8 Medical Management of Benign Thyroid Disease
8.1 Hypothyroidism
Hypothyroidism is a condition characterized by decreased thyroid hormone production. The particular biochemical profile is determined by the endocrine gland initially responsible for the failure to maintain adequate thyroid hormone levels, with a raised serum thyroid-stimulating hormone (TSH) level indicating primary hypothyroidism and a low or inappropriately normal serum TSH level characterizing secondary hypothyroidism. The clinical syndrome is notable for wide-ranging symptoms associated with thyroid hormone deficiency at the level of all tissues and organ systems (Fig. 8.1). Secondary hypothyroidism is also likely to be accompanied by signs and symptoms of pituitary dysfunction. Myxedema coma can result from organ system decompensation, generally after long-standing hypothyroidism.
8.1.1 Primary Hypothyroidism
Failure of the thyroid gland itself causes primary hypothyroidism. The most common cause in the United States is lymphocytic infiltration of the thyroid gland associated with autoimmune thyroid disease (Hashimoto’s thyroiditis), which had a prevalence of 5.13% in one population-based study. 1 Other causes of primary hypothyroidism are destruction of thyroid tissue by surgery, radioiodine therapy, external beam radiation, or infiltrative diseases. Subclinical hypothyroidism, in which thyroid hormone levels are still maintained in the normal range, is the more common abnormality (4–8% of the U.S. population), compared with overt hypothyroidism, which occurs in 0.3 to 0.4% of the population. 2 , 3
Iodine deficiency, while common as a cause of hypothyroidism in inland regions of Africa (e.g., Ethiopia, Algeria, and Sudan), and mountainous areas (e.g., the Andes and the Himalayas), is an uncommon cause of hypothyroidism in the United States. Other uncommon causes of primary hypothyroidism include goitrogens, enzyme deficiencies, and thyroid agenesis.
Diagnosis
An elevated serum TSH indicates reduced thyroid hormone feedback on the pituitary thyrotropes, which secrete TSH, and is the cardinal feature of primary hypothyroidism. Many patients will have a free thyroxine (T4) level within the normal range and few symptoms of hypothyroidism. With progression of hypothyroidism, the free T4 concentration will drop below the normal level. Thyroidal hormone production will shift toward greater amounts of tri-iodothyronine (T3); thus T3 concentrations will often be maintained in the normal range in spite of a low T4. 4 If the disease is not recognized, serum T3 levels will also progressively fall below the normal range. Symptoms of hypothyroidism include fatigue, weight gain, depression, exercise intolerance, cold intolerance, dry skin, coarse hair, constipation, and impaired mentation. Clinical features of myxedema coma include hypothermia, bradycardia, and altered sensorium ranging from diminished consciousness to coma.
Treatment
The goal of therapy for hypothyroidism is to reverse the myriad symptoms of thyroid hormone deficiency and the accompanying biochemical abnormalities. Levothyroxine (LT4) is the mainstay of therapy and is easily administered, efficacious, and inexpensive, and it ameliorates the symptoms of hypothyroidism in the vast majority of cases. 5 Approximately 75% of an oral dose of LT4 is absorbed, with impaired absorption being associated with close proximity to meals, medications that adsorb the LT4, and medications that decrease gastric acidity, to name but a few culprits. 5 Serum TSH can be checked approximately 6 weeks after initiating or changing an LT4 dose, when a steady state has been reached, and the LT4 can be titrated up or down if the TSH is above or below the reference interval, respectively. Although many practitioners will attempt to achieve a serum TSH within the range of 1 to 2 mIU/L in order to replicate the values seen in a population free of thyroid disease, 2 there is currently little evidence to support that this approach improves patients’ symptoms or well-being. 6 , 7 However, most experts agree on very specific TSH goals when hypothyroidism is being treated in the pregnant population. TSH reference intervals are 0.1 to 2.5 mIU/L during the first trimester, 0.2 to 3 mIU/L during the second trimester, and 0.3 to 3 mIU/L during the third trimester, and treatment to keep the serum TSH within these values is generally endorsed. 8 Modified, higher TSH targets may also be appropriate for older age groups.
Iatrogenic thyroid disease should be avoided due to the attendant risks, but several studies suggest that this goal may not be achieved in as many as 40% of patients. 2 , 3 , 9 There has been a trend to initiate hypothyroidism therapy for milder disease in recent years, thus placing more individuals at risk for iatrogenic thyroid disease. 10 In addition, there is a high rate of LT4 initiation in older age groups, potentially exposing these individuals who may have additional medical problems to risks of overtreatment. 11
A subset of those treated with LT4 therapy will continue to have residual symptoms, such as fatigue, weight gain, and impaired well-being, despite full resolution of their biochemical abnormalities. 5 The thyroid gland usually contributes about 20% of circulating serum T3 levels. 12 Animal studies have demonstrated closer replication of normal T4 and T3 levels in serum and tissues during intravenous LT4 and liothyronine (LT3) infusion compared with LT4 alone. 13 , 14 Based on these findings, it has been hypothesized that combination therapy with both LT4 and LT3 may provide greater patient satisfaction. Obtaining proof of this concept, however, has been an elusive goal. Despite 13 trials with various regimens of combination therapy, superiority of combination therapy has not been consistently shown. 5 , 15 , 16 , 17 The preference for T3 therapy noted in some of these trials could potentially indicate an unrecognized parameter or end point affected by the T3-containing combination. However, it should be emphasized that most trials have been of short duration (~ 8–16 weeks) and have targeted middle-aged women. Therefore, long-term risk and benefits have not been assessed, especially in older age groups. Other shortcomings of this body of evidence include heterogeneity of study design and results and varying and nonvalidated end points 5 (Table 8.1). A single randomized trial of desiccated thyroid extract compared with LT4 showed an average weight loss of 3 lb with the extract and preference for the extract in 49% of studied patients. 18 A small, randomized cross-over trial of three times daily LT4 compared with LT3 illustrated the difficulties in adhering to a thrice daily regimen, and demonstrated a modest weight loss and improved LDL cholesterol with the T3 regimen. 19
Myxedema coma should be treated with intravenous LT4 to ensure adequate absorption in the setting of impaired gastrointestinal functioning. 5 A loading dose of LT4, adjusted for the weight of the patient, is indicated to ensure both reoccupation of depleted protein-binding sites and an incremental increase in serum free T4 levels. Concomitant use of intravenous LT3 is recommended by some experts.
8.1.2 Secondary Hypothyroidism
Adequate TSH stimulation is required for normal thyroid function. Thyrotrope insufficiency due to pituitary tumors, pituitary surgery, pituitary irradiation, or pituitary hemorrhage is associated with thyroid atrophy and secondary hypothyroidism. Secondary hypothyroidism is considerably less common than primary hypothyroidism, with a prevalence of 1:80,000 to 1:120,000. 20
Diagnosis
Hypothyroidism in patients with pituitary disease is characterized by low or normal serum TSH concentrations. A serum TSH concentration in the normal range is clearly inappropriate if the patient also has a low free T4.
Treatment
As is the case with primary hypothyroidism, LT4 is the recommended treatment for secondary hypothyroidism. Because the serum TSH concentration cannot be used to make therapeutic adjustments, the serum free T4, combined with nonthyroid analytes, such as serum lipids and patient symptoms, must suffice. 5 Several studies have attempted to determine the optimum serum free T4 in treated patients, and based on these studies it seems reasonable to keep the free T4 in the upper half of the reference interval based on successful reversal of the symptoms of hypothyroidism and favorable effects on the lipid profile and body composition. 21
8.2 Hyperthyroidism
Thyrotoxicosis results when tissues are exposed to excessive levels of thyroid hormones, either T4, T3, or both. With appropriate negative feedback on the pituitary thyrotropes, thyroid autonomy is accompanied by lowering of the serum TSH concentration. In contradistinction, thyrotrope autonomy is characterized by both elevated serum TSH and elevated thyroid hormone concentrations. As is the case with hypothyroidism, the symptoms are due to the effects of thyroid hormone on multiple organ systems and tissues (Fig. 8.1). Thyroid storm occurs when there is failure to compensate for these systemic derangements. The prevalence of hyperthyroidism in the U.S. population was 1.3% in the third National Health and Nutrition Examination Survey (NHANES III), with 0.75% being subclinical disease and 0.55% overt hyperthyroidism. 2
8.2.1 Diffuse Goiter
A diffuse goiter can be responsible for excessive production of thyroid hormones either due to stimulation of the gland by thyroid autoantibodies, such as thyroid-stimulating antibodies (TSAbs), as occurs in Graves’ disease, or to stimulation by TSH, as occurs with development of a TSH-secreting adenoma (Fig. 8.2).
8.3 Graves’ Disease
Graves’ disease is an autoimmune condition that typically includes hyperthyroidism and diffuse thyroid enlargement. There is also accompanying ophthalmopathy (orbitopathy) in some patients, with at least 50% having some mild symptoms of eye disease and approximately 5% having severe ophthalmopathy. 22 , 23 Less commonly there may also be Graves’ dermopathy (pretibial myxedema) and thyroid acropachy. Graves’ dermopathy is noted on physical examination in about 13% of those with severe ophthalmopathy. 22
Graves’ disease is the most common cause of hyperthyroidism in iodine-sufficient countries, in which it accounts for about 80% of cases. When countries with iodine sufficiency are compared to those with iodine deficiency, the incidence of Graves’ disease is greater in the former and the incidence of toxic multinodular goiter is greater in the latter. 24 Graves’ hyperthyroidism results from the action of TSAbs, which are directed against the thyrotropin receptor on the surface of the thyroid cell. Having bound to the receptor, they induce thyrocyte proliferation and hyperfunction by activating the adenylyl cyclase signaling pathway in the same manner as TSH. 25 Autoantibodies that react with orbital muscle and fibroblast tissue in the skin are responsible for the extrathyroidal manifestations of Graves’ disease. 22 Interestingly, the extrathyroidal disorders may not appear at the same time as the hyperthyroidism but may precede or follow the hyperthyroidism.
8.3.1 Diagnosis
Laboratory testing in Graves’ disease is characterized by suppressed or undetectable TSH due to negative feedback by elevated levels of thyroid hormone acting on the pituitary. In mild Graves’ disease that has resulted only in subclinical hyperthyroidism, the thyroid hormone levels will remain within the normal range. Overt hyperthyroidism will be characterized by frankly elevated thyroid hormone concentrations due to an increase in the overall hormone production rate. Symptoms include tachycardia, hyperdefecation, proximal muscle weakness, tremors, and heat intolerance. There is often a disproportionate increase in serum T3 relative to serum T4 due to the stimulation of the type 2 deiodinase by TSAb. 26 The disproportionate production of T3 can result in a T3 thyrotoxicosis in which only the serum T3 concentration is increased. If the patient is not pregnant or lactating, a 24-hour radioactive iodine uptake (RAIU) should be obtained if there is any diagnostic uncertainty. An increased RAIU documents that the thyroid gland is inappropriately using the iodine to produce more thyroid hormone at a time when the patient is thyrotoxic. In contrast, a low RAIU is suggestive of damaged thyroid tissue that is not able to transport iodine. A homogeneous pattern of uptake is consistent with the generalized glandular stimulation characteristic of Graves’ disease.
Thyroid storm ensues when the patient is no longer able to compensate for the effects of the persistent increases in thyroid hormone levels and is characterized by hyperthermia and altered sensorium, with resultant features such as severe tachycardia, heart failure, agitation, disorientation, mania, coma, nausea, vomiting, volume depletion, diarrhea, jaundice, and fever.
8.3.2 Treatment
To treat Graves’ disease, dual therapy to reduce the tissue effects of the excessive thyroid hormone and also to lower the thyroid hormone levels is needed. Beta-blockers serve to reduce the tachycardia and tremulousness and to decrease the patient’s symptoms. A thionamide is concurrently used to reduce further thyroid hormone synthesis. The thionamides approved for use in the United States are methimazole (MMI) and propylthiouracil (PTU) (Table 8.2).
Both of these agents prevent the incorporation of iodine into tyrosine residues and inhibit the coupling of iodotyrosine residues. They are both well absorbed from the gastrointestinal tract and are actively concentrated within the thyroid gland. 27 This latter feature accounts for the fact that, despite their short plasma half-lives, MMI, and sometimes even PTU, can effectively be given as a single daily dose. Initial doses for therapy with MMI are 10 to 30 mg/d, sometimes given in two divided doses. Initial doses for therapy with PTU range from 150 to 300 mg/d, often given in three divided doses. Patients with severe hyperthyroidism may require larger initial doses, 28 and may also respond better if the dose is divided. The maximal blocking doses of PTU and MMI are 1,200 mg and 120 mg daily, respectively. Once the intrathyroidal pool of thyroid hormone is reduced and new hormone synthesis is sufficiently blocked, clinical improvement should ensue. MMI may be associated with a more rapid achievement of euthyroidism than PTU. 29 Usually within 4 to 8 weeks of initiating therapy, symptoms will diminish, and circulating thyroid hormone levels will return toward normal. At this time a tapering regimen can be started. Changes in dose for each drug should be made on a monthly basis, because the endogenously produced T4 will reach a new steady-state concentration in this interval. Effective daily maintenance doses for PTU and MMI vary widely, but typical ranges are 100 to 150 mg and 5 to 15 mg, respectively.
Side effects can occur in approximately 5 to 25% of those treated with thionamides, depending on the thoroughness of the documentation and the doses used. With MMI, the side effects generally appear to be dose related, whereas they tend to be more idiosyncratic with PTU (Table 8.2). Minor adverse reactions, which occurred in about 5% of patients in one literature review, 30 included rashes, arthralgias, fevers, and gastrointestinal symptoms. Rashes may sometimes regress spontaneously. Leukopenia may also occur. The leukopenia is often transient, may be confused with the mild leukopenia seen in Graves’ disease itself, 31 and is not usually a predictor of subsequent agranulocytosis. Agranulocytosis is seen more frequently at higher doses of thionamides and may be a direct toxic effect following concentration of the drug within granulocytes or an immune-mediated process, or it may have a dual pathogenesis. Agranulocytosis often occurs within the first 3 months of therapy, but its onset is sudden and may not be detected with monitoring of complete blood counts. 32 The development of agranulocytosis is heralded by fever, malaise, oropharyngeal infection, and a granulocyte count of < 500/mm3; hence the recommendation that patients discontinue therapy and contact their physician when flulike symptoms, such as fever, malaise, or sore throat, develop. Supportive care with antibiotic therapy is critical for the recovery of affected patients. Use of colony-stimulating factors has not been shown to speed recovery or shorten hospital stay in a randomized trial. 33 Nevertheless, these agents are generally recommended, particularly in patients with poor prognostic factors. 34 Patients who have suffered this side effect should not be reexposed to either thionamide because the agranulocytosis may be immunologically mediated and thus could recur with either drug.
Hyperthyroidism may be associated with abnormal liver tests, with 14 to 23% of hyperthyroid patients having transaminase elevations in one small study. 35 Use of MMI and PTU may also be associated with transaminase elevations, 28 , 36 as can be seen in 6 to 9% of MMI-treated patients and 26% of patients treated with PTU. A study of PTU therapy reported in 1993 suggested that initial enzyme elevations eventually normalize in most patients with continued therapy. 37 The authors suggested that subclinical liver injury is common and that PTU therapy could be continued with caution in the absence of symptoms and hyperbilirubinemia. 37 However, more substantial hepatotoxicity may also occur, and PTU is no longer considered a first-line drug (Table 8.2). The liver injury seen with PTU seems to be hepatocellular in nature. 30 , 38 , 39 A literature review performed in 1997 documented 49 cases of serious hepatoxicity: 28 cases associated with PTU use and 21 cases associated with MMI use. 40 Accompanying the hepatoxicity were seven deaths in the PTU-treated group and three deaths in the MMI-treated group. The dose or duration of thionamide treatment did not appear to predict the outcome. 40 A more recent analysis of 20 years of PTU use in the United States revealed that 22 adults had developed severe hepatoxicity leading to nine deaths and five liver transplants. 41 The risk of this complication was greater in children (1:2,000) than in adults (1:10,000). Finally, an analysis of data reported to the Food and Drug Administration (FDA) from 1982 to 2008 found that toxicity in children was generally related to higher doses of PTU and that toxicity in both children and adults was associated with therapy lasting more than 4 months in duration. 42 In light of such evidence for hepatotoxicity, PTU carries a black box warning. It has been recommended that PTU not be considered as first-line therapy in either adults or children. One exception includes the first trimester of pregnancy, when the risk of MMI-induced embryopathy may exceed that of PTU-induced hepatotoxicity. Other exceptions include intolerance to MMI and thyroid storm.
MMI use can also be associated with severe hepatotoxicity. Based on animal studies the toxicity of MMI to the liver may be due to the formation of N-methylthiourea. 43 From a review of cases of MMI-induced hepatotoxicity, it appears that the nature of the liver injury was cholestatic in many of these cases. 44 Older patient age and higher drug doses appeared to be risk factors for hepatotoxicity.
There are some special considerations regarding medical treatment of hyperthyroidism during pregnancy (Table 8.2). Although historically both thionamides were thought to be safe during pregnancy, MMI has now been clearly linked to embryopathy, including tracheoesophageal fistulas and choanal atresia. 45 PTU was then considered the preferred antithyroidal agent during pregnancy until the incidence of its hepatotoxicity was fully appreciated. At this juncture most clinicians recommend use of PTU during the first trimester of pregnancy when organogenesis is occurring, with subsequent consideration of transition to MMI for the remainder of pregnancy based on the avoidance of the greater hepatotoxicity risk of PTU. 8 This approach may minimize the congenital malformations associated with MMI and the length of exposure to PTU. Supporting this approach, a recent Japanese study 46 reported that the incidence of major anomalies associated with first trimester MMI use was 4.1%, compared with 1.9% in the PTU-treated group. The anomalies associated with MMI included aplasia cutis, omphalocele, omphalomesenteric duct anomaly, and esophageal atresia. However, worryingly, an analysis of data from a Danish registry showed similar rates of anomalies when MMI or carbimazole (9.1%) versus PTU (8%) were used during early pregnancy. 47 The main difference between the two drug classes was the spectrum of anomalies, which consisted of malformations in the face and neck region with PTU and choanal atresia, esophageal atresia, omphalocele, omphalomesenteric duct anomalies, and aplasia cutis with MMI.
Mild hyperthyroidism is well tolerated by both mother and fetus, so the concerns about thionamide use during pregnancy, and the unresolved issues about their safety, underscore the need to use the lowest effective dose that will maintain the thyroid hormone levels in the upper part of the normal range. As was discussed previously for serum TSH values, total and free thyroid hormones have reference intervals that are specific for pregnancy. 8 Total thyroid hormone values are increased by approximately 50%. 48 Free T4 values are usually lower than nonpregnant values but differ greatly between various immunoassays 48 , 49 and mass spectrometry assays. 50 These caveats should be considered when adjustments are being made in thionamide dose. As is the case for pregnancy, the lowest effective thionamide dose should also be used during lactation. Both MMI and PTU are excreted in the breast milk of thionamide-treated nursing mothers, and using the thionamide in divided doses administered after each feeding is recommended. 8
Nonmedical management options for the treatment of Graves’ hyperthyroidism include radioiodine therapy and surgery. If pretreatment with thionamides is used prior to radioactive iodine therapy, there can be a decrease in the efficacy of the radioiodine therapy. 51 However, some individual studies have not shown that MMI was associated with treatment failures after radioiodine therapy. Prior surveys of practicing physicians in North America have shown a preference for using radioiodine therapy to treat patients with uncomplicated Graves’ disease. However, a survey conducted in 2011 showed a trend for increasing use of thionamide therapy. In fact, 40.5% of physicians indicated their choice of thionamide therapy for an index patient, compared with 30% in 1990. 52 A study of prescriptions written for MMI and PTU during the period 1991 to 2008 revealed a ninefold increase in annual MMI prescriptions, compared with a 19% increase in annual PTU prescriptions. 53 The number of MMI prescriptions exceeded the number of PTU prescriptions from 1996 onward. Study of future trends will shed light on whether this apparent trend to favor pharmacological therapy for Graves’ disease will be mitigated by concern for the adverse effects of these drugs.
The cornerstone of treating thyroid storm is multimodality therapy with a thionamide, beta-blockers, inorganic iodide, and glucocorticoids, along with appropriate supportive care and treatment of precipitating conditions in an intensive care unit setting. 38
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