Iodine deficiency and goiter

CHAPTER 4

Iodine deficiency and goiter Contents Iodine deficiency: a global health problem Epidemiology Risk factors Management Complications Goiter Diffuse nontoxic goiter Nontoxic multinodular goiter Toxic multinodular goiter Amyloid goiter Epidemiology Pathogenesis and etiology Clinical presentation Diagnosis Treatment Clinical cases Case 1 Case 2 Case 3 Further reading

66 68 70 71 72 73 74 77 79 79 80 81 82 83 84 84 84 85 85 86

Throughout the world, iodine deficiency is a major public health issue—especially for pregnant women and young children. The most serious outcomes are higher perinatal mortality rates and mental retardation. Iodine deficiency is the most significant cause of brain damage in children, which is preventable. The most visible manifestation of iodine deficiency is goiter, prevalence of which is found to be high. A goiter is a swelling in the neck resulting from an enlarged thyroid gland. It can be associated with a thyroid that is not functioning properly. The degree of thyroid enlargement is proportional to the level and duration of thyroid hormone (TH) deficiency. Goiters are broadly divided into two types: diffuse nontoxic and multinodular. Worldwide, over 90% of goiter cases are caused by iodine deficiency.

Epidemiology of Thyroid Disorders DOI: https://doi.org/10.1016/B978-0-12-818500-1.00004-9

r 2020 Elsevier Inc. All rights reserved.

65

66

Epidemiology of Thyroid Disorders

Iodine deficiency: a global health problem The primary factor that causes iodine deficiency is a low dietary supply of iodine. This is most common in areas where the soil has a low content of iodine, caused by significant temperature changes and effects of heavy rainfall and snowfall. When populations in these areas grow crops, the soil cannot provide enough iodine for them. Iodine in the human body is primarily present in the thyroid gland, but even in this location, the amounts of iodine are very small. The thyroid gland primarily serves to synthesize THs. Iodine deficiency causes impaired TH synthesis, and the common symptoms of hypothyroidism. These include cold intolerance, sluggishness, decreased body temperature, and weight gain. The body’s reactions to iodine deficiency also occur at the hypothalamic, pituitary, and peripheral tissue levels. A group of functional abnormalities known as iodine deficiency disorders (IDD) may develop (see Table 4.1). When iodine is insufficient in the diet, there is a quick decrease in serum thyroxine concentrations, with a simultaneous increase in serum thyroid-stimulating hormone (TSH) (Fig. 4.1). However, there is no identifiable decrease in triiodothyronine. This may indicate that the signal that increases TSH is derived from a decrease in triiodothyronine generated intracellularly from thyroxine in the pituitary, hypothalamus, or Table 4.1 Iodine deficiency disorders. Age-group

Disorders

Fetuses

Abortion Congenital anomalies Deaf mutism Endemic cretinism Increased perinatal mortality Stillbirth Endemic mental retardation Increased susceptibility of thyroid to nuclear radiation Neonatal goiter Neonatal hypothyroidism Goiter Impaired mental function Increased susceptibility of thyroid to nuclear radiation Retarded physical development Subclinical hyperthyroidism or hypothyroidism Goiter, with complications Hypothyroidism Impaired mental function Increased susceptibility of thyroid to nuclear radiation Iodine-induced hyperthyroidism Spontaneous hyperthyroidism in the elderly

Neonates

Children and adolescents

Adults

Iodine deficiency and goiter

HO

I O

MIT 3-Monoiodotyrosine HO

DIT 3,5-Diiodotyrosine

HO

OH

H

Glucuronidation (T4G)

O

I

OH Sulfation (T4S)

NH2 3,5,3′,5′-Tetraiodo-L-thyronine (Thyroxine, T4)

O OH

Inactivation via D1

NH2

Precursors

I H

I H

O I

NH2

I

Biliary excretion

I

D2

D1

D3

I

I O

HO

HO

I

O

O

I H

I O

I OH

NH2 3,5,3′-Triiodo-L-thyronine (T3)

D3

H

OH

NH2 3,3′,5′-Triiodo-L-thyronine (reverse T3) D2

D1

I HO

O

I O H

OH

NH2 3,3′-Diiodo-L-thyronine (T3)

Figure 4.1 Major pathways of thyroid hormone metabolism.

both. During pregnancy, a severe iodine deficiency increases the risks of prenatal death. It may also result in birth defects, cretinism, and death of the infant. In cretinism, most-affected children have poor development and growth and are unable to hear or speak. Mental retardation is common. Goitrogens are compounds that block the body’s ability to absorb and use iodine. They are contained in large amounts in cassava, cabbage, rutabagas, and turnips. When these foods are consumed uncooked, the goitrogens are absorbed. However, cooking inactivates the goitrogens. Therefore conditions linked to iodine deficiency are common in developing countries that have low consumption of iodine and where these vegetables make up a large part of the diet. Other food sources of goitrogens include lima beans, linseed, sorghum, sweet potato, kale, cauliflower, broccoli, soy, and millet. Additional sources of goitrogens include sulfurated organics, flavonoids, phenol derivatives, pyridines, phthalate esters and metabolites, biphenyls, various insecticides, polycyclic aromatic hydrocarbons, excessive inorganic iodine, and lithium.

67

68

Epidemiology of Thyroid Disorders

Focus on iodine and fetal development Iodine is one of the most important minerals required by a fetus for brain and cognitive development. However, the content of iodine in most of the foods and beverages is low. About 18 million babies are born mentally impaired, due to maternal iodine deficiency, with 38 million born at risk of iodine deficiency.

Epidemiology Worldwide, iodine deficiency is very common, primarily in undeveloped countries (Fig. 4.2). However, it has reemerged in many developed countries, with increases in low maternal iodine status in areas believed to be iodine-sufficient. More than 70 countries, including the United States, have salt-iodization programs. Approximately 90% of households in this country use iodized salt. However, worldwide, this figure is only 70%. In Europe and the Eastern Mediterranean regions, it is as low as 50% of households. Over the past 45 years, iodine deficiency in developed countries has increased by more than four times. Nearly 74% of normal and healthy adults may no longer consume enough iodine. Iodine is extremely critical in the early developmental stages, with the fetal brain depending upon sufficient iodine. In 2017 about 38 million babies were born globally with iodine deficiency. In severely iodine-deficient areas of the world, there has been a recorded loss of an average of 13.5 intelligence quotient points. As of 2010, World Health Organization (WHO) estimated that iodine deficiency resulting in goiter occurred in 187 million people worldwide. Iodine deficiency is most common in Africa, Southeast Asia, and the Western Pacific countries. In severely endemic locations, cretinism may affect up to 5% 15% of the population. Some affected nations, such as China and Kazakhstan, have begun taking action to combat the condition.

Figure 4.2 Worldwide prevalence of iodine deficiency (darker colors indicate more deficiency).

Iodine deficiency and goiter

Others, such as Russia, have not done so. The cost of adding iodine to dietary salt is very inexpensive. They believed that the reason for the increase in iodine deficiency in developed countries involves reductions in salt consumption and changes in dairy processing practices, which eliminate the use of iodine-based disinfectants. Australia and New Zealand have also seen increased prevalence of this condition. In one study of the United Kingdom in 2011, nearly 70% of test subjects were iodine deficient. Recent studies have shown links between iodine deficiency and obesity, psychiatric disorders, fibromyalgia, and even cancer. According to the Iodine Global Network (IGN), because of sustainable universal salt-iodization programs, iodine deficiency is on the verge of being eliminated. At the end of 2017, there were only 19 countries classified as having insufficient iodine intake. This is down from 54 countries in 2003 and 113 countries in 1993. The IGN is working to reach countries that are still vulnerable to iodine deficiency. They are extending their efforts worldwide to support the most vulnerable populations—especially pregnant women. Nineteen countries still vulnerable to iodine deficiency are Angola, Burkina Faso, Burundi, Finland, Haiti, Israel, Italy, Korea, Democratic People’s Republic of Lebanon, Mali, Madagascar, Mozambique, Russia, Samoa, South Sudan, Sudan, Ukraine, Vanuatu, and Vietnam. However, in Norway, a country no longer termed “vulnerable,” a 2018 study of about 1000 pregnant women showed iodine deficiency to be significantly high. This data was collected multiple times during their pregnancies, with follow-up until their infants reached 18 months of age, and the deficiency was still present. Over the past 25 years, more than 750 million new cases of goiter have been prevented. In North America, iodine intake is classified as optimal at the population level. The median concentrations of urinary iodine in the populations of the United States, between 1971 and 2002, are summarized in Fig. 4.3. This data is from the National Health and Nutrition Examination Survey.

Urinary iodine (ng/mL)

500 400 300 200 100 0 Total population

Children 6–11 years

1971–1974

Women 20–39 years 1988–1994

Persons 60 years and older 2001–2002

Figure 4.3 Median concentrations of urinary iodine in the United States, 1971 2002.

69

70

Epidemiology of Thyroid Disorders

Primary sources of dietary iodine in the United States and Canada have been milk and other dairy products for many years. Sales of iodized salt are low in the United States. There has been a rise in the popularity of dairy alternatives such as soymilk, which can affect iodine nutrition. In 2017 the IGN worked to increase awareness of iodine nutrition among medical providers and the general public. They also advocated for the inclusion of iodine nutrition in medical guidelines and recommended that iodine to be included in all prenatal vitamins. Recent data shows that pregnant women in the United States may be slightly iodine deficient. Nearly all countries in Central America and the Caribbean have established and sustained salt-iodization programs. In South America in 2016, iodine deficiency was virtually eliminated. In Western and Central Europe, optimal iodine nutrition has not been achieved in a number of countries, especially in pregnant women. Iodine deficiency transcends economic development. It is as much of a problem in industrialized countries as in other regions of the world. In Eastern Europe and Central Asia, most countries have successfully established iodization programs, while others still have not taken steps to do so. In the Middle East and North Africa, IGN has had to fight food insecurity and political instability in order to promote iodination programs. In West and Central Africa, there has been a constant program of education about iodized food sources. In Eastern and Southern Africa, great progress has been made in the past decade, with education and iodination programs increasing widely. As of 2017, all countries in South Asia are currently classified as “optimal” in their dietary iodine consumption. In China, new regulations have replaced the country’s long-term salt monopoly, resulting in an open and free market for the salt industry. While many countries in the Southeast Asia and Pacific region have had successful iodination programs that appears to be slowing and even reversing in some areas. Focus on iodine in seaweed The main place on earth where iodine is plentiful is within our oceans. Iodine is most highly concentrated in seaweed. Kelp and other forms of seaweed can concentrate and store iodine at extremely high levels. It is believed that seaweed uses iodine to protect itself from oxidative stress in the ocean. Iodine in seaweed is in its most biologically available form, making it ideal for a dietary source.

Risk factors There are a variety of risk factors that may lead to iodine deficiency: low dietary iodine, selenium deficiency, pregnancy, radiation exposure, increased intake and plasma levels of calcium and other goitrogens, and the female gender. Additional risk factors include smoking tobacco products, alcohol use, oral contraceptive use, perchlorates (which are used in food packaging), thiocyanates (which are competitive inhibitors of the thyroid sodium-iodide symporter), and aging.

Iodine deficiency and goiter

Management Though IDD affect entire populations, a school-based sampling method is recommended for urinary iodine and total goiter prevalence as the best way to monitor deficiencies. This is because school-age children (basically 6 12 years of age) are an easily accessible group that can be used as a model for the general population. Four primary strategies are needed to correct iodine deficiencies. These include the following: • Correcting iodine deficiency • Surveillance (monitoring and evaluation) • Intersectorial collaboration • Advocacy and communication to coordinate public health authorities and to educate the public The oral form of iodized oil is preferred over the intramuscular form. It does not require specialized storage, or training of individuals to administer doses, and can be given once per year. However, it is more expensive than iodized salt and may be harder to implement since it requires direct provider-to-patient contact. Since iodized salt has been introduced in many areas, iodized oil is now only indicated for populations in severely endemic areas that lack access to iodized salt. It is recommended to add 20 40 ppm of iodine to salt, assuming an average salt intake of 10 g per capita per day. Potassium iodate and potassium iodide are the two forms used in this case. Potassium iodate is more stable in extreme climatic conditions. Therefore it is the preferred form, especially in hot and humid climates. Adequate control of amounts of these substances must occur in order to prevent iodine toxicity in people who have previously been chronically deficient. Iodine-induced hyperthyroidism is the most common complication of iodine prophylaxis, usually affecting the elderly with chronic thyroid nodules. The most effective ways to prevent this hyperthyroidism and its consequences are to monitor salt quality and iodine status, and to properly train healthcare staff members. Governments usually determine the adequate level of iodine being added to salt, but monitoring controls the activities of the salt industry in providing safe levels. Iodine levels are monitored in factories, households, and sometimes in retail settings. When imported into a country, iodized salt is monitored at ports of entry. Field test kits that utilize titration are used to monitor iodine content. They indicate if iodine is present or not but do not provide accurate quantities. They are used for training and education of the providers. Monitoring the iodine status of each population helps ensure that changing dietary habits is not altering the amounts needed versus amounts consumed. The WHO has provided guidance and support in worldwide iodization efforts. Effective processes require collaboration between various sectors, regulated by the Global Network for Sustained Elimination of Iodine Deficiency. This body works with many Ministries of Health to design and supervise iodine deficiency control

71

72

Epidemiology of Thyroid Disorders

Table 4.2 The World Health Organization criteria for iodine deficiency disorders (IDD) elimination. Indicators

Goals

Salt-iodization coverage

Proportion of households consuming adequately iodized salt (at least 15 ppm at household level)

More than 90%

Urinary iodine

Proportion of population with urinary iodine levels below 100 µg/L Proportion of population with urinary iodine levels below 50 µg/L

Less than 50% Less than 20%

Programmatic indicators

• National body responsible to government for IDD elimination; should be multidisciplinary, with relevant fields of nutrition, medicine, education, salt industry, media, and consumers; with a chairman appointed by Minister of Health • Evidence of political commitment to universal salt iodization (USI) and elimination of IDD • Appointing a responsible executive officer for IDD elimination program • Legislation or regulation of USI • Commitment to regular IDD elimination efforts; with access to laboratories that can provide accurate data on salt and urinary iodine • A program of public education and social mobilization on importance of IDD and consumption of iodized salt • Regular data on iodized salt at the factor, retail, and household levels • Regular laboratory data on urinary iodine in school-age children with appropriate sampling for higher risk areas • Cooperation from salt industry in maintaining quality control • A database for recording results or regular monitoring procedures, especially for salt iodine, urinary iodine, and when available, neonatal thyroid-stimulating hormone, with mandatory public reporting

At least 8 of these 10

plans. The International Resource Laboratories Network to provide technical support to national laboratories requiring assistance through regional or subregional resource laboratories that monitor the programs. There is at least one resource laboratory in every WHO region. The WHO has established criteria for monitoring progress toward sustainable IDD elimination (Table 4.2).

Complications The complications of iodine deficiency are varied and differ between age-groups of affected individuals. In the fetus, complications include miscarriage, stillbirth, congenital anomalies, increased perinatal morbidity and mortality, and endemic cretinism. In the neonate, complications include goiter, hypothyroidism, endemic neurocognitive impairment, and increased susceptibility of the thyroid gland to nuclear radiation.

Iodine deficiency and goiter

In children and adolescents, complications include goiter, subclinical hypothyroidism, impaired mental function, retarded physical development, and increased susceptibility of the thyroid gland to nuclear radiation. In adults, complications include goiter and related complications, hypothyroidism, impaired mental function, spontaneous hyperthyroidism (in the elderly), iodine-induced hyperthyroidism, and increased susceptibility of the thyroid gland to nuclear radiation.

Goiter Goiter is caused by impaired TH synthesis, usually because of dietary iodine deficiency. There are two primary types of goiter: diffuse nontoxic goiter (simple goiter) and multinodular goiter (nontoxic or toxic, which is associated with overproduction of TH). Thyroid enlargement can be caused by proliferation of thyrocytes, stimulated by circulating factors, which include TSH and thyroid-stimulating autoantibodies. It can also be caused by infiltration with inflammatory or malignant cells, or from benign or malignant neoplastic changes in the thyroid gland. When a patient presents with a goiter, the three primary considerations are enlargement, which can cause localized compression or cosmetic problems, hyperfunction or hypofunction of the gland, and the possibility of malignancy. The most common cause of goiter, worldwide, is dietary iodine deficiency. In the United States, this deficiency is only among immigrants who come from iodinedeficient areas of the world. In younger patients, diffuse or simple goiters may be present, which shrink when adequate iodine supplementation is given. In older people, iodine-deficient goiters become multinodular. They do not decrease in size with iodine repletion. In these patients, excessive iodine exposure can cause thyrotoxicosis. A benign adenoma or multinodular goiter can originate from genetic defects leading to dyshormonogenesis. These include mutations of genes related to thyroglobulin, pendrin, thyroid peroxidase, and dual oxidase. Goiter is also caused by exposure to goitrogenic substances in foods, waters, or lithium carbonate. These substances inhibit normal steps in the synthesis of THs. Usually, the underlying cause of goiter is not known. In diffuse goiter the entire thyroid gland swells and is smooth to the touch. In nodular goiter, solid or fluid-filled lumps (thyroid nodules) develop. A thyroid nodule is a discrete lesion caused by an abnormal and focal growth of thyroid cells. The nodules may be inactive or toxic. A goiter may be associated with hyperthyroidism, hypothyroidism (see Chapter 5: Hypothyroidism and Chapter 6: Hyperthyroidism), or normal levels of thyroid function. It may be cystic or fibrous, containing nodules or an increased number of follicles. Goiter is caused by impaired TH synthesis, usually because of dietary iodine deficiency. Impaired synthesis of THs causes a rise in serum levels of TSH. As the thyroid gland’s functional mass increases, it overcomes the hormone deficiency, establishing a euthyroid rate of metabolism in most patients. When an

73

74

Epidemiology of Thyroid Disorders

underlying condition is relatively severe, such as an endemic iodine deficiency or a congenital biosynthetic defect, responses may be insufficient and result in goitrous hypothyroidism. The amount of thyroid enlargement is related to the levels and duration of deficient THs. Hashimoto’s thyroiditis and Graves’ disease are also related to goiter.

Diffuse nontoxic goiter Diffuse nontoxic goiter, a form of simple goiter, is the enlargement of the entire thyroid gland (see Fig. 4.4). This produces nodules and is not associated with hyperthyroidism. Since the enlarged follicles are full of colloid, this condition is also sometimes called colloid goiter. There may be either endemic or sporadic types of distribution. Diffuse nontoxic goiter evolves in two phases: the hyperplastic and the colloid involution phases. The thyroid gland is enlarged, diffusely and symmetrically, in the hyperplastic phase. The increase is usually slight, with the gland not commonly exceeding 100 150 g. Crowded columnar cells line the follicles. These may pile on one another, forming projections that appear similar to those of Graves’ disease (see Chapter 7: Thyroiditis

Figure 4.4 Diffuse nontoxic goiter.

Iodine deficiency and goiter

and Graves’ disease). This accumulation is not even throughout the thyroid gland. Some follicles are extremely distended while others remain small in size. If there is an increase in iodine, or if demand for TH decreases, the stimulated follicular epithelium undergoes involution. The surface of the thyroid is usually translucent, slightly glassy in appearance, and brown in color. Via histology, the follicular epithelium is flat and cuboidal. The colloid is abundant when involution is occurring. Most of the patients with simple goiters are clinically euthyroid. Therefore clinical manifestations are mostly related to mass effects of the enlarged gland. While serum T3 and T4 levels remain normal, serum TSH is usually elevated, or near the upper range of normal. This is expected to exist in patients who are marginally euthyroid. Dyshormonogenetic goiter, due to a congenital biosynthetic defect, may induce cretinism in children. Simple goiter in teenagers is sometimes referred to as juvenile goiter. The known causes of simple nontoxic goiter, which includes the diffuse and nodular forms, involve either intrinsic TH production defects, ingestion of foods that have substances inhibiting TH synthesis, or drugs that decrease TH synthesis. Amiodarone and lithium are examples of drugs that can decrease TH synthesis. Nontoxic nodular goiters may result from recurring cycles of stimulation and involution. Overall, true causes of most nontoxic goiters in iodine-sufficient areas are unknown. Patients may have a history of low iodine intake or overingestion of goitrogens from food sources. These conditions are rare in North America. The goiter, early in its development, is usually soft, symmetrical, and smooth. Over the time, multiple nodules and cysts may develop. Diagnosis involves thyroidal radioactive iodine uptake, thyroid scan, ultrasonography, and measuring of TH and TSH levels. Treatment is based on the cause. When medications are indicated, moderate doses of levothyroxine are useful for younger patients, reducing serum TSH to the low-normal range. Levothyroxine is contraindicated in older patients with nontoxic nodular goiter. It is because these goiters rarely shrink and may have autonomic areas, meaning that levothyroxine may cause hyperthyroidism. When large, these goiters may require surgery or 131I to shrink the thyroid enough to prevent problems with breathing, swallowing, or cosmetic appearance. Endemic goiter Endemic goiter is prevalent in areas of the world in which low levels of iodine are contained in the food, water, and soil. When goiters are present in over 10% of a region’s population, the term endemic is used. Endemic goiter is most common in mountainous areas, including the Himalayas and Andes, where there is significant iodine deficiency. It is also common in large parts of Africa, areas of Central Europe, and in Papua New Guinea. Some highly developed countries such as the United Kingdom and Australia sill have mild-to-moderate levels of iodine deficiency. Daily requirements of optimal iodine for various age-groups and conditions are listed in Table 4.3.

75

76

Epidemiology of Thyroid Disorders

Table 4.3 Optimal iodine daily requirements. Age or condition

Recommended dietary allowance for iodine (µg)

Birth to 6 months 7 12 months 1 8 years 9 13 years 14 years and older Pregnant women Breastfeeding women

110 130 90 120 150 220 290

In endemic areas, daily intake and urinary excretion of iodine are below 50 µg/ day. In areas in which iodine is extremely low, excretion is below 20 µg per day. In these areas, 90% of people have goiters, and 5% 15% of infants are delivered with myxedematous or neurologic alterations of cretinism. Lack of iodine causes decreased synthesis of TH as well as an increase in TSH. This causes hypertrophy and hyperplasia of the follicular cells and enlargement of the thyroid gland. As dietary iodine supplements have increased, endemic goiter cases have decreased in frequency and severity throughout the world. However, up to 200 million people, globally, are at risk for severe iodine deficiency. Other causative influences exist, which are shown by variations in occurrence of endemic goiter in areas that have similar amounts of iodine deficiency. These influences include dietary goitrogens. Consuming substances that interfere with TH synthesis has been proven to be goitrogenic. Dietary substances such as vegetables of the Brassicaceae or Cruciferae family may act as goitrogens. These include cauliflower, cabbage, Brussels sprouts, cassava, and turnips. The highest risk comes from cassava root that is a large part of the diet of various native populations. Cassava contains a thiocyanate, which slows iodide transport in the thyroid, exacerbating any concurrent deficiency of iodine. Cassava, or Manihot esculenta, is a woody shrub originally native to South America. It is extensively cultivated as an annual crop for its edible starchy tuberous root, a primary source of carbohydrates. Cassava, when dried to a powdery or pearly extract, is called tapioca, as used in pudding. Its fried, granular form is called garri. Cassava is also called yuca, but this term is not related to the term yucca, which is a different type of shrub with other uses. It is the third-largest source of food carbohydrates in tropical regions, after rice and corn. It is a major staple food in the developing world, providing a basic part of the diet of more than half a billion people. Nigeria is the world’s largest producer of cassava, and Thailand is the largest exporter of dried cassava. It is either classified as sweet or bitter. The bitter type has larger amounts of antinutritional substances as well as toxins. The preparation of cassava must be done correctly, or

Iodine deficiency and goiter

there will be enough residual cyanide to cause acute cyanide intoxication, goiters, ataxia, partial paralysis, and even death. Sporadic goiter Sporadic goiter is less common than endemic goiter. It is much more common in females, with highest incidence at puberty or in young adulthood. Several conditions cause sporadic goiter. These include ingesting substances that interfere with TH synthesis, and hereditary enzymatic defects interfering with TH synthesis. These defects are transmitted as autosomal-recessive conditions, such as in dyshormonogenetic goiter. However, the primary cause of sporadic goiter is not understood. Some clinicians theorize that sporadic goiter may arise from relative iodine deficiency resulting from disturbance of iodine ingestion, or from liver dysfunction. Sporadic goiter, like endemic goiter, requires a differential diagnosis with chronic autoimmune thyroiditis, Riedel’s thyroiditis, neck cysts, lipomas, other neck or mediastinal tumors, malignant neoplasms of the thyroid, and metastases of tumors in the cervical lymph nodes.

Nontoxic multinodular goiter Multinodular goiter occurs over the time, as recurrent hyperplasia and involution episodes combine, producing a more irregular thyroid enlargement. Nearly all cases of simple goiter that have been present for a long time will convert into multinodular goiters. They cause extreme enlargements of the thyroid. Nontoxic goiters are often mistaken with neoplasms. Since they evolve from simple goiter, they also occur in endemic and sporadic forms. They also have the same distribution between females and males, and possibly the same origins. However, they affect older people since they are late complications. In various populations, multinodular goiter or nodular thyroid enlargement affect up to 12% of adults. Multinodular goiter is believed to occur due to variations in follicular cells, as to their response to trophic hormones and other stimuli. Some cells in a follicle may have a growth advantage. This could be because of intrinsic genetic abnormalities that are similar to those ones that cause adenomas. Therefore these cells can develop clones of proliferating cells. This may be due to formation of a nodule with continued autonomous growth, but without an external stimulus. Primary factors that cause nontoxic multinodular goiter include functional heterogeneity of the normal follicular cells. This is probably due to genetics and the acquiring of new inheritable factors from replicating epithelial cells. An important factor is the female gender. There may also be further functional and structural abnormalities as the goiter increases in size. Secondary causative factors include elevated TSH, endogenous (gender) factors, certain drugs, smoking, stress, and the effects of IGF-1 and other thyroid stimulators.

77

78

Epidemiology of Thyroid Disorders

Polyclonal and monoclonal nodules exist at the same time within a multinodular goiter. The monoclonal nodules may have developed because of acquiring a genetic abnormality that favors their growth. Activating mutations that affect proteins in the TSH-signaling pathway have been revealed as a subgroup of autonomous thyroid nodules. Uneven follicular hyperplasia, new follicle generation, and colloid accumulation cause physical stress, which may result in rupture of follicles and vessels, and larger, hemorrhage, scarring, and occasionally, calcifications. Scarring causes nodularity to appear, which can be made more prominent by the gland’s preexisting stromal framework. Multinodular goiters can weigh more than 2000 g. They are multilobulated and asymmetrically enlarged, in extremely varying patterns. One lobe may be involved extensively, while the other is not. This produces lateral pressure on the esophagus, trachea, and other midline structures. Sometimes, the goiter enlarges behind the clavicles and sternum, producing an intrathoracic or plunging goiter. Less commonly, the majority of the goiter is hidden behind the esophagus and trachea. Sometimes just a single nodule is greatly enlarged, making it appear as if only one nodule is present. When the thyroid is sectioned, there are irregular nodules filled with varying amounts of colloid that is brown and gelatinous (Fig. 4.5). Chronic lesions show areas of calcification, cystic changes, fibrosis, and hemorrhage. Microscopically, there are follicles rich in colloid that is lined by flat, inactive epithelium and locations of follicular hyperplasia. There are often degenerative changes due to physical stress. The difference between multinodular goiters and follicular neoplasms is that the multinodular goiters do not have a prominent capsule between the hyperplastic nodules and residual, compressed parenchyma. The primary clinical features are caused by mass effects, including airway obstruction, compression of large neck and upper thorax vessels, and dysphagia. When these vessels are affected, it is called superior vena cava syndrome. The majorities of patients are euthyroid or have subclinical hyperthyroidism, which is revealed only by reduced

Figure 4.5 (A) Cross-section of goiter and (B) Histology of goiter.

Iodine deficiency and goiter

TSH levels. However, a large minority of patients with an autonomous nodule will develop a long-standing goiter and hyperthyroidism. This is known as toxic multinodular goiter.

Toxic multinodular goiter Toxic multinodular goiter is also known as Plummer syndrome. It is characterized by a hyperfunctioning nodule or adenoma and thyrotoxicosis. Toxic multinodular goiter does not involve infiltrative ophthalmopathy and dermopathy, as seen in Graves’ disease. It is believed that clinically obvious autonomous nodules develop in about 10% of multinodular goiters, in 10-year follow-ups. There is a low incidence of malignancy in long-term multinodular goiters. This is less than 5%, but goiters that suddenly change in size or symptoms, such as hoarseness, have a higher risk for malignancy. Dominant nodules may present as a solitary thyroid nodule that mimics a thyroid neoplasm. Radioiodine scans show uneven iodine uptake, with occasional “hot” nodules, which are related to diffuse parenchymal involvement. Radioiodine scans also reveal admixtures of hyperplastic and involuting nodules. Fine-needle aspiration biopsy is productive and sometimes allows the distinction of follicular hyperplasia from thyroid neoplasms. Genetic abnormalities that confer functional autonomy are not usually present in the autonomous areas of toxic multinodular goiter. These include activating TSH receptor (TSHR) or GS-alpha mutations. The patient with toxic multinodular goiter is usually an elderly adult and may have mild thyrotoxicosis or subclinical hyperthyroidism. Signs and symptoms include heat intolerance, hyperactivity, muscle weakness and wasting, fatigue, irritability, osteoporosis, increased appetite, and tracheal compression. There are sometimes atrial fibrillation or palpitations, nervousness, tachycardia, tremor, or weight loss. Recent iodine exposures may precipitate or worsen thyrotoxicosis. The TSH levels are low, and uncombined T4 levels are normal or slightly increased. The T3 levels are often higher. Thyroid scan reveals heterogeneous uptake, with many regions of increased and decreased uptake. The 24-hour uptake of radioiodine may not be higher but is most often in the upper-normal range. Ultrasound should be done to assess any discrete nodules related to areas of decreased uptake— known as “cold” nodules. If these are present, fine-needle aspiration may be indicated. Treatment is based on these considerations. Medications include propylthiouracil or methimazole and radioactive iodine. Another option is injection of ethanol into the nodules. If there are undefined or suspicious cytology results, surgery may be required.

Amyloid goiter Amyloid goiter is a symptomatic mass, or clinically detected thyroid enlargement, due to deposition of amyloid, which is an aggregate of various proteins. Amyloids become folded into a shape that allows a large amount of protein copies to stick together and

79

80

Epidemiology of Thyroid Disorders

form fibrils. The presence of amyloid, related to thyroid enlargement, is seen in 50% 80% of medullary carcinoma of the thyroid cases (see Chapter 10: Global epidemiology of thyroid neoplasms). Amyloid goiter occurs with primary and secondary systemic amyloidosis but is more common in the secondary form. Though rare, it should be suspected in patients with a diffuse, enlarging thyroid gland, and in people with appropriate clinical history. The neck mass usually causes pressure symptoms of hoarseness, and the patient is usually euthyroid. If there is a thyroid swelling of soft consistency, with vascularization, biopsy should be made and frozen sections should be sent in for examination. Amyloid goiter in secondary amyloidosis is characterized by amyloid deposits that are associated with atrophic follicles. More rarely, amyloid goiter can present as a first manifestation of systemic amyloidosis. There is no effective treatment for amyloidosis. Overall prognosis is better for patients with secondary amyloidosis. Colchicine treatments may prevent amyloid deposits.

Epidemiology According to the American thyroid association in 2019, more than 12% of the population of the United States will develop a thyroid condition at some point in life. A goiter prevalence of 5% or more in school-age children indicates iodine deficiency in a specific population. Therefore the goiter rate in school-age children is used to determine severity of a population’s iodine deficiency since they are easily susceptible to this deficiency. In areas where daily iodine intake is less than 50 µg, goiter is usually endemic. When daily intake falls below 25 µg, congenital hypothyroidism is seen. Prevalence of goiter in areas of severe iodine deficiency can be as high as 80%. The most common thyroid disease is simple (diffuse) goiter. Nodular thyroid disease is common, affecting 3% 7% of adults, from physical examination alone. The use of ultrasound, however, reveals nodules present in as much as 50% of adults. Most of these nodules are less than 1 cm in diameter. Thyroid nodules can be multiple or single, and functional or nonfunctional. In pregnant women, enlargement of the goiter is physiologic. It usually subsides after delivery. The prevalence of goiter among females is basically four times as often as males, and this primarily involves premenopausal women. According to the Framingham, England survey, for patients aged 60 years or older, clinically apparent thyroid nodules were present in 6.4% of females and 1.5% of males. The prevalence of single thyroid nodule was 3% and multinodular was 1%. Autopsy surveys have revealed that up to 50% of patients had thyroid nodules. Ultrasound of females revealed that 20% 76% had at least one thyroid nodule. In Germany, thyroid nodules or goiter were found via ultrasound in 33% of working adults between ages 18 and 65. Thyroid nodules larger than 1 cm were found in 12% of this population, increasing with age. In those with only one palpable nodule, 20% 48% had additional

Iodine deficiency and goiter

nodules detected by ultrasound. Variables related to the epidemiology of goiter include regional iodine intake levels, smoking, age, gender, and even the methods used to assess thyroid size.

Pathogenesis and etiology The pathogenesis and etiology of goiter can be complex to understand. Not every inhabitant of an iodine-deficient area will develop goiter. Low dietary intake of iodine contributes greatly to development of goiter. Therefore increasing dietary intake of iodine by consuming iodized salt is the key to eradicate goiters caused by iodine deficiency. Also, endemic goiter has occurred in areas with no iodine deficiency, and even in some areas with excessive iodine. Also, it has not occurred in certain regions that have severe iodine deficiency. This is probably related to genetic or other factors. Genetic factors are emphasized by the clustering of goiters in certain families, a higher concordance rate in monozygotic than in dizygotic twins, different female-to-male ratios, and the amount of goiters in areas where large iodine prophylaxis programs have been correctly introduced. An important consideration is that in endemic goiter, the female-to-male ratio is 1:1 while 7:1 9:1 for sporadic goiters. Environmental factors are also involved. Endocrine disrupting agents include drugs, tobacco products, insulin resistance, selenium deficiency, oral contraceptives, alcohol use, and parity. Increased serum TSH concentrations usually cause thyroid enlargement in the rare case of functional TSH-secreting pituitary adenomas. Also, goiter is typical in Graves’ disease, where stimulation of thyroid tissue growth is due to thyroid-stimulating antibody via TSHR activation. Thyroid enlargement can appear in Graves’ disease when increased levels of TSH occur from overadministration of antithyroid drugs. Autoimmune thyroiditis often produces a moderate goiter because of glandular infiltration with lymphocytes, fibrosis, and inflammatory alterations of thyrocytes. Toxic thyroid hyperplasia is often seen in nonautoimmune autosomal dominant hyperthyroidism. This disorder is related to germ-line activating TSHR gene mutations. This highlights the role of TSH TSHR system activation in thyroid hyperplasia. In most patients with nontoxic goiter, serum TSH concentration is normal. It has been shown in studies that iodine depletion promotes thyroid growth by normal TSH levels. Therefore anything that impairs intrathyroidal iodine levels can cause gradual goiter development, responding to normal TSH levels. Iodine supplies and TSH levels are also interrelated. Slight differences in iodine intake are linked to significant TSH changes. This has been shown in 11-year followup studies. TSH-dependent and TSH-independent pathways are complex. They control thyroid follicular cell growth and function, while also acting in the goitrogenic process. A group of growth factors from the bloodstream or either autocrine or paracrine secretion may help regulate thyroid cell proliferation and differentiation. Early

81

82

Epidemiology of Thyroid Disorders

goiter formation involves areas of microheterogeneity in structure and function. These are intermingled with areas of functional autonomy and others of focal hemorrhage. Hyperplastic nodules may indicate that thyroid nodules are either monoclonal or polyclonal. Monoclonal adenomas in hyperplastic thyroid glands may show one progressive stage of the hyperplasia neoplasia spectrum. Multiple accumulating somatic mutations may provide a selective growth advantage to this single-cell clone. Histological examination shows nodules with irregularly enlarged and involuted follicles. These are distended with colloid or clustered, smaller follicles lined by higher epithelium, with small colloid droplets. Usually, these nodules are totally encapsulated. They are poorly demarcated from internodular tissue and also merged with it, additionally with alterations of structure. Nodules in certain glands are localized, accompanying areas of normal structural appearance. It may be hard in this case to distinguish them from follicular adenomas. Therefore the lesions are often called colloid or adenomatous.

Clinical presentation Patients often discover swelling of the thyroid upon self-examination, which lead them seeking medical advice. Usually, appropriate examination by a medical professional results in the diagnosis of a goiter or nodule being benign. With multinodular goiter, autonomous nodules or functional areas may cause increased TH secretion, followed by subclinical or clinical thyrotoxicosis. Goiter is rare in the United States since it is primarily related to iodine deficiency. Generally, thyroid nodules are not related to abnormal secretion of TH. The affected patient does not show clinical signs of thyroid dysfunction and, often, is asymptomatic. Nontoxic goiter may simply cause thyroid enlargement and no other features. With cross-sectional imaging, many clinically relevant thyroid nodules are detected during routine carotid ultrasonography or via CT or MRI of the head, neck, and chest. However, even if discovered accidentally, the same risk of malignancy exists as with nodules identified during clinical examination. The majority of thyroid nodules are asymptomatic. When they become large, they can displace or compress the esophagus, trachea, and blood vessels of the neck. Rarely, there may be signs and symptoms of dysphagia, neck tightness, and a sensation of choking. Such obstructive symptoms may be accentuated by the Pemberton maneuver, which involves the patient keeping the arms elevated against the sides of the head. If a substernal goiter is present, there will be venous congestion, which causes congestion and cyanosis of the face, with distress. Rarely, thyroid nodules cause compression or invasion of the recurrent laryngeal nerve, which may cause hoarseness, suggesting advanced thyroid carcinoma. More often, acute hemorrhaging into a cystic nodule can cause acute and painful neck enlargement and is able to worsen or cause obstructive symptoms. Most thyroid nodules are benign hyperplastic or colloid nodules or benign follicular adenomas. Many studies show that 5% 15% of clinically relevant nodules are malignant. Thyroid cancer has been steadily increasing in most countries. This is

Iodine deficiency and goiter

related to better detection and reporting of small malignancies. Also, more advanced thyroid cancers have been discovered with regularity, but fortunately, mortality rates from these are extremely low.

Diagnosis Clinical evaluation of a suspected goiter must exclude any extra skin or subcutaneous fat in the lower anterior neck. Palpating the thyroid beneath the soft tissue, and observing that the fullness will not rise or fall when swallowing is usually sufficient, confirmed by ultrasound. Patient history helps evaluate any previous iodine deficiency. Symptoms of hypothyroidism can suggest autoimmune thyroiditis. Evidence of thyrotoxicosis can suggest toxic multinodular goiter or Graves’ disease. Also, diagnostic is any pain, in subacute thyroiditis, or postpartum status, in lymphocytic thyroiditis. Any symptom suggesting invasion of nearby structures increases concerns of malignancies or Riedel’s thyroiditis. Diffuse enlargement suggests a type of thyroiditis, Graves’ disease, or a diffuse, infiltrative malignancy. Enlargement of thyroid nodules more often reflects a benign multinodular goiter or a malignant neoplasm. There must be accurate documentation of the size of the thyroid gland. Any cervical lymphadenopathy, dysphonia, tracheal deviation, or venous engorgement in the neck must be recorded. If the patient is asked to touch the hands together above the head, known as Pemberton’s maneuver, a subtotal obstruction of the thoracic outlet may be revealed, as the examiner checks for signs of facial plethora and cervical venous distention. The TSH level determines if there is primary hypothyroidism or thyrotoxicosis. Suspected autoimmune thyroiditis may be confirmed by elevating antithyroid peroxidase antibody titers. If there is a modest diffuse goiter, and the patient is asymptomatic, no additional evaluation may be needed. If clinical clues suggest a specific diagnosis, other blood tests that may be useful include erythrocyte sedimentation rate for subacute thyroiditis, or calcitonin for medullary thyroid cancer. To define the size and shape of a goiter that is limited only to the neck, cervical ultrasonography is preferred, which helps in assessing if the goiter is diffuse or nodular. It also shows if the thyroid gland is impinging upon other cervical structures and lymphadenopathy is present. Ultrasonography is a vital component of guidance of fine-needle aspiration for differential cytologic diagnosis. If a goiter is extended posteriorly or beneath the sternal notch into the thorax, a CT scan or MRI may be needed. Radiocontrast dye containing iodine is usually avoided when evaluating goiters since the stable load of iodide may interfere with later radioiodine studies or therapies. The functional abilities of the gland can be determined by using thyroid radionuclide uptake studies that feature 123I or 99mTc pertechnetate. The etiology of the goiter, and if any superior mediastinal mass is thyroid tissue, can be determined with radionuclide scanning. Symptoms directly related to esophageal compression can be determined by using barium swallow radiographs with

83

84

Epidemiology of Thyroid Disorders

controlled-diameter markers. Symptoms directly related to tracheal compression can be determined by using pulmonary function testing with flow-volume loops. In a patient with possible recurrent laryngeal nerve involvement, laryngoscopy is useful for evaluating the function of the vocal cords.

Treatment It is important to understand that in endemic areas, the total goiter prevalence may not return to normal for months or years after iodine deficiency is corrected. For simple nontoxic goiter, in iodine-deficient areas, treatments include iodine supplementation of salt, oral administration of iodized oil, intramuscular administration of iodized oil once per year, and iodination of water, crops, or animal foods. Any goitrogens being ingested must be stopped. In some cases, suppression of the hypothalamic pituitary axis with TH blocks TSH production. Moderate doses of levothyroxine, 100 150 µg per day orally based on serum TSH, are useful in younger patients, reducing serum TSH to the low-normal range. Levothyroxine is contraindicated in older patients with nontoxic nodular goiter since these goiters rarely shrink and may contain areas of autonomy. Levothyroxine therapy would therefore result in hyperthyroidism. Large goiters sometimes require surgery or 131I to shrink the gland enough to prevent interferences with respiration or swallowing, or to correct cosmetic appearance. For congenital goiter, surgery is performed to correct thyroid enlargement that is compromising breathing or swallowing. Hypothyroidism is treated with TH. For multinodular goiter, treatments include observation of the patient, radioactive iodine, medications to decrease TH levels, and if breathing or swallowing is compromised, surgical removal of part or all of the thyroid. Surgery is generally preferred when the patient has significant thyroid enlargement, with compressive complications, primarily when there is substernal goiter extension, or acute obstruction. When surgery cannot be performed due to health status, radioactive iodine therapy can reduce goiter size by an average of 50%, over a course of 1 2 years. Ultrasonography is a great technique for monitoring the size of an enlarged thyroid. Thyroxine therapy that suppresses TSH levels only shrinks goiters in a small number of patients. Chronic TH treatment brings with it risks for symptomatic thyrotoxicosis, atrial fibrillation, and loss of bone minerals.

Clinical cases Case 1 1. Where do the highest levels of iodine occur on earth? 2. Why may iodine deficiency result in a goiter? 3. How should this patient be treated?

Iodine deficiency and goiter

A 25-year-old Brazilian woman was examined because of a goiter. She was allergic to shellfish and did not use iodized salt by choice. Previously, her aunt had been diagnosed with hyperthyroidism. The thyroid gland was palpable, and she had a normal thyroid function test but was negative for thyroid peroxidase antibody. Thyroid sonogram revealed a diffuse goiter. All these facts are combined to raise the suspicion of iodine deficiency. Answers: 1. The highest levels of iodine on earth are found in the seaweed that grows in the oceans. 2. Iodine deficiency may result in a goiter because thyroid hormone requires iodine in order for it to be manufactured. When there is insufficient thyroid hormone, release of TSH from the pituitary gland increases, which stimulates the thyroid to work harder and release more hormone, causing it to enlarge. 3. Treatments include use of iodized salt and a multivitamin that contains iodine.

Case 2 1. Based on your study, which continents have the highest incidence of goiter? 2. If the multiple nodules are benign, what would be the treatment? 3. How can multinodular goiters be differentiated from simple goiters? A 57-year-old Asian woman is examined, having had a long history of multinodular goiter. Sonography confirms multiple solid and cystic nodules. The largest of the nodules is in the isthmus, measuring 1.5 cm. The patient is referred for fine-needle aspiration of the dominant nodule. Answers: 1. The continents with the highest incidence of goiter include Asia and South America. This is especially true in extremely mountainous regions, such as the Himalayas and Andes. 2. Treatments include observation, radioactive iodine, medications to decrease thyroid hormone levels, and surgery. 3. In simple (diffuse) goiters, the entire thyroid is enlarged but smooth. In multinodular goiter, there are solid or fluid-filled lumps.

Case 3 1. Based on the symptoms, and appearance of this patient’s thyroid tissues, what was the likely diagnosis?

85

86

Epidemiology of Thyroid Disorders

2. If this patient had recurrent episodes of painful inflammation of the abdomen, chest, or joints, plus a fever and rash, what would this point toward in relation to her diagnosis? 3. Is this condition visibly different that other forms of goiter? A 44-year-old woman presented with a large, growing goiter that she said had been present for years. She had no history of pain but experienced regular hoarseness of her voice. She was euthyroid, with normal blood and biochemistry results. Fineneedle aspiration cytology revealed a nodular goiter. A bilateral subtotal thyroidectomy was performed, preserving the parathyroid glands and laryngeal nerves. Examination of the tissue revealed that the thyroid lobes and isthmus were enlarged, soft, and extremely vascular. There were obvious amyloid and fatty deposits throughout. Answers: 1. The likely diagnosis is amyloid goiter. 2. These symptoms indicate the presence of amyloidosis and would be understood to be related to an amyloid goiter. 3. Amyloid deposits and fatty deposits would be visible throughout the thyroid tissue, which is different than the appearance of nodular or smooth goiters.

Key terms amyloidosis colloid goiter colloid involution cretinism endemic goiter euthyroid goitrogens hyperplastic

involution juvenile goiter multinodular goiter Riedel’s thyroiditis sporadic goiter superior vena cava syndrome thyroid nodules toxic multinodular goiter

Further reading 1. Ameen, M. Thyroid Dysfunctions and Emergency of Goiter. (2017) Lap Lambert. 2. Aronson, J.K. Meyler’s Side Effects of Endocrine and Metabolic Drugs (Meyler’s Side Effects of Drugs). (2009) Elsevier Science. 3. Bao, S.S., and Winter, B. Thyroid Nodules: Questions From Real Patients. (2018) ACE Health Publisher. 4. Bram, I. Exophthalmic Goiter and Its Nonsurgical Treatment. (2015) Andesite Press. 5. Brownstein, D. Iodine: Why You Need It, Why You Can’t Live Without It. (2014) Medical Alternative Press. 6. Cooper, D.S., and Sipos, J. Medical Management of Thyroid Disease, 3rd Edition. (2018) CRC Press. 7. Dennison, J., Oxnard, C., and Obendorf, P. Endemic Cretinism. (2011) Springer.

Iodine deficiency and goiter

8. Farrow, L., and Brownstein, D. The Iodine Crisis: What You Don’t Know About Iodine Can Wreck Your Life. (2013) Devon Press. 9. Gharib, H. Thyroid Nodules: Diagnosis and Management (Contemporary Endocrinology). (2018) Humana Press. 10. Gnepp, D.R. Diagnostic Surgical Pathology of the Head and Neck, 2nd Edition. (2009) Saunders. 11. Halenka, M., and Frysak, Z. Atlas of Thyroid Ultrasonography. (2017) Springer. 12. Honda, M., and Sellman, S. Reverse Thyroid Disease Naturally: Alternative Treatments for Hyperthyroidism, Hypothyroidism, Hashimoto’s Disease, Graves’ Disease, Thyroid Cancer, . . . and More. (2018) Hatherleigh Press. 13. Icon Group International. The World Market for Fluorine, Bromine, and Iodine: A 2018 Global Trade Perspective. (2018) Icon Group International, Inc. 14. Kocjan, G., Gray, W., Levine, T., Kardum-Skelin, I., and Vieth, P. Diagnostic Cytopathology Essentials: Expert Consult. (2013) Churchill Livingstone. 15. Lathrop Steman, T. Twentieth Century Practice: Diseases of the Vascular System and Thyroid Gland. (2015) Sagwan Press. 16. Lawrence, M. Food Fortification: The Evidence, Ethics, and Politics of Adding Nutrients to Food. (2013) Oxford University Press. 17. Miller, J.L., and Pribitkin, E.D.A. Thyroid Nodules and Cancer: A Simplified Case Oriented Approach Endocrinology Research and Clinical Developments. (2017) Nova Science Publishers Inc. 18. Monaco, F. Thyroid Diseases. (2012) CRC Press. 19. Orell, S.R., and Sterrett, G.F. Orell and Sterrett’s Fine Needle Aspiration Cytology, 5th Edition. (2011) Churchill Livingstone. 20. Pearce, E.N. Iodine Deficiency Disorders and Their Elimination. (2017) Springer. 21. Randolph, G.W. Surgery of the Thyroid and Parathyroid Glands, 2nd Edition. (2012) Elsevier. 22. Roman, S.A., Sosa, J.A., and Solorzano, C.C. Management of Thyroid Nodules and Differentiated Thyroid Cancer. (2017) Springer. 23. Vitti, P., and Hegedus, L. Thyroid Diseases: Pathogenesis, Diagnosis, and Treatment (Endocrinology). (2018) Springer. 24. William, A. Medical Medium Thyroid Healing: The Truth Behind Hashimoto’s, Graves’, Insomnia, Hypothyroidism, Thyroid Nodules & Epstein-Barr. (2017) Hay House Inc. 25. Ziessman, H.A., O’Malley, J.P., and Thrall, J.H. Nuclear Medicine: The Requisites (Requisites in Radiology), 4th Edition. (2013) Saunders.

87