Hyperthyroidism

CHAPTER 6

Hyperthyroidism Mohtashem Samsam Contents Etiology of hyperthyroidism Epidemiology of hyperthyroidism Pathophysiology of hyperthyroidism Clinical presentation Nervous system Cardiovascular system Integumentary system Gastrointestinal system Respiratory system Muscular system Skeletal system Hematopoietic system Electrolyte metabolism Reproductive system Diagnosis of hyperthyroidism Treatment of hyperthyroidism Propylthiouracil and methimazole Beta-blockers Radioiodine Surgery Subclinical hyperthyroidism Clinical cases Clinical case 1 Clinical case 2 Clinical case 3 Clinical case 4 Further reading

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The various manifestations of excessive amounts of thyroid hormones (THs) are described today as either hyperthyroidism or thyrotoxicosis. However, these two terms are not synonymous. The difference is that thyrotoxicosis is a state of excessive TH, while hyperthyroidism is the result of excessive thyroid function. Hyperthyroidism, however, is just one cause of thyrotoxicosis. Primary hyperthyroidism may arise from an intrinsic thyroid abnormality. Secondary hyperthyroidism may arise from processes outside of the thyroid, such as a thyroid-stimulating hormone (TSH)-secreting pituitary tumor. Epidemiology of Thyroid Disorders DOI: https://doi.org/10.1016/B978-0-12-818500-1.00006-2

r 2020 Elsevier Inc. All rights reserved.

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The terms thyrotoxicosis and hyperthyroidism will therefore be used interchangeably in this chapter. The thyroid gland is usually enlarged, secreting greater than normal amounts of THs. The metabolic processes of the body become accelerated.

Etiology of hyperthyroidism Hyperthyroidism may occur from increased TH synthesis and secretion, due to thyroid stimulators in the blood, or from autonomous thyroid hyperfunction. It can also develop from excessive release of TH from the thyroid, without increased synthesis. This release is usually due to destructive changes from various forms of thyroiditis. Various clinical syndromes also cause hyperthyroidism. The following three common causes of thyrotoxicosis are related to hyperfunction of the thyroid gland: • Diffuse hyperplasia of the thyroid—associated with Graves’ disease (approximately 85% of cases) • Hyperfunctional multinodular goiter • Hyperfunctional thyroid adenoma The etiology of hyperthyroidism is due to overproduction of T4, T3, or both. Diagnosis of overactive thyroid and treatment of underlying causes can relieve symptoms and prevent complications. Causes of hyperthyroidism include the autoimmune disorder known as Graves’ disease; as well as excess iodine, thyroiditis, toxic adenomas, and other tumors, toxic multinodular goiter, and large amounts of tetraiodothyronine received through dietary supplements of medications (Fig. 6.1). Overstimulation of the thyroid gland by the TSH receptor and mutations of this receptor are common causes of hyperthyroidism. Other causes include damage to thyroid follicles that cause them to passively release thyroid hormones. Additional causes of hyperthyroidism include as follows: • Thyroiditis (inflammatory thyroid disease)—includes Hashimoto’s thyroiditis, subacute granulomatous thyroiditis, and silent lymphocytic thyroiditis; there are destructive thyroid gland changes and release of stored hormone not because of increased synthesis; hypothyroidism may then follow. • Excessive iodine ingestion—there is a low thyroid radioactive iodine uptake (RAIU); this usually occurs with a nontoxic nodular goiter of patients (mostly in elderly) who are given iodine-containing drugs or who have radiologic studies that use iodine-rich contrast agents; the excess iodine may provide substrate for non-TSH regulated, autonomous areas of the thyroid to produce hormone; hyperthyroidism usually lasts as long as the excess iodine is in the circulation. • Thyrotoxicosis factitia—due to conscious or accidental overingestion of TH. • High human chorionic gonadotropin (hCG) levels—due to molar pregnancy, choriocarcinoma, or hyperemesis gravidarum; levels of hCG are highest in the first trimester of pregnancy, causing decreased serum TSH and slightly increased

Hyperthyroidism

Graves disease (TSH receptor antibodies) TSH receptor TSH IgG

4

Low TSH

Thyroid pill

1

Nodular goiter

2 3

T3, T4

Adenoma

Figure 6.1 Various causes of hyperthyroidism.

serum fT4; increased thyroid stimulation may be due to higher levels of partially desialated hCG, which seems to be stronger in its thyroid stimulation than more sialated hCG; overall, this cause is transient; normal function resumes once the condition resolves or is treated. • Plummer’s disease—also called toxic solitary or multinodular goiter; may be due to TSH receptor gene mutations that produce continuous thyroid stimulation; toxic nodular goiter results in no autoimmune manifestations or circulating antibodies seen in patients with Graves’ disease; toxic solitary and multinodular goiters usually do not remit. • Drug-induced hyperthyroidism—can be from amiodarone and interferon alfa; these can cause thyroiditis with hyperthyroidism and other disorders; lithium, in rare cases, can cause hyperthyroidism but is more commonly a cause of hypothyroidism; patients receiving these drugs require close monitoring.

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•

Struma ovarii—occurs when ovarian teratomas have enough thyroid tissue to cause true hyperthyroidism; in the pelvis, RAIU occurs; uptake by the thyroid is usually suppressed. • Nonautoimmune autosomal dominant hyperthyroidism—in infancy, this results from TSH receptor gene mutations, producing continuous thyroid stimulation. • Metastatic thyroid cancer—rarely, overproduction of thyroid hormone occurs from functioning metastatic follicular carcinoma—especially in pulmonary metastases. • Inappropriate TSH secretion—rare; in hyperthyroidism, TSH is basically undetectable, except when there is a TSH-secreting anterior pituitary adenoma or pituitary resistance to TH; the TSH levels are high; the TSH produced by both disorders is biologically of higher activity than normal TSH; increased alpha-subunits of TSH in the blood occur when there is a TSH-secreting pituitary adenoma. Graves’ disease will be discussed in detail in Chapter 7, Thyroiditis and Graves’ disease. Various causes of hyperthyroidism are illustrated in Fig. 6.1.

Epidemiology of hyperthyroidism Hyperthyroidism occurs in people over the age of 60 years in as many as 15% of cases. However, hyperthyroidism affects 1 in 500 pregnancies. In the United States, about 1.2% of the population has hyperthyroidism, which is slightly more than 1 of every 100 people. This is equivalent to approximately 3,290,000 individuals. Hyperthyroidism is also varied in populations based on iodine sufficiency. According to the National Health and Nutrition Examination Survey (NHANES III), along with United Kingdom surveys, females are also more affected than males, and there is a lower prevalence of hyperthyroidism in comparison to hypothyroidism. The predominant ages for the condition are in the third and fourth decades. It is important to note that the various studies have only been of small amounts of volunteers. The global prevalence of hyperthyroidism in women is between 0.5% and 2%. It is 10 times more common in women than in men. The prevalence in elderly people ranges between 0.4% and 2%. A higher prevalence is seen in iodine-deficient areas. Overt hyperthyroidism affects 0.4 of every 1000 women and 0.1 of every 1000 men, but there is a large variance between ages regarding susceptibility. The risk factors for hyperthyroidism include positive family history, female gender, other autoimmune disorders, and iodide repletion after iodide deprivation—especially in multinodular goiter. However, various studies have shown different results concerning hyperthyroidism. In 1992 the Cardiovascular Health Study that revealed the prevalence of overt hyperthyroidism in people aged 65 years or older was 0.33%. An article that examined various studies between 1990 and 2013 showed that the relative incidence of overt hyperthyroidism during pregnancy was estimated as ranging between 0.1% and 0.4%. In the United Kingdom the 20-year follow-up of the Whickham Study revealed annual

Hyperthyroidism

incidence of hyperthyroidism to be 0.008% in females but undetectable in males. Prevalence of previously unsuspected hyperthyroidism was 0.5% in women and, again, undetectable in men. In Scotland an increase in primary hyperthyroidism, between 1994 and 2001, was shown in a population-based study. The overall prevalence increased in females from 0.86% to 1.26% and in males from 0.17% to 0.24%. Standardized incidence increased from 0.68 to 0.87 per 1000 women annually. This represented a 6.3% annual increase. More recently, a study in Denmark showed mild-to-moderate iodine deficiency in two major cities. Overall standardized incidence rate per 100,000 person-years was 81.6. The ratio between mild- versus moderate iodine-deficiency areas was 1.6. There is limited incidence data for hyperthyroidism in the United States. This is based on the number of new prescriptions of thionamide antithyroid drugs. The incidence per 1000 subjects, by age group, in 2010 is shown in Table 6.1. Referring back to the NHANES III study, prevalence of hyperthyroidism only differs slightly by ethnicity. Table 6.2 summarizes the prevalence of hyperthyroidism for patients aged 12 years and older, by race or ethnicity in the United States. In reference to hyperthyroidism and mortality a study of British patients who presented with their first episode of hyperthyroidism between 1989 and 2003 included a follow-up until 2012. This study found that 32% of the initial cohort of patients, aged 40 years and older, had died. This was 15% higher for all-cause mortality than expected deaths for this population. Comorbidities were also high in the population. Those with atrial fibrillation had a 59% higher risk of death. Cardiovascular and Table 6.1 Incidence per 1000 subjects of overt hyperthyroidism, by age. Age (years)

Incidence per 1000 subjects

4 11 12 17 18 44 56 64 65 and older

0.44 0.26 0.59 0.78 1.01

Table 6.2 Prevalence of overt and subclinical hyperthyroidism in the United States. Race or ethnicity

Overt (%)

Subclinical (%)

Overall (%)

All Black, non-Hispanic Mexican American White, non-Hispanic Other races or ethnicities

0.5 0.5 0.2 0.6 0.4

0.7 0.6 0.5 0.8 0.3

1.3 1.1 0.7 1.4 0.7

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cerebrovascular causes were 20% higher than anticipated. Excessive mortality was not seen in the subgroup of patients who had no preceding comorbidities. In those with Graves’ disease, all-cause mortality was increased by 16%. A 2013 study focused on long-term adverse effects due to subclinical hyperthyroidism. This included an increased 24-hour heart rate and increased frequency of atrial and ventricular ectopic beats. Large studies of older adults revealed a 13% increase in the frequency of atrial fibrillation. The highest risk of coronary heart disease mortality and atrial fibrillation was found in patients with serum TSH under 0.10 mU/L. Focus on prevalence of hyperthyroidism Hyperthyroidism is about five times more common in women than in men. Overall prevalence is about 1.3%, but this increases in older women from 4% to 5%. The condition is also more common in smokers.

Pathophysiology of hyperthyroidism With hyperthyroidism, serum T3 usually increases more than thyroxine. This is probably due to increased T3 secretion, along with conversion of thyroxine to T3 in the peripheral tissues. Sometimes, just the T3 is elevated—known as T3 toxicosis. This may occur in any disorders commonly causing hyperthyroidism, including Graves’ disease, multinodular goiter, and autonomously functioning solitary thyroid nodule. When T3 toxicosis is not treated, the patient usually develops abnormalities such as elevated thyroxine and 123I uptake. Various types of thyroiditis usually have a hyperthyroid phase, followed by a hypothyroid phase.

Clinical presentation The clinical manifestations of hyperthyroidism are common to all causes of thyrotoxicosis and also Graves’ disease. The condition may be dramatic or subtle, with or without a goiter or nodule. Common signs and symptoms resemble those of adrenergic excess, including nervousness, hyperactivity, palpitations, heat hypersensitivity, increased sweating, fatigue, increased appetite, insomnia, weight loss, frequent bowel movements that may involve diarrhea, and weakness (Fig. 6.2). Hypomenorrhea can be present. Signs include tremor, warm and moist skin, tachycardia, atrial fibrillation, widened pulse pressure, and palpitations. Elderly patients, especially with toxic nodular goiter, may have atypical presentations. This apathetic (masked) hyperthyroidism may resemble depression or dementia, usually without exophthalmos or tremor. More likely symptoms include atrial fibrillation, altered sensorium, syncope, heart failure, and weakness. Signs and symptoms may only affect one organ system.

Hyperthyroidism

Hypofunction Loss of hair coarse, brittle hair Periorbital edema Puffy face Normal, enlarged, or small thyroid Heart failure (bradycardia)

Hyperfunction Thin hair Exophthalmos Normal or enlarged thyroid: • Diffuse (warm on palpation) • Nodular • Solitary "toxic" nodule Heart failure (tachycardia)

Weight loss Constipation

Diarrhea

Cold intolerance Warm skin, sweaty palms

Muscle weakness Hyperreflexia Decreased bone mineral density (osteoporosis) Edema of the extremities

Pretibial myxedema

Figure 6.2 Symptoms of Graves’ disease.

Excessive adrenergic stimulation may cause staring, eyelid lag or retraction, and mild conjunctival injection. With adequate treatment, these usually remit. Infiltrative ophthalmopathy is more serious and specific to Graves’ disease. It involves lacrimation, orbital pain, irritation, increased retro-orbital tissue, photophobia, exophthalmos, and lymphocytic infiltration of the extraocular muscles. This results in ocular muscle weakness, and often, double vision. Infiltrative dermopathy is confusedly also called pretibial myxedema (Fig. 6.3) and is signified by nonpitting infiltration by proteinaceous ground substances that is usually

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Mechanisms of hypothyroidism Secondary causes Primary thyroid malfunction

Pituitary malfunction

Hypothalamic malfunction

Lack of TH negative feedback on pituitary TSH secretion and hypothalamic TRH secretion

Lack of negative feedback to hypothalamic release of TRH by TSH and thyroid TH

Decreased TRH

Low levels of TH and high levels of TSH and TRH

Low levels of TSH and TH and high levels of TRH

Low levels of TRH, TSH, and TH

Figure 6.3 Mechanisms of hypothyrodism. Table 6.3 Thyrotoxicosis signs and symptoms, from most common to least. Signs

Symptoms

1. 2. 3. 4. 5. 6. 7. 8.

1. 2. 3. 4. 5. 6. 7. 8.

Tachycardia; atrial fibrillation in elderly patients Tremor Goiter Skin that is warm and moist Muscle weakness; proximal myopathy Eyelid retraction or lag Gynecomastia Oligomenorrhea

Hyperactivity, dysphoria, irritability Heat intolerance, sweating Palpitations Fatigue and weakness Weight loss with increased appetite Diarrhea Polyuria Loss of libido

Note: The “signs” listed in this table do not include ophthalmopathy and dermopathy, which are specific for Graves’ disease (see Chapter 7: Thyroiditis and Graves’ disease).

in the pretibial area. It rarely occurs without Graves’ ophthalmopathy. Lesions are usually erythematous and pruritus in early stages, then becoming brawny. This condition can appear years before or after hyperthyroidism. The most common signs and symptoms of thyrotoxicosis, from those of highest frequency to least, are listed in Table 6.3. Clinical presentation is based on severity of the thyrotoxicosis, disease duration, the patient’s susceptibility to excessive thyroid hormone, and age. In elderly patients, signs and symptoms may be subtle or hidden. The patient may primarily present with fatigue and weight loss. This is known as apathetic thyrotoxicosis. With thyrotoxicosis, there may be unexplained weight loss even with an increased appetite. This is because of the increased metabolic rate. About 5% of patients

Hyperthyroidism

experience weight gain, however, due to increase food intake. Other primary features include hyperactivity, irritability, and nervousness that lead to easy fatigue in some patients. Commonly, impaired concentration and insomnia are seen. For elderly patients, apathetic thyrotoxicosis is sometimes mistaken for depression. Fine tremor is common, usually induced by having the patient stretch out the fingers while feeling the fingertips with the palm of the hand. Hyperthyroidism affects various body systems that are explained further.

Nervous system As the nervous system functions are altered, the patient experiences nervousness, hyperkinesia, and emotional lability. Fatigue may occur from insomnia and muscle weakness. Emotional lability is common. Rarely, mental disturbances are severe, including manic depressive, paranoid, and schizoid reactions. Hyperkinesia is characteristic of the thyrotoxic patient. The patient, when interviewed, changes position often. Movements are fast, exaggerated, jerky, and often without any purpose. In children, these movements are usually more severe. There may be an inability to focus, resulting in poor school performance, and suggesting attention deficit hyperactivity disorder. Fine tremors may affect the eyelids when they are lightly close, the hands, or the tongue. An electroencephalogram will reveal increased fast wave activity. If the patient has convulsions, there is increased frequency of seizures. Sympathetic nervous system activation and thyrotoxicosis manifestations are often similar. However, in patients with thyrotoxicosis, plasma epinephrine and norepinephrine, along with urinary excretion of these substances and their metabolites, are not increased. Thyroid hormones have separate effects to those of the catecholamines, but are similar to them, and also additive to them. Improved cardiac function in hyperthyroidism by beta-adrenergic blockade has resulted in the idea that there is increased sympathetic tone or cardiac sensitivity to the sympathetic nervous system. Animal studies have shown that overexpression of heart type 2 deiodinase increases myocardial T3 and cyclic adenosine monophosphate (cAMP) responses to norepinephrine in cardiac myocytes because of altered G proteins. Also, adipocytes in thyrotoxic patients have 3 times higher levels of norepinephrine-induced lipolysis, 15 times higher levels of responses to beta2-adrenergic receptor agonists, and 3 times higher increases in response to cAMP or forskolin. Therefore thyroid hormones increase sensitivity to catecholamines in adipocytes and cardiomyocytes in many ways.

Cardiovascular system In hyperthyroidism, altered cardiovascular function is partly due to increased circulatory demands caused by hypermetabolism and a need to dissipate excess heat. During resting, there is decreased peripheral vascular resistance. Cardiac output increases as a

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result of increased heart rate and then, with more severe disease, stroke volume. Excess thyroid hormones have a direct inotropic effect upon heart contraction, regulated by an increased ratio of alpha- to beta-myosin heavy chain expression. Tachycardia is nearly always present. It is caused by increased sympathetic and decreased vagal tone. Widened pulse pressure is caused by increased systolic and decreased diastolic pressure, due to reduced resistance. The decreased resistance is caused by increased production of nitric oxide via the PI3K/protein kinase B (AKT) signaling pathway. The patient often feels increased systolic force, experienced as a palpitation. This is evident on inspection or palpation of the precordium. The heart can be enlarged due to the diffuse, forceful nature of the apex beat. Echocardiography reveals an increased size of the ventricles. Also, the preejection period is shortened. There is a decrease in the ratio of the preejection period to left ventricular ejection time. Heart sounds are enhanced—especially S1. There is a scratch-like systolic sound along the left sternal border. This is similar to a pleuropericardial friction rub called the Means Lerman scratch. Once a normal metabolic state is restored, these occurrences disappear. If the patient has never been in heart failure, the increased cardiovascular demands of standard workloads or metabolic challenges are met. Cardiac competence is maintained in most patients with no underlying heart disease. Without heart failure, mild peripheral edema may still occur. Heart failure usually occurs in patients with preexisting heart disease. It is more common in elderly, but sometimes it may not be determined to exist until thyrotoxicosis is relieved. Atrial fibrillation decreases efficient cardiac response to increased circulatory demands. It may be causative for cardiac failure. While thyrotoxicosis is present, there should be no attempts to convert atrial fibrillation to sinus rhythm. Approximately 60% of patients revert spontaneously to sinus rhythm following treatment, usually within 4 months. Because of this, and the fact that thromboembolism is rare in patients under age of 50 years with hyperthyroidism, routine anticoagulation is not suggested for younger patients who have no history of underlying heart disease or a thrombotic disorder. For thyrotoxicosis-induced atrial fibrillation, medical or electrical cardioversion is usually successful even after 1 year has passed.

Integumentary system The most significant change due to long-standing hyperthyroidism is that the skin feels warm and moist. This occurs due to cutaneous vasodilation and excessive sweating. There may be a smoothness and pink color of the elbows. The patient has a rosy complexion and blushes easily. Palma erythema may resemble the palms of a liver patient, and telangiectasia may develop. The hair becomes fine and brittle, with hair loss sometimes increasing. The nails also become soft and brittle. Uncommonly, there are Plummer nails or onycholysis that usually affects the fourth and fifth fingers.

Hyperthyroidism

Another autoimmune disease, vitiligo is more common if the patient has autoimmune thyroid disease. Thyroid dermopathy is a condition that usually does not require treatment. It may cause cosmetic problems or interfere with how the patient’s shoes fit. Surgical removal is not helpful. If required, treatments involve topical, high-strength glucocorticoid ointments under occlusive dressings. Octreotide may be beneficial for some patients.

Gastrointestinal system The appetite often increases but not when the disease is only mild. With more severe disease, increased food intake is insufficient to meet increased caloric needs. Weight is lost at various rates. Usually, the patient reports good success with weight loss that previously did not occur. There are more bowel movements. Diarrhea is rare but can become problematic. With thyrotoxicosis, increased gastric emptying and intestinal motility may cause slight fat malabsorption. These functions normalize once a normal metabolic state has been restored. Celiac and Graves’ diseases are coexisting more often than previously believed. There is an increased prevalence of pernicious anemia. When thyrotoxicosis is severe, hepatic dysfunction occurs more commonly. There may be hypoproteinemia, increased serum alanine aminotransferase, and elevated bone or liver alkaline phosphatase.

Respiratory system In severe hyperthyroidism, dyspnea is common. There may be several contributing factors. There is usually a reduction of vital capacity, mostly from weakness of the respiratory muscles. With exercise, ventilation is increased, but this is not proportional to the increase in oxygen uptake. The diffusing capacity of the lungs remains normal. Due to the general oxygen consumption increase related to thyrotoxicosis, the patient with a chronic lung disease may have a severe worsening of the condition when he or she becomes thyrotoxic.

Muscular system Muscle disease along with hyperthyroidism is not usually suggested by weakness or fatigue. There is usually generalized wasting related to weight loss. Weakness is most common in the proximal limb muscles. The patient has difficulty climbing stairs or becomes fatigued just from lifting relatively lightweight objects. Proximal muscle wasting may be out of proportion for overall weight loss. This is often called thyrotoxic myopathy. In very severe forms, myopathy may affect more distal muscles of the extremities, and the trunk or facial muscles. Myopathy of the ocular muscles is unusual but, if present, may mimic myasthenia gravis or ophthalmic myasthenia. Muscle

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strength improves once a normal metabolic state is restored, but muscle mass takes a longer time to recover.

Skeletal system Hyperthyroidism is usually related to increased excretion of calcium and phosphorus in the urine and stool. There is an increase in bone turnover, with a net demineralization of bone—shown by routine bone densitometry. Sometimes, especially in elderly women, there are pathologic fractures. In these, pathologic changes are varied. They may include osteitis fibrosa, osteomalacia, or osteoporosis, usually with varied vitamin D levels. Urinary excretion of telopeptides, which are collagen breakdown products, is increased. Kinetic studies show increased exchangeable calcium and acceleration of bone resorption and accretion—especially resorption. The T3 hormone accelerates osteoclast activity, and TSH may have localized actions, which can balance TH action upon osteoclasts and enhance osteoblast activity. This TSH action would be absent in hyperthyroidism and allows accentuated TH effects. These changes lead to decreased bone density in many individuals. With treatment, bone density of younger patients can normalize. In postmenopausal females, there may be accelerated bone density reduction, requiring treatment. Induction of decreased bone density via TSHsuppression therapy, with thyroid cancer, is controversial. Postmenopausal women given a TSH-suppressive dosage of TH are at risk of osteopenia. They require prophylaxis with calcium and vitamin D, or more aggressive treatments. Relaxation of TSH suppression in low-risk patients may be based on bone status. Hypercalcemia may develop along with severe hyperthyroidism for the same reasons. Total serum calcium is increased in up to 27% of patients. Ionized serum calcium is elevated in 47% of them. There are common elevations of heat labile serum alkaline phosphatase and osteocalcin. This resembles primary hyperparathyroidism, but concentrations of parathyroid hormone in the serum are usually low normal. Try primary hyperparathyroidism and hyperthyroidism sometimes exist at the same time. Plasma 25-hydroxycholecalciferol levels are decreased in thyrotoxic individuals. This change could add to the decreased intestinal absorption of calcium and osteomalacia that sometimes develops.

Hematopoietic system Thyrotoxicosis increases red blood cell (RBC) mass, but the RBCs are otherwise normal. The increased erythropoiesis is related to direct effects of thyroid hormone upon the erythroid marrow and to increased erythropoietin production. There is a parallel increase in plasma volume. Therefore the hematocrit remains normal. There are normal platelet levels, and the intrinsic clotting mechanism is also normal. Concentration of factor VIII is commonly increased. It normalizes once

Hyperthyroidism

thyrotoxicosis is treated. There is enhanced sensitivity to warfarin due to accelerated clearance of vitamin K dependent clotting factors. Therefore warfarin dosage must be reduced. This is important to remember when beginning anticoagulant treatment for atrial fibrillation in older patients. Coincidental autoimmune thrombocytopenia may occur.

Electrolyte metabolism The only symptoms related to the urinary tract produced by hyperthyroidism are mild polyuria and, possibly, nocturia. Renal blood flow, glomerular filtration, and tubular resorptive and secretory functions are increased. There is a decrease in total exchangeable potassium. This may be linked to decreased lean body mass. Electrolytes are normal, except when there is hypokalemic periodic paralysis.

Reproductive system In early life, there may be delayed sexual maturation. However, physical development will be normal, and there may be accelerated skeletal growth. After puberty, hyperthyroidism affects reproductive function—especially in females. There may be prolongation of the intermenstrual interval—or it may be shortened. Menstrual flow is at first diminished and eventually stops. There may be reduced fertility. If conception occurs, there is a higher risk of miscarriage and various complications. Sometimes, menstrual cycles are mostly anovulatory with oligomenorrhea. Mostly, ovulation occurs, indicated by a secretory endometrium. In anovulatory patients a subnormal mid-cycle increase of luteinizing hormone (LH) may be causative. In the premenopausal female with thyrotoxicosis, there are usually normal basal plasma concentrations of LH and folliclestimulating hormone (FSH). However, these may have enhanced responsiveness to gonadotropin-releasing hormone (GnRH). Whether the condition is spontaneous or caused by exogenous hormone, it is accompanied with an increase in concentration of sex hormone binding globulin in the plasma. Therefore plasma concentrations of total testosterone, estradiol, and dihydrotestosterone are increased. However, their unbound fractions are normal or slightly decreased. Increased binding in the plasma may cause decreased metabolic clearance rates of testosterone and dihydrotestosterone. The metabolic clearance rate of estradiol will be normal, which suggests increased tissue metabolism of this hormone. There is increased conversion of androstenedione to testosterone, estrone, and estradiol, along with testosterone to dihydrotestosterone. The increased conversion of androgens to estrogenic byproducts may cause gynecomastia and erectile dysfunction in about 10% of thyrotoxic men. It could be once cause of menstrual irregularities in females. Another possible cause of menstrual changes is disruption in amplitude and frequency of LH FSH pulses, caused by thyroid hormone influences upon GnRH signaling.

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Thyroid storm Thyroid storm is also called thyrotoxic crisis. It is a severe and acute form of hyperthyroidism that results from lack of treatment or inadequate treatment. Thyroid storm is a rare but life-threatening condition, occurring in patients with Graves’ disease or toxic multinodular goiter. Its incidence is estimated at only 0.20 cases per 100,000 populations. Delirium, fever, seizures, vomiting, diarrhea, jaundice, and coma accompany thyroid storm. Mortality rates are due to cardiac failure, arrhythmia, or hyperthermia. They are as high as 30% even when treatment is given. Thyroid storm is usually precipitated by an acute illness or surgery. Acute illnesses that may cause thyroid storm include infections, stroke, diabetic ketoacidosis, and trauma. Intensive monitoring and supportive care are required. Thyroid storm can also be caused by overreplacement of thyroid hormones or when medications used to treat hyperthyroidism are discontinued abruptly. The precipitating cause must always be identified and treated. Steps are taken to reduce synthesis of thyroid hormone. Treatments include propylthiouracil, iodine, Lugol’s solution, sodium iodide, propranolol, esmolol, intravenous dextrose, cooling blankets, calcium channel blockers, adenosine, beta-blockers, and corticosteroids. Focus on geriatrics The characteristic signs and symptoms may be absent, known as apathetic hyperthyroidism. They can mimic depression or malignancy. Atrial fibrillation is common in patients over age of 60 years when TSH is less than 0.1 mU/L.

Diagnosis of hyperthyroidism Diagnosis of hyperthyroidism is based on history, physical examination, and thyroid function tests. The best test is serum TSH measurement, since TSH is suppressed, except rarely, when the etiology is a TSH-secreting pituitary adenoma or pituitary resistance to TH. Screening certain populations for TSH levels is suggested. In hyperthyroidism, there will be increased fT4. However, thyroxine may be false-normal when the patient has a severe systemic illness and in T3 toxicosis. If the fT4 is normal and the TSH is low, with subtle signs and symptoms of hyperthyroidism, the serum T3 must be measured to detect T3 toxicosis. An elevated level is confirmative. Fig. 6.4 shows the relationship between TSH, fT4, and clinical conditions. Exposure to a drug or Graves’ disease manifestations can often be clinically diagnosed. If not, the use of 123I may help obtain thyroid RAIU. When the cause is hormone overproduction, thyroid RAIU is usually elevated. TSH receptor antibodies may be measured to detect Graves’ disease. However, this is rarely needed, except in the third trimester of pregnancy, to assess risks of neonatal Graves’ disease. TSH receptor antibodies easily cross the placenta and stimulate the fetal thyroid. Most of the

Hyperthyroidism

TSH Deficient T3/T4 receptor or autonomous TSH secretion

Primary failure of thyroid gland

Euthyroid reference values

Failure of pituitary gland

Autonomous function of thyroid gland

Free T4 concentration

Figure 6.4 The relationship between TSH, fT4, and clinical conditions. World Health Organization.

Graves’ patients have circulating antithyroid peroxidase (TPO) antibodies. Less of them have antithyroglobulin antibodies. Inappropriate TSH secretion is rare. Diagnosis is confirmed if hyperthyroidism occurs with elevated circulating free-TH concentrations and normal or elevated serum TSH. Serum thyroglobulin can be measured if thyrotoxicosis factitia is suspected. The thyroglobulin is usually low or low-normal—different from all other causes of hyperthyroidism. If excess iodine ingestion is the cause, low RAIU is common, since uptake is inversely proportional to iodine intake. There are various types of diagnostic methods used to determine the presence and cause of hyperthyroidism. For secondary hyperthyroidism caused by a TSH-secreting pituitary tumor, there will also be a diffuse goiter. This diagnosis can be suggested by the presence of a nonsuppressed TSH level, with pituitary tumor (found on computed tomography scan or magnetic resonance imaging). The clinical features of thyrotoxicosis can be mimic mania, panic attacks, pheochromocytoma, and weight loss that is related to malignancies, diabetes mellitus, and menopause. Diagnosis of thyrotoxicosis is easily excluded when TSH and unbound T4 and T3 levels are normal. A normal TSH level also excludes Graves’ disease as a cause of a diffuse goiter. Usually, increases in thyroid iodide uptake and clearance rate are reflected in the RAIU test, over 24 hours. This can be inappropriately normal in patients with milder disease related to the suppressed serum TSH level. It can also be relatively low compared with 24-hour uptake in patients with very fast iodine turnover in a hyperactive thyroid gland. Free T4 concentration levels are suggested to be measure for diagnosis. Determining the RAIU is not helpful when the clinical presentation is compatible

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Hyperthyroidism Elevated TH and suppressed TSH

Radioactive iodine uptake and scan

Low uptake

Thyroiditis -Postpartum -Painless -de Quervain (viral) Exogenous thyroid hormone

Normal or elevated uptake*

Graves disease Toxic multinodular goiter Toxic adenoma

*Isotope scan aids in differentiation of causes

Figure 6.5 Evaluation of hyperthyrodism.

with clear Graves’ disease symptoms, or in a thyrotropin receptor antibodies (TRAb)positive thyrotoxic patient. However, it may be useful to exclude thyrotoxicosis not caused by Graves’ disease. Very low RAIU values or absent thyroid uptake on a thyroid scan related to thyrotoxicosis signal the presence of either: thyroiditis, factitious thyrotoxicosis, ectopic thyroid tissue, or iodine contamination by recent administration of an iodinated contrast agent. Fig. 6.5 displays how hyperthyroidism is evaluated. Focus on differential diagnosis Hyperthyroidism must be distinguished from anxiety, diabetes mellitus, malignancy, pregnancy, menopause, and pheochromocytoma.

Treatment of hyperthyroidism Treatment of hyperthyroidism is based on the cause. Pharmacologic doses of iodine inhibit release of TH within hours, as well as the organification of iodine. This transitory effect lasts from a few days to a week, with inhibition usually stopping. Iodine helps in the emergency management of thyroid storm, for hyperthyroid individuals having emergency nonthyroid surgery, and since it decreases thyroid vascularity, for preoperative preparation before subtotal thyroidectomy. Iodine is not usually used for routine hyperthyroidism treatment. Complications include salivary gland inflammation, conjunctivitis, and rash. For infiltrative dermopathy and ophthalmopathy, treatments include corticosteroids, orbital radiation, and surgery.

Hyperthyroidism

Propylthiouracil and methimazole The primary antithyroid drugs are called thionamides. These include propylthiouracil and methimazole. They function by inhibiting TPO to reduce oxidation and organification of iodide. They also reduce thyroid antibody levels by unclear mechanisms, appearing to enhance remission rates. Propylthiouracil inhibits the deiodination of T4 to T3. This minor effect, except for the most severe cases of thyrotoxicosis, is offset by the extremely short half-life of the drug—only 90 minutes—compared to the 6-hour half-life of methimazole. Propylthiouracil has significant hepatotoxicity. Therefore the FDA has limited its use to the first trimester of pregnancy, for treating thyroid storm and in patients with slight adverse reactions to methimazole. When propylthiouracil is used, there must be monitoring of liver function. There are many variations of antithyroid drug treatments. Initially, methimazole may be given twice or three times per day, though once per day is usually enough after euthyroidism has been restored. Propylthiouracil is given three-to-four times per day, often with divided doses. In areas of low iodine intake, lower doses of either drug may be sufficient. Starting doses can be slowly reduced as the condition resolves. Also, high doses may be given in combination with supplements of levothyroxine to avoid drug-induced hypothyroidism. This is called a block replace regimen. Titration helps minimize doses and provides an index of response to treatment. After treatment begins, thyroid function tests and clinical manifestations are reviewed every 4 6 weeks. Doses are titrated based on unbound T4 levels. Euthyroidism is not usually achieved until 6 8 weeks of treatment have occurred. Since TSH levels are often suppressed for several months, they do not give a sensitive index of response. For block replace regimens, initial doses are kept constant while doses of levothyroxine are adjusted to maintain normal unbound T4 levels. Once TSH suppression stops, TSH levels can be used to monitor therapy. The block replace regimen achieves maximum remission rates of up to 30% 60% in some populations within 6 months, and the titration regimen achieves similar rates within 12 18 months. Remission rates seem to differ between geographic areas. Those most likely to relapse once treatment stops are males, younger patients, smokers, and those with severe hyperthyroidism and large goiters. All patients must be followed closely for relapse during the first year following treatments and at least once per year after that. Between 1% and 5% of patients experience minor side effects of arthralgia, fever, urticaria, and rash. These can resolve on their own or after a different antithyroid drug is substituted. Propylthiouracil is not used in children and can rarely cause hepatitis in adults. Rare but major side effects with methimazole include cholestasis, a systemic lupus erythematosus like syndrome, and, most significantly, agranulocytosis. Antithyroid drugs must be stopped and not restarted if major side effects develop. Written instructions must be given to the patient regarding symptoms of

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agranulocytosis, which include fever, mouth ulcers, and sore throat. The patient must be educated about stopping treatment until an immediate complete blood count is performed to confirm that agranulocytosis is not present. Since agranulocytosis occurs idiosyncratically and abruptly, monitoring blood counts prospectively is not helpful. Large doses of propylthiouracil are given orally, via nasogastric tube, or via the rectum. It is the antithyroid drug of choice because of its inhibitory action on T4 to T3 conversion. If it is not available, methimazole may be used in controlled doses. Stable iodide is given 1 hour of the initial dose of propylthiouracil to block thyroid hormone synthesis via the Wolff Chaikoff effect. In this effect the delay allows the antithyroid drug to prevent excessive iodine from being incorporated into new thyroid hormone. A saturated solution or potassium iodide, ipodate, or iopanoic acid can be given orally. Sodium iodide is also an option but is usually not available. Propranolol may help reduce tachycardia and other adrenergic effects, and doses can be easily adjusted. However, other beta-adrenergic blockers can be used. It is important to avoid acute negative inotropic effects. Controlling heart rate is important since some patients develop a type of high-output heart failure. Short-acting intravenous esmolol helps decrease heart rate as signs of heart failure are monitored. Other therapies include glucocorticoids such as hydrocortisone, antibiotics for infections, cooling, oxygen, and IV fluids. Thyroid cells are progressively destroyed by radioiodine. It can be used initially, or for relapses after a trial regimen of antithyroid drugs. There is a slight chance of thyrotoxic crisis following radioiodine. This can be minimized with antithyroid drug pretreatment for at least 1 month prior to treatment. Additional antithyroid drug treatments must be considered for elderly patients, or if there are cardiac problems, to use up thyroid hormone stores prior to administration of radioiodine. Methimazole must be stopped 3 5 days before radioiodine is administered in order to achieve the highest iodine uptake. Propylthiouracil is believed to have a lengthened radioprotective effect. It should be stopped for a longer time period prior to administration of radioiodine. If not, a larger dose of radioiodine will be needed. Beta-blockers To control adrenergic symptoms, mostly in early stages before antithyroid drugs can take effect, propranolol or a longer acting selective beta1 receptor blocker such as atenolol may be effective. For those with thyrotoxic periodic paralysis, beta-blockers are also effective, as long as thyrotoxicosis is corrected. For those with cardiovascular conditions, anticoagulation with warfarin must be considered if the patient has atrial fibrillation. These patients often spontaneously revert to sinus rhythm when hyperthyroidism is controlled. If the patient is thyrotoxic, decreased doses of warfarin are required. If digoxin is being used, increased doses are often required.

Hyperthyroidism

Radioiodine After a few days of radioiodine, there are radiation safety precautions required. Generally, the patient should not have any close, prolonged contact with children or pregnant women for 5 7 days, so that the residual isotope and radiation emanating from the thyroid gland cannot be transmitted. After treatment, there are rare reports of mild pain due to radiation thyroiditis within 1 2 weeks. Hyperthyroidism can continue for 2 3 months prior to radioiodine taking its full effect. Therefore beta-adrenergic blockers or antithyroid drugs may help control symptoms in this period. A second dose of radioiodine, usually 6 months after the fist, can be effective for persistent hyperthyroidism. Risks of hypothyroidism following radioiodine are based on dosage. They are at least 10% 20% in the first year, and 5% each year after that. The patient must be informed of these facts before treatment. Close follow-up is required during the first year, and then annual thyroid function tests should occur. Radioiodine cannot be used during pregnancy or breast-feeding, though patients can conceive safely 6 months following treatment. If severe ophthalmopathy is present, caution must be taken. Some physicians suggest using prednisone during radioiodine treatment that is tapered over 6 12 weeks to prevent worsening of ophthalmopathy. Overall cancer risk after radioiodine treatment in adults is not increased. Many physicians avoid radioiodine in children and adolescents due to possible malignancy. However, new evidence suggests that it can be safely used in older children. There is no optimal dose of radioiodine to achieve euthyroidism without significant relapses or progression to hypothyroidism. Some patients relapse after just one dose, since radiation has varied biologic effects between patients. Hypothyroidism cannot be avoided on a regular basis even with accurate doses. Therefore a fixed dose is suggested, based on clinical features such as thyrotoxicosis severity, goiter size (which increases needed doses), and radioiodine uptake level which decreases needed doses. Most physicians focus on thyroid ablation instead of euthyroidism, if levothyroxine replacement is straightforward. Most patients become hypothryoidic over 5 10 years, often with a delay in its diagnosis. Surgery For patients who relapse after antithyroid drugs or prefer this treatment over radioiodine, subtotal or near-total thyroidectomy is an option. In younger patients, especially when the goiter is very large, surgery is often recommended. Before surgery, to avoid thyroid storm and reduce vascularity of the gland, careful control of hyperthyroidism is required. This utilizes antithyroid drugs followed by potassium iodide. Primary complications of surgery include bleeding, hypoparathyroidism, laryngeal edema, and damage to recurrent laryngeal nerves. However, these are rare when

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experienced surgeons perform the surgery. Recurrence rates are at best less than 2%. However, hypothyroidism rates are only slightly less than those after radioiodine treatment. Focus on alternative therapies Traditional Chinese herbal medications are not currently recommended due to the quality of available trials, which suggest that they may have a therapeutic potential for people with hyperthyroidism.

Focus on pediatrics Neonates and children are treated with antithyroid medications for 12 24 months. Less than 50% of them will obtain permanent remission from this method. Up to 25% of children experience significant adverse effects of antithyroid drugs. Radioactive iodine is controversial in patients under the age of 15 18 years. An alternate treatment plan should be developed for any child who does not obtain remission with antithyroid drugs.

Subclinical hyperthyroidism Subclinical hyperthyroidism was identified as a result of sensitive assays for TSH. Serum TSH is subnormal while free thyroid hormone concentrations in the serum are normal. The preferred clinical term for subclinical hyperthyroidism is mild thyroid dysfunction. The hypothalamic pituitary axis is sensitive to free thyroid hormones in the serum, while the heart and other peripheral tissues mostly sense only free T3. Therefore individuals with a low-normal free thyroxine set point for TSH secretion likely have reduced TSH, if that concentration was increased by 50% yet could still remain in the normal range. The reported overall prevalence of subclinical hyperthyroidism is about 3% of the global population. Prevalence is highest in people aged 20 39 years and also in those more than age 79. The prevalence of subnormal serum TSH levels is higher in iodine-deficient populations, by 6% 10%, because of functional autonomy from nodular goiters. Patients with primary hypothyroidism but normal TSH levels, if given small amounts of levothyroxine, will have decreased TSH below normal, with no supranormal free thyroxine. Older studies showed cumulative incidence of atrial fibrillation, over 10 years, at 28% in patients with serum TSH of 0.1 mU/L or lower. This was only 11% in patients with serum TSH between 0.1 and 0.4 mU/L, only slightly more than that of the normal population. Regardless, heart failure is the primary cause of cardiovascular mortality rates, for over as well as mild hyperthyroidism. Also, thyroid hormone causes a net resorption of cortical bone. This may be added to by a lack of TSH. Lower bone density has been shown in some studies of patients

Hyperthyroidism

with mild thyrotoxicosis. This is much more common than overt thyrotoxicosis (0.7% of the population). It is a significant factor concerning diagnosis, treatment, and follow-ups. Basically, normalized thyroid function in postmenopausal women who have subclinical hyperthyroidism appears to improve bone density and some amount of cardiac function. Although this information may support treatment for older adults, no large random studies have been conducted to assist risks versus benefits. Diagnosis of subclinical hyperthyroidism uses tests that reveal several subnormal TSH concentration results. These are done months apart, along with normal free T3 and T4 concentrations. Suppressed TSH may normalize on its own over several years, especially when the patient does not have a nodular goiter. Similarly to over thyrotoxicosis, the two sources of excessive thyroid hormones are endogenous and exogenous. Approximately 58% of patients with a TSH lower than 0.3 mU/L received thyroid hormone therapy. If this is not being administered to treat a persistent thyroid carcinoma, it is easily treated by careful use of levothyroxine and measuring serum TSH. Endogenous subclinical thyrotoxicosis is caused by the same factors as overt thyrotoxicosis. In adults over the age of 60 years, multinodular goiter is more causative of hyperthyroidism than in younger people. Not enough is known regarding whether hyperthyroidic people with serum TSH over 0.1 mU/L will actually be benefitted from treatment. When the patient has consistently subnormal TSH, less than 0.1 mU/L, with normal free thyroid hormones, he or she should be evaluated for conditions benefitting from treatment, as well as finding the cause. In older adults, primary indications for treatment include some cardiac diseases and postmenopausal osteoporosis. In young females, menstrual disorders or infertility are important to consider. Identifying the cause correctly will determine treatment. The patient with subclinical hyperthyroidism from toxic nodular goiter or a single hyperfunctioning adenoma may often be treated with just one dose of radioactive iodine. This carries a relatively low risk of resultant hypothyroidism. Therefore threshold for treatment of these patients is lower. All rationales for treatment must be fully discussed with the patient.

Clinical cases Clinical case 1 1. To assess this patient further, what tests will be performed? 2. If, over time, this patient’s thyroid nodule enlarged, or multiple nodules formed, what laboratory and imaging studies should be performed? 3. What is the significance of a thyroid nodule? A 65-year-old woman presents with a palpable mass in her right anterior neck. She has no neck pain, dysphagia, hoarseness, or symptoms of any compression. She has no symptoms of thyroid dysfunction and is not taking any medications. Physical

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examination reveals an enlarged thyroid with a 2-cm thyroid nodule that moves when the patient swallows. There is no palpable cervical lymphadenopathy. Family history is negative for thyroid cancer, but several of her family members have had a goiter. The patient has no history of irradiation to the head or neck. Answers: 1. A TSH level and a thyroid ultrasound will be performed. The normal reference range for TSH will be between 0.29 and 5.1 mIU/L. 2. With these developments, there should be tests of TSH, free thyroid hormone, radionuclide thyroid testing, ultrasound, fine-needle aspiration, and sometimes if needed, serum calcitonin tests. 3. The prevalence of palpable thyroid nodules is 4% 7% of patients. Increased prevalence is associated with older age, iodine deficiency, female gender, and exposure to ionizing radiation. Colloid nodules, cysts, and thyroiditis occur in 80% of cases. Benign follicular neoplasms occur in 10% 15% of cases, and thyroid carcinoma occurs in only 5% of cases.

Clinical case 2 1. Are this patient’s symptoms consistent with hyperthyroidism as well as hypothyroidism? 2. To distinguish between the two conditions, what tests are needed? 3. If this patient has thyroid nodules, are these likely to occur with hyperthyroidism or hypothyroidism? A 49-year-old woman presents to her physician with significant weight gain over the previous months. She tells the physician that she sleeps for as many as 15 hours every day, and her movements are obviously slowed. She has a slight enlargement of her neck area, with coarse-textured hair and dry skin. A blood test reveals thyroxine levels lower than the normal range and high levels of TSH. Answers: 1. Somewhat, yes. Her weight gain could be linked to hyperthyroidism, hypothyroidism, or Cushing syndrome. The slowed movements could be due to hypothyroidism or Addison’s disease. The dry skin could be related to hypothyroidism. The swelling in her neck could be linked to hyperthyroidism or a thyroid tumor. Therefore her signs and symptoms could be described as consistent with hyperthyroidism as well as hypothyroidism. 2. A T4 (thyroxine) and a TSH test are required. The TSH test is usually chosen for evaluation of thyroid function and for the patient’s symptoms; it is often performed with or following the T4 test. 3. Thyroid nodules are common in both hyperthyroidism and hypothyroidism and are usually benign. In hyperthyroidism, they can lead to increased size of the thyroid or the production of too much T4.

Hyperthyroidism

Clinical case 3 1. What is the most likely cause of this patient’s illness? 2. What tests are needed to confirm the cause? 3. What are the treatment options? A 35-year-old woman complained of nervousness, weakness, and palpitations with exertion. These symptoms have existed for about 6 months. She recently noticed excessive sweating. Her weight is the same as it was over the past year, yet she is able to eat much more food than previously. Her menstrual periods were regular but have involved less bleeding than before. Examination revealed warm and moist skin, a fine tremor, bounding cardiac apical impulses, and three thyroid nodules. Answers: 1. The likely cause is a toxic multinodular goiter, resulting in symptoms of hyperthyroidism. 2. A thyroid scan is needed to verify the autonomy of the thyroid nodules. 3. Treatment options include radioactive iodine or surgery with antithyroid drug and iodine pretreatment.

Clinical case 4 1. What is the likely diagnosis? 2. In type 1 diabetes mellitus patients with hyperthyroidism, what considerations must be made? 3. What is the standard thyroid hormone replacement therapy? A 32-year-old man who has had type 1 diabetes mellitus for 8 years visited his doctor because of an unintentional 22-lb weight loss. Laboratory studies showed a suppressed TSH concentration and an elevated thyroxine level. This antithyroid peroxidase antibodies were positive. His thyroid-stimulating immunoglobulin test was negative. Uptake of radioactive iodine by scanning was 0.5% at 24 hours. Answers: 1. The likely diagnosis is hyperthyroidism caused by autoimmune thyroiditis. 2. In patients with type 1 diabetes mellitus who present with hyperthyroidism, Graves’ disease and other types of hyperthyroidism must be excluded, since autoimmune thyroiditis can quickly progress to hypothyroidism, requiring thyroid hormone replacement therapy. 3. Synthetic thyroxine (T4) is the standard form of replacement therapy. The reason for this is that most of the T3 in the body came from T4. The benefit of taking just T4 therapy is that the body is allowed to perform normal actions, including the changing of T4 into T3. Also, the half-life of T4 is longer, so it remains for a longer time in the body after administration.

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Key terms Addison disease anovulatory apathetic thyrotoxicosis catecholamines celiac disease chemosis cholestasis diabetic ketoacidosis epigenetic influences erythropoietin forskolin Graves’ disease Graves’ orbitopathy Hashimoto’s thyroiditis immunomodulating intermenstrual interval Means Lerman scratch multinodular nitric oxide

organification paranoid pheochromocytoma pleuropericardial Plummer nails schizoid scintigraphy stochastic telangiectasia thionamides thyroiditis thyroid storm thyrotoxic myopathy thyrotoxicosis transantral V genes vitiligo Wolff Chaikoff effect

Further reading 1. Baker, M., Barliya, T., et al. Perspectives on Nitric Oxide in Disease Mechanisms (Targeted Therapy Opportunities). (2013) Leaders in Pharmaceutical Business Intelligence. 2. Blum, S. The Immune System Recovery Plan: A Doctor’s 4-Step Program to Treat Autoimmune Disease. (2013) Scribner. 3. Brownstein, D. Overcoming Thyroid Disorders. (2002) Medical Alternatives Press, Inc. 4. Centers for Disease Control and Prevention. National Health and Nutrition Examination Survey (NHANES): Balance Procedures Manual. (2014) CreateSpace Independent Publishing Platform. 5. Eaton, J.L. Thyroid Disease and Reproduction: A Clinical Guide to Diagnosis and Management. (2018) Springer. 6. Garber, J.R. Thyroid Disease: Understanding Hypothyroidism and Hyperthyroidism, 4th Edition. (2015) Harvard Health Publications. 7. Halenka, M., and Frysak, Z. Atlas of Thyroid Ultrasonography. (2017) Springer. 8. Icon Group International. Telangiectasia: Webster’s Timeline History, 1925 2007. (2010) Icon Group International, Inc. 9. Johnson, G. Atlas of Gallium-67 Scintigraphy: A New Method of Radionuclide Medical Diagnosis. (2011) Springer. 10. Loriaux, L. Endocrine Emergencies: Recognition and Treatment (Contemporary Endocrinology). (2014) Humana Press. 11. Mertens, L., and Bogaert, J. Handbook of Hyperthyroidism Etiology, Diagnosis and Treatment. (2010) Nova Science Publishers. 12. Nystrom, E., and Berg, G.E.B. Thyroid Disease in Adults. (2011) Springer.

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13. Oertli, D., and Udelsman, R. Surgery of the Thyroid and Parathyroid Glands, 2nd Edition. (2012) Springer. 14. Osansky, E.M. Natural Treatment Solutions for Hyperthyroidism and Graves’ Disease, 2nd Edition. (2013) Natural Endocrine Solutions. 15. Osman, F. The Cardiovascular Consequences of Hyperthyroidism. (2010) LAP Lambert Academic Publishing. 16. Ozulker, T., Adas, M., and Gunay, S. Thyroid and Parathyroid Diseases: A Case-Based Guide. (2018) Springer. 17. Randolph, G.W. Surgery of the Thyroid and Parathyroid Glands: Expert Consult, 2nd Edition. (2012) Saunders. 18. Simpson, K., and Hertoghe, T. The Women’s Guide to Thyroid Health: Comprehensive Solutions for All Your Thyroid Symptoms. (2009) New Harbinger Publications. 19. Skugor, M., and Wilder, J.B. The Cleveland Clinic Guide to Thyroid Disorders. (2009) Kaplan Publishing. 20. Smith, P.W. What You Must Know About Thyroid Disorders & What to Do About Them. (2016) Square One. 21. Taaru, H. The Battle I Fought Against Heart Failure, Hypertension and Thyrotoxicosis: A Living Nightmare. (2010) Xlibris U.K. 22. United States Department of Health and Human Services, Agency for Healthcare Research and Quality. Screening and Treatment of Subclinical Hypothyroidism or Hyperthyroidism: Comparative Effectiveness Review, Number 24. (2013) CreateSpace Independent Publishing Platform. 23. Vitti, P., and Hegedus, L. Thyroid Diseases: Pathogenesis, Diagnosis, and Treatment (Endocrinology). (2018) Springer. 24. Walker, M.H. Forskolin: Sources, Mechanisms of Action and Health Effects. (2015) Nova Science Publishers Inc. 25. Wondisford, F.E., and Radovick, S. Clinical Management of Thyroid Disease. (2009) Saunders.

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