually all the steps of thyroid hormone biosynthesis and secretions have been described and account for 10-15% of permanent congenital hypothyroidism. Dyshormonogenesis leads to goitrous hypothyroidism; however, this is rarely seen in babies detected by newborn screening [52]. Most commonly, dyshormonogenesis is due to defects of thyroid peroxidase activity [53]. Less severe mutations cause partial iodide organification defects (PIOD).

Pendred’s syndrome is a well-known form of syndromic hypothyroidism and is characterized by a triad of hypothyroidism, goiter and deafness. This syndrome is caused by a genetic defect in the transmembrane protein pendrin (encoded on 7q31). Defects in pendrin lead to impaired iodide organification and these patients have a positive perchlorate discharge test [35].

More recently, mutations in the enzyme dual oxidase 2 (known as DUOX2 or THOX2) have been found. Mutations in the dual oxidase maturation factor (DUOXA2) gene also lead to deficient iodide organification through similar mechanisms and can cause partial iodide organification defects [54].

Other, rare causes of dyshormonogenesis include defects in sodium/iodide transport, resulting from a mutation in the gene encoding the sodium-iodide symporter [55], and defective thyroglobulin action, resulting from a mutation in the gene encoding thyroglobulin [56]. A defect in the enzyme iodotyrosine deiodinase which aids in the peripheral conversion of T4 to T3 has been shown in hypothyroid individuals. This can be due to homozygous mutations in the genes DEHAL1 or SECISBP2 [57, 58].

Secondary or Central hypothyroidism

Congenital secondary or central hypothyroidism generally results from defects of TSH production; most commonly, it is part of a disorder causing congenital hypopituitarism. Congenital hypopituitarism often is associated with midline defects such as septo-optic dysplasia or cleft lip and/or palate and can be part of a larger genetic syndrome. Mutations in genes regulating pituitary gland development, which include HESX1, LHX3, LHX4, PIT1 and PROP1 have been reported to be a cause of familial hypopituitarism. Besides TSH deficiency, other pituitary hormones are often deficient, including growth hormone, adrenocorticotrophic hormone and antidiuretic hormone. Rarely, specific gene defects lead to central hypothyroidism. These include isolated TSH deficiency (autosomal recessive, caused by mutations in the TSH b subunit gene), and thyrotropin releasing hormone (TRH) resistance, resulting from mutations in the TRH receptor gene (see Table 2).

Peripheral defects in thyroid hormone

Metabolism Passage of thyroid hormone into cells is facilitated by thyroid hormone plasma membrane transporters. A mutation in a gene encoding monocarboxylase transporter 8 (MCT8) has been reported in five boys as a cause of X-linked hypothyroidism associated with mental retardation and neurologic abnormalities including quadriplegia. The defective transporter appears to impair the passage of T3 into neurons and is characterized by elevated serum T3 levels, low T4 and normal TSH [59]. This is also known as Allan-Herndon-Dudley syndrome. Peripheral resistance to the action of thyroid hormone has been described. This is due in 90% of cases to mutations in genes encoding for thyroid hormone receptor b (TR b). These mutations are dominantly inherited and affected individuals are generally euthyroid, however some hypothyroid individuals have been described. Circulating T3 and T4 are mildly elevated without suppression of TSH. Thus these infants are usually not detected by newborn screening [60].

Transient congenital hypothyroidism

Transient congenital hypothyroidism is found to be more common in Europe (1:100) than the United States (1:50,000) [17]. In a report of over twenty years in the French newborn screening program, the incidence of transient congenital hypothyroidism was found to be 40 percent [17]. Causes of transient congenital hypothyroidism include: Iodine deficiency [17, 27, 61]; Transfer of maternal blocking antibodies [62, 63]; Fetal exposure to antithyroid [64]; Maternal iodine exposure [65]. Neonatal Iodine exposure [66]; Liver hemangiomas [67]; Mutations in DUOX2 (THOX2) and DUOXA2 [54].

Environmental factors in Hypothyroidism:

The common model of the onset of autoimmune thyroid disease involves an underlying genetic predisposition and a trigger(s) that initiate the cascade of events and sustain the process, culminating in thyroid hypofunction or hyperfunction. This process has been extensively studied and described [68]. It has been estimated, based on twin studies [69], that 70%–80% of susceptibility to autoimmune thyroid disease is on a genetic basis. The remaining 20%–30% contribution to the onset of autoimmune thyroid disease is thought to be due to environmental exposures or triggers. There are a number of exposures that have been identified and proposed, both from human and animal studies [70-73]. These include infections, life stress, iodine intake, smoking, medications such as amiodarone and interferon, radiation, and environmental toxicants.

The relative importance of these environmental factors in the development of autoimmune thyroid disease is not established. Only a few prospective studies have followed at risk individuals to determine the relative importance of these exposures. A recent prospective study followed a cohort of 521 individuals, with a family history of autoimmune thyroid disease, but negative thyroid autoantibodies [74]. Stressful life events, pregnancy, drug exposure, iodine intake, and other factors were assessed. All of these events were equal in the group that developed autoimmune thyroid disease and the group of those that did not, except smoking. There was a significant association with cessation of smoking and an increase in the incidence of hypothyroidism. Smoking has been associated with reduced thyroid hormone action [75] and exacerbating Graves’ disease, especially Graves’ ophthalmopathy [76]. The increase in the onset of autoimmune thyroid disease with cessation of smoking fits with an overall lower incidence of hypothyroidism and TPO antibody positivity in smokers compared to nonsmokers [77].

The environmental factors most closely associated with susceptibility to autoimmune thyroid disease include radiation, iodine intake, and environmental toxicants. The mechanism of action for most thyroid toxicants is not established, but this information is not required to make an association of exposure with thyroid dysfunction. Although there are limited data in this area to translate to the management of individual patients, there are findings that can contribute to a strategy of risk reduction.

Radiation

Radiation is perhaps the best characterized environmental exposure linked to effects on the thyroid. The most common thyroid manifestation of radiation is hypofunction, as well as thyroid nodules and thyroid cancer. Autoimmune thyroid disease has been linked to therapeutic medical radiation [78-80], as well as environmental radiation exposure [81-86]. Both the atomic bomb detonations in Japan [82] and nuclear contamination from the Chernobyl nuclear power plant accident [85] have been associated with an increased risk of autoimmune thyroid disease. This association, however, has not been a consistent finding in all studies, with several showing no effect [82, 86]. Several studies showed thyroid dysregulation in the human body due to radiation exposure [87, 88]. The thyroid manifestations of radiation exposure vary, likely due to underlying genetic susceptibility, iodine intake, and pattern of radiation exposure. Some individuals have thyroid destruction, others develop nodules and cancer, and others activate thyroid autoantibodies, some of whom, in a specific time frame, develop autoimmune thyroid disease.

Environmental chemicals:

A wide range of environmental toxicants have been identified that interfere with thyroid hormone production, metabolism and action (1–3). Most of these agents, at sufficient doses, interfere with thyroid function and their effect can be detected by an elevation in serum TSH or a reduction in serum thyroxine (T4) or T3 [89]. There are also some agents, such as polychlorinated biphenyls (PCBs) that may have intrinsic thyroid hormone agonist actions [89]. The challenge with any toxicant is to link exposure in an individual to specific actions on thyroid function.

The ways in which environmental toxicants and chemicals affect thyroid function include; [90, 91]

1. Alteration of thyroid hormone metabolism

2. Direct toxic effect on the gland changing function and regulation

3. Production of thyroid antibodies (leading to autoimmune thyroid disorders)

4. Interaction with thyroid carrier proteins

5. Block iodine uptake by the thyroid gland

Polychlorinated biphenols (PCBs) and Dioxins. PCB’s were once used in electrical transformers, capacitators, plasticizers and adhesives. Although many are no longer used in the U.S. they still persist in the environment. Eating fish from contaminated waters, and farm-raised fish, are a major source of PCB’s as well as dairy and meat products. Dioxin a primary toxic component of agent orange, is formed as a byproduct of industrial processes involving chlorine such as waste incineration, chemical and pesticide manufacturing and paper bleaching. The main way we are currently exposed to dioxin is through our food. It is a contaminant in meat, dairy and fish. PCB’s and Dioxins induce thyroid hormone metabolism through an enzyme called UDP-glucuronyl transferase. This simply means they alter liver function of the enzyme that metabolizes thyroid hormone. They also directly attack the thyroid gland and thyroid hormone carrier proteins [92]. There are numerous studies linking PCBs and Dioxins to thyroid dysfunction [93, 94].

Pesticides have also been linked to thyroid disease in numerous studies. We are exposed to pesticides everyday whether we chose to be or not. There are numerous studies that link pesticides to thyroid dysfunction. Specifically Maneb and Mancozeb which are sprayed on fruits such as bananas and has been found to alter thyroid stimulating hormone (TSH), inhibit thyroid peroxidase enzyme, and cause thyroid nodules. [95]

Pentachlorophenol (PCP) is a toxic byproducts is linked to alteration of thyroid hormones and the formation of a goiter [96]. Bisphenol-A (BPA) is another common chemical that is linked to thyroid disorders [97]. Perfluoro octanoic Acid (PFOA) is found in stain and water resistant coatings for carpet, furniture, fast-food containers, paints, and foams. These chemicals build up in our adipose tissue, or fat, and alter thyroid function [98].

Heavy metals are found to affect the thyroid as well. One of the main heavy metals studied is cadmium. Cadmium is a component of cigarette smoke and a product of industry. It is in the air, soil and water of most cities. We are exposed through cigarette smoke, food grown in contaminated soil, air pollution and water contamination. There are numerous studies linking thyroid disease to cadmium exposure. Mercury is also linked to thyroid disease in women and children, which depletes selenium & it is a mineral that is essential for proper thyroid function [99]. Lead is another heavy metal that we are exposed to on a daily basis through our food, air and water. It too is linked to thyroid disorders in many studies.

One of the note shows how sensitive a woman’s hormonal system is compared to men. Women’s hormones appear to be more interconnected than men’s hormones. For example many women develop thyroid disease during pregnancy due to increases in estrogen and progesterone. One study compared men and women’s blood levels of lead and mercury to alterations in thyroid hormones and found women were more affected by the heavy metals. [100]. On the other hand deficiency of the heavy metal Se was found to be a major cause of hypothyroidism specially silent hypothyroditis [101].

A recent study suggested that there may be a significant association between vitamin D deficiency and hypothyroidism [102] which is in harmony with the previous studies that showed the prevalence of vitamin D insufficiency in Hashimoto’s cases (92%) was significantly higher than that observed in healthy controls (63%, p < 0.0001).[103, 104]. Another study shows vitamin C deficiency is in close connection with hypothyroidism.

Current Status of Bangladesh regarding Thyroid related disease:

Clinical experience and few laboratory tests were the only means for evaluating thyroid disorders in Bangladesh even in the early eighties of the last century. Modern laboratory tests evolved gradually over the last 25 years making available the thyroid function tests with high sensitivity and specificity [105]. The absolute and relative number of different thyroid disorders have changed over time as iodine deficiency disorders started to decline since early nineties of the last century. There was paucity of published reports on the spectrum of thyroid disorders in Bangladesh. The range of thyroid disorders other than iodine deficiencies was considered same in Bangladesh as in other countries of Asia [106]. However the relative prevalence of the different thyroid disorders was dominated by iodine deficiency disorders. Such a study published in 1995 where the author was a member reported 35% cases of all thyroid disorders to be due to iodine deficiency as the primary etiology. The rest were autoimmune (26%), malignant (2.58%) and other thyroid disorders. [107].

There has not been enough studies done throughout Bangladesh to get a statistical view of prevalent area with thyroid disease or gender or specific disease associated with thyroid disorders. But some studies are remarkably done and some significant data were achieved through these studies.

A study conducted in Khulna district which is one of the six districts in Bangladesh situated in the southern part of the country showed that overall occurrence of thyroid disease was estimated to be 20.43%. The spectrum of thyroid disorders showed highest incidence of diffuse goitre (7.35 %), followed by sub-clinical hypothyroidism (6.59%), hypothyroidism (4.97%), hyperthyroidism (0.86%) and sub-clinical hyperthyroidism (0.65 %). The incidence of thyroid disorders was observed to be highest in the 11-45 years age group (79.89%). Female outnumbered male, the ratio being 2.5: 1 with preponderance of female subjects in all disease groups. The prevalence of all goitre was 10.49%. Of the total sub-clinical and overt hypothyroidism, the incidence of autoimmune thyroid disease was 29.29% and nongoitrous thyroid dysfunction was more common than goitrous one. [108]

Another study conducted in Khulna district by Rasul et al showed that Male to female baby ratio was 1.2:1. Regarding the birth weight 33.4% babies were low birth weight. TSH above 10 was found in 35 babies among whom one baby was hypothyroid and the other member of the twin was also hypothyroid although the TSH level was below 10. None of newborn had TSH level above 20. Thus frequency of congenital hypothyroidism was 1.5 per thousand living newborn. [109]

Alam et al conducted a study among the diabetic and non-diabetic thyroid patients and found that Out of 140 diabetic subjects studied, 70% had euthyroidism (normal), 18.6% had hypothyroidism, and 11.4% had hyperthyroidism. Serum T3, T4 and FT3 levels were low, TSH and FT4 levels were high in diabetic subjects whereas, in non-diabetic subjects all these levels were normal. In this study, 30% diabetic patients were found to abnormal thyroid hormone levels. The prevalence of thyroid disorder was higher in women (17.1%) than in men (12.9%), while hyperthyroidism were higher in males (13.3%) than in females (10%) and hypothyroidism was higher in females (20%) than in males (16.7%) [110]. Another study conducted among diabetic patients in BIRDEM hospital by Islam et al. showed similar outcome [111].

Another study conducted by Alam et al. depicted that sub-clinical thyroid dysfunction prevails in females with 12.17% occurrence whereas 6.52% in males. Furthermore, the evaluation and subsequent presence of sub-clinical conditions predicts future progression to overt disease. [112].

In 2008 a study conducted showed that prevalence of subclinical hyperthyroidism and hypothyroidism was 6.5% and 15%, and prevalence of hyperprolactinemia was 43% and 21% in primary and secondary infertility respectively. Prevalence of hyperprolactinemia was higher in primary infertility and prevalence of sub-clinical hypothyroidism was higher in secondary infertility, showing no correlation between TSH and prolactin levels in these two groups [113].

In 1981-82, the Government of Bangladesh and WHO jointly conducted a survey on the status of iodine deficiency disorders of the country. It was reported that more than 30 million people in the country have the benign or primary state of goiter and other form of iodine deficiency maladies. About 11 percent of the population is affected by visible goiter, the prevalence being much higher in females. About 30 percent of the population of greater Rangpur and Dinajpur districts in the north show incidences of goiter. The incidence in Chittagong, Khulna and Mymensingh areas is also fairly high [114].

Conclusion:

This review indicated the factors associated with congenital hypothyroidism, environmental thyroiditis and current condition of thyroid disorder in Bangladesh which covers the prevalent reasons for being affected by this disease. The awareness of patients is affected by their educational level and family history of the disease. Another obvious reason is that patients are conscious about their treatment but still they do not have any clear perception about their disease. From this study the need for strategic plan to increase the awareness of patients about hypothyroidism is recommended. We think, for having better understanding on hypothyroidism in our country this study should be done on a handsome number of patients not only in the big cities but also in other districts and rural regions in Bangladesh. In those study we can include the not only the hypothyroid patients but also general people both in urban and rural areas that will help people to become conscious about this disease.

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Essay Sauce, Hypothyroidism. Available from:<http://www.essaysauce.com/health-essays/hypothyroidism/> [Accessed 18-02-18].