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InternalMed_Harrison. Very sick patients may exhibit a dramatic fall in total T4 and T3 levels (low T4 syndrome). With decreased tissue perfusion, muscle and liver expression of the type 3 deiodinase leads to accelerated T4 and T3 metabolism. This state has a poor prognosis. Another key factor in the fall in T4 levels is altered binding to TBG. The commonly used free T4 assays are subject to artifact when serum binding proteins are low and underestimate the true free T4 level. Fluctuation in TSH levels also creates challenges in the interpretation of thyroid function in sick patients. TSH levels may range from <0.1 mIU/L in very ill patients, especially with dopamine or glucocorticoid therapy, to >20 mIU/L during the recovery phase of SES. The exact mechanisms underlying the subnormal TSH seen in 10% of sick patients and the increased TSH seen in 5% remain unclear but may be mediated by cytokines including IL-12 and IL-18.


InternalMed_Harrison

InternalMed_Harrison. Any severe illness can induce changes in thyroid hormone levels, but certain disorders exhibit a distinctive pattern of abnormalities. Acute liver disease is associated with an initial rise in total (but not unbound) T3 and T4 levels due to TBG release; these levels become subnormal with progression to liver failure. A transient increase in total and unbound T4 levels, usually with a normal T3 level, is seen in 5–30% of acutely ill psychiatric patients. TSH values may be transiently


InternalMed_Harrison

InternalMed_Harrison. Disorders of the Thyroid Gland 2300 low, normal, or high in these patients. In the early stage of HIV infection, T3 and T4 levels rise, even if there is weight loss. T3 levels fall with progression to AIDS, but TSH usually remains normal. Renal disease is often accompanied by low T3 concentrations, but with normal rather than increased rT3 levels, due to an unknown factor that increases uptake of rT3 into the liver. The diagnosis of SES is challenging. Historic information may be limited, and patients often have multiple metabolic derangements. Useful features to consider include previous history of thyroid disease and thyroid function tests, evaluation of the severity and time course of the patient’s acute illness, documentation of medications that may affect thyroid function or thyroid hormone levels, and measurements of rT3 together with unbound thyroid hormones and TSH. The diagnosis of SES is frequently presumptive, given the clinical context and pattern of laboratory values;


InternalMed_Harrison

InternalMed_Harrison. hormone levels, and measurements of rT3 together with unbound thyroid hormones and TSH. The diagnosis of SES is frequently presumptive, given the clinical context and pattern of laboratory values; only resolution of the test results with clinical recovery can clearly establish this disorder. Treatment of SES with thyroid hormone (T4 and/or T3) is controversial, but most authorities recommend monitoring the patient’s thyroid function tests during recovery, without administering thyroid hormone, unless there is historic or clinical evidence suggestive of hypothyroidism. Sufficiently large randomized controlled trials using thyroid hormone are unlikely to resolve this therapeutic controversy in the near future, because clinical presentations and outcomes are highly variable.


InternalMed_Harrison

InternalMed_Harrison. Amiodarone is a commonly used type III antiarrhythmic agent (Chap. 277). It is structurally related to thyroid hormone and contains 39% iodine by weight. Thus, typical doses of amiodarone (200 mg/d) are associated with very high iodine intake, leading to greater than forty-fold increases in plasma and urinary iodine levels. Moreover, because amiodarone is stored in adipose tissue, high iodine levels persist for >6 months after discontinuation of the drug. Amiodarone inhibits deiodinase activity, and its metabolites function as weak antagonists of thyroid hormone action. Amiodarone has the following effects on thyroid function: (1) acute, transient suppression of thyroid function; (2) hypothyroidism in patients susceptible to the inhibitory effects of a high iodine load; and (3) thyrotoxicosis that may be caused by either a Jod-Basedow effect from the iodine load, in the setting of MNG or incipient Graves’ disease, or a thyroiditis-like condition.


InternalMed_Harrison

InternalMed_Harrison. The initiation of amiodarone treatment is associated with a transient decrease of T4 levels, reflecting the inhibitory effect of iodine on T4 release. Soon thereafter, most individuals escape from iodide-dependent suppression of the thyroid (Wolff-Chaikoff effect), and the inhibitory effects on deiodinase activity and thyroid hormone receptor action become predominant. These events lead to the following pattern of thyroid function tests: increased T4, decreased T3, increased rT3, and a transient TSH increase (up to 20 mIU/L). TSH levels normalize or are slightly suppressed within 1–3 months.


InternalMed_Harrison

InternalMed_Harrison. The incidence of hypothyroidism from amiodarone varies geographically, apparently correlating with iodine intake. Hypothyroidism occurs in up to 13% of amiodarone-treated patients in iodine-replete countries, such as the United States, but is less common (<6% incidence) in areas of lower iodine intake, such as Italy or Spain. The pathogenesis appears to involve an inability of the thyroid gland to escape from the Wolff-Chaikoff effect in autoimmune thyroiditis. Consequently, amiodarone-associated hypothyroidism is more common in women and individuals with positive TPO antibodies. It is usually unnecessary to discontinue amiodarone for this side effect, because levothyroxine can be used to normalize thyroid function. TSH levels should be monitored, because T4 levels are often increased for the reasons described above.


InternalMed_Harrison

InternalMed_Harrison. The management of amiodarone-induced thyrotoxicosis (AIT) is complicated by the fact that there are different causes of thyrotoxicosis and because the increased thyroid hormone levels exacerbate underlying arrhythmias and coronary artery disease. Amiodarone treatment causes thyrotoxicosis in 10% of patients living in areas of low iodine intake and in 2% of patients in regions of high iodine intake. There are two major forms of AIT, although some patients have features of both. Type 1 AIT is associated with an underlying thyroid abnormality (preclinical Graves’ disease or nodular goiter). Thyroid hormone synthesis becomes excessive as a result of increased iodine exposure (Jod-Basedow phenomenon). Type 2 AIT occurs in individuals with no intrinsic thyroid abnormalities and is the result of drug-induced lysosomal activation leading to destructive thyroiditis with histiocyte accumulation in the thyroid; the incidence rises as cumulative amiodarone dosage increases. Mild forms of type 2


InternalMed_Harrison

InternalMed_Harrison. drug-induced lysosomal activation leading to destructive thyroiditis with histiocyte accumulation in the thyroid; the incidence rises as cumulative amiodarone dosage increases. Mild forms of type 2 AIT can resolve spontaneously or can occasionally lead to hypothyroidism. Color-flow Doppler thyroid scanning shows increased vascularity in type 1 AIT but decreased vascularity in type 2 AIT. Thyroid scintiscans are difficult to interpret in this setting because the high endogenous iodine levels diminish tracer uptake. However, the presence of normal or rarely increased uptake favors type 1 AIT.


InternalMed_Harrison

InternalMed_Harrison. In AIT, the drug should be stopped, if possible, although this is often impractical because of the underlying cardiac disorder. Discontinuation of amiodarone will not have an acute effect because of its storage and prolonged half-life. High doses of antithyroid drugs can be used in type 1 AIT but are often ineffective. In type 2 AIT, oral contrast agents, such as sodium ipodate (500 mg/d) or sodium tyropanoate (500 mg, 1–2 doses/d), rapidly reduce T4 and T3 levels, decrease T4 → T3 conversion, and may block tissue uptake of thyroid hormones. Potassium perchlorate, 200 mg every 6 h, has been used to reduce thyroidal iodide content. Perchlorate treatment has been associated with agranulocytosis, although the risk appears relatively low with short-term use. Glucocorticoids, as administered for subacute thyroiditis, have modest benefit in type 2 AIT. Lithium blocks thyroid hormone release and can also provide some benefit. Near-total thyroidectomy rapidly decreases thyroid hormone levels


InternalMed_Harrison

InternalMed_Harrison. subacute thyroiditis, have modest benefit in type 2 AIT. Lithium blocks thyroid hormone release and can also provide some benefit. Near-total thyroidectomy rapidly decreases thyroid hormone levels and may be the most effective long-term solution if the patient can undergo the procedure safely.


InternalMed_Harrison

InternalMed_Harrison. Five factors alter thyroid function in pregnancy: (1) the transient increase in hCG during the first trimester, which stimulates the TSHR; (2) the estrogen-induced rise in TBG during the first trimester, which is sustained during pregnancy; (3) alterations in the immune system, leading to the onset, exacerbation, or amelioration of an underlying autoimmune thyroid disease (see above); (4) increased thyroid hormone metabolism by the placenta; and (5) increased urinary iodide excretion, which can cause impaired thyroid hormone production in areas of marginal iodine sufficiency. Women with a precarious iodine intake (<50 μg/d) are most at risk of developing a goiter during pregnancy or giving birth to an infant with a goiter and hypothyroidism. The World Health Organization recommends a daily iodine intake of 250 μg during pregnancy and prenatal vitamins should contain 150 μg per tablet.


InternalMed_Harrison

InternalMed_Harrison. The rise in circulating hCG levels during the first trimester is accompanied by a reciprocal fall in TSH that persists into the middle of pregnancy. This reflects the weak binding of hCG, which is present at very high levels, to the TSH-R. Rare individuals have been described with variant TSH-R sequences that enhance hCG binding and TSH-R activation. hCG-induced changes in thyroid function can result in transient gestational hyperthyroidism that may be associated with hyperemesis gravidarum, a condition characterized by severe nausea and vomiting and risk of volume depletion. However, since the hyperthyroidism is not causal, antithyroid drugs are not indicated unless concomitant Graves’ disease is suspected. Parenteral fluid replacement usually suffices until the condition resolves.


InternalMed_Harrison

InternalMed_Harrison. During pregnancy, subclinical hypothyroidism occurs in 2% of women, but overt hypothyroidism is present in only 1 in 500. Prospective randomized controlled trials have not shown a benefit for universal thyroid disease screening in pregnancy. Targeted TSH testing for hypothyroidism is recommended for women planning a pregnancy if they have a strong family history of autoimmune thyroid disease, other autoimmune disorders (e.g., type 1 diabetes), prior preterm delivery or recurrent miscarriage, or signs or symptoms of thyroid disease. Thyroid hormone requirements are increased by up to 50% during pregnancy in levothyroxine-treated hypothyroid women (see above section on treatment of hypothyroidism).


InternalMed_Harrison

InternalMed_Harrison. Goiter refers to an enlarged thyroid gland. Biosynthetic defects, iodine deficiency, autoimmune disease, and nodular diseases can each lead to goiter, although by different mechanisms. Biosynthetic defects and iodine deficiency are associated with reduced efficiency of thyroid hormone synthesis, leading to increased TSH, which stimulates thyroid growth as a compensatory mechanism to overcome the block in hormone synthesis. Graves’ disease and Hashimoto’s thyroiditis are also associated with goiter. In Graves’ disease, the goiter results mainly from the TSH-R–mediated effects of TSI. The goitrous form of Hashimoto’s thyroiditis occurs because of acquired defects in hormone synthesis, leading to elevated levels of TSH and its consequent growth effects. Lymphocytic infiltration and immune system–induced growth factors also contribute to thyroid enlargement in Hashimoto’s thyroiditis. Nodular disease is characterized by the disordered growth of thyroid cells, often combined with the


InternalMed_Harrison

InternalMed_Harrison. system–induced growth factors also contribute to thyroid enlargement in Hashimoto’s thyroiditis. Nodular disease is characterized by the disordered growth of thyroid cells, often combined with the gradual development of fibrosis. Because the management of goiter depends on the etiology, the detection of thyroid enlargement on physical examination should prompt further evaluation to identify its cause.


InternalMed_Harrison

InternalMed_Harrison. Nodular thyroid disease is common, occurring in about 3–7% of adults when assessed by physical examination. Using ultrasound, nodules are present in up to 50% of adults, with the majority being <1 cm in diameter. Thyroid nodules may be solitary or multiple, and they may be functional or nonfunctional.


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InternalMed_Harrison. DIFFUSE NONTOXIC (SIMPLE) GOITER Etiology and Pathogenesis When diffuse enlargement of the thyroid occurs in the absence of nodules and hyperthyroidism, it is referred to as a diffuse nontoxic goiter. This is sometimes called simple goiter, because of the absence of nodules, or colloid goiter, because of the presence of uniform follicles that are filled with colloid. Worldwide, diffuse goiter is most commonly caused by iodine deficiency and is termed endemic goiter when it affects >5% of the population. In nonendemic regions, sporadic goiter occurs, and the cause is usually unknown. Thyroid enlargement in teenagers is sometimes referred to as juvenile goiter. In general, goiter is more common in women than men, probably because of the greater prevalence of underlying autoimmune disease and the increased iodine demands associated with pregnancy.


InternalMed_Harrison

InternalMed_Harrison. In iodine-deficient areas, thyroid enlargement reflects a compensatory effort to trap iodide and produce sufficient hormone under conditions in which hormone synthesis is relatively inefficient. Somewhat surprisingly, TSH levels are usually normal or only slightly increased, suggesting increased sensitivity to TSH or activation of other pathways that lead to thyroid growth. Iodide appears to have direct actions on thyroid vasculature and may indirectly affect growth through vasoactive substances such as endothelins and nitric oxide. Endemic goiter is also caused by exposure to environmental goitrogens such as cassava root, which contains a thiocyanate; vegetables of the Cruciferae family (known as cruciferous vegetables) (e.g., Brussels sprouts, cabbage, and cauliflower); and milk from regions where goitrogens are present in grass. Although relatively rare, inherited defects in thyroid hormone synthesis lead to a diffuse nontoxic goiter. Abnormalities at each step in hormone


InternalMed_Harrison

InternalMed_Harrison. from regions where goitrogens are present in grass. Although relatively rare, inherited defects in thyroid hormone synthesis lead to a diffuse nontoxic goiter. Abnormalities at each step in hormone synthesis, including iodide transport (NIS), Tg synthesis, organification and coupling (TPO), and the regeneration of iodide (dehalogenase), have been described.


InternalMed_Harrison

InternalMed_Harrison. If thyroid function is preserved, most goiters are asymptomatic. Examination of a diffuse goiter reveals a symmetrically enlarged, nontender, generally soft gland without palpable nodules. Goiter is defined, somewhat arbitrarily, as a lateral lobe with a volume greater than the thumb of the individual being examined. If the thyroid is markedly enlarged, it can cause tracheal or esophageal compression. These features are unusual, however, in the absence of nodular disease and fibrosis. Substernal goiter may obstruct the thoracic inlet. Pemberton’s sign refers to symptoms of faintness with evidence of facial congestion and external jugular venous obstruction when the arms are raised above the head, a maneuver that draws the thyroid into the thoracic inlet. Respiratory flow measurements and CT or MRI should be used to evaluate substernal goiter in patients with obstruc-2301 tive signs or symptoms.


InternalMed_Harrison

InternalMed_Harrison. Thyroid function tests should be performed in all patients with goiter to exclude thyrotoxicosis or hypothyroidism. It is not unusual, particularly in iodine deficiency, to find a low total T4, with normal T3 and TSH, reflecting enhanced T4 → T3 conversion. A low TSH with a normal free T3 and free T4, particularly in older patients, suggests the possibility of thyroid autonomy or undiagnosed Graves’ disease, and is termed subclinical thyrotoxicosis. The benefit of treatment (typically with radioiodine) in subclinical thyrotoxicosis, versus follow-up and implementing treatment if free T3 or free T4 levels become abnormal, is unclear, but treatment is increasingly recommended in the elderly to reduce the risk of atrial fibrillation and bone loss. TPO antibodies may be useful to identify patients at increased risk of autoimmune thyroid disease. Low urinary iodine levels (<50 μg/L) support a diagnosis of iodine deficiency. Thyroid scanning is not generally necessary but will reveal


InternalMed_Harrison

InternalMed_Harrison. patients at increased risk of autoimmune thyroid disease. Low urinary iodine levels (<50 μg/L) support a diagnosis of iodine deficiency. Thyroid scanning is not generally necessary but will reveal increased uptake in iodine deficiency and most cases of dyshormonogenesis. Ultrasound is not generally indicated in the evaluation of diffuse goiter unless a nodule is palpable on physical examination.


InternalMed_Harrison

InternalMed_Harrison. Iodine replacement induces variable regression of goiter in iodine deficiency, depending on how long it has been present and the degree of fibrosis that has developed. Surgery is rarely indicated for diffuse goiter. Exceptions include documented evidence of tracheal compression or obstruction of the thoracic inlet, which are more likely to be associated with substernal MNGs (see below). Subtotal or near-total thyroidectomy for these or cosmetic reasons should be performed by an experienced surgeon to minimize complication rates. Surgery should be followed by replacement with levothyroxine, with the aim of keeping the TSH level at the lower end of the reference range to prevent regrowth of the goiter.


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InternalMed_Harrison. NONTOXIC MULTINODULAR GOITER Etiology and Pathogenesis Depending on the population studied, MNG or nodular enlargement of the thyroid occurs in up to 12% of adults. MNG is more common in women than men and increases in prevalence with age. It is more common in iodine-deficient regions but also occurs in regions of iodine sufficiency, reflecting multiple genetic, autoimmune, and environmental influences on the pathogenesis.


InternalMed_Harrison

InternalMed_Harrison. There is typically wide variation in nodule size. Histology reveals a spectrum of morphologies ranging from hypercellular regions to cystic areas filled with colloid. Fibrosis is often extensive, and areas of hemorrhage or lymphocytic infiltration may be seen. Using molecular techniques, most nodules within an MNG are polyclonal in origin, suggesting a hyperplastic response to locally produced growth factors and cytokines. TSH, which is usually not elevated, may play a permissive or contributory role. Monoclonal lesions also occur within an MNG, reflecting mutations in genes that confer a selective growth advantage to the progenitor cell.


InternalMed_Harrison

InternalMed_Harrison. Clinical Manifestations Most patients with nontoxic MNG are asymptomatic and euthyroid. MNG typically develops over many years and is detected on routine physical examination, when an individual notices an enlargement in the neck, or as an incidental finding on imaging. If the goiter is large enough, it can ultimately lead to compressive symptoms including difficulty swallowing, respiratory distress (tracheal compression), or plethora (venous congestion), but these symptoms are uncommon. Symptomatic MNGs are usually extraordinarily large and/or develop fibrotic areas that cause compression. Sudden pain in an MNG is usually caused by hemorrhage into a nodule but should raise the possibility of invasive malignancy. Hoarseness, reflecting laryngeal nerve involvement, also suggests malignancy.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis On examination, thyroid architecture is distorted, and multiple nodules of varying size can be appreciated. Because many nodules are deeply embedded in thyroid tissue or reside in posterior or


InternalMed_Harrison

InternalMed_Harrison. Disorders of the Thyroid Gland 2302 substernal locations, it is not possible to palpate all nodules. Pemberton’s sign, characterized by facial suffusion when the patient’s arms are elevated above the head, suggests that the goiter has increased pressure in the thoracic inlet. A TSH level should be measured to exclude subclinical hyperor hypothyroidism, but thyroid function is usually normal. Tracheal deviation is common, but compression must usually exceed 70% of the tracheal diameter before there is significant airway compromise. Pulmonary function testing can be used to assess the functional effects of compression, which characteristically causes inspiratory stridor. CT or MRI can be used to evaluate the anatomy of the goiter and the extent of substernal extension or tracheal narrowing. A barium swallow may reveal the extent of esophageal compression. The risk of malignancy in MNG is similar to that in solitary nodules. Ultrasonography can be used to identify which nodules should be


InternalMed_Harrison

InternalMed_Harrison. A barium swallow may reveal the extent of esophageal compression. The risk of malignancy in MNG is similar to that in solitary nodules. Ultrasonography can be used to identify which nodules should be biopsied based on sonographic features (see section above on ultrasound) and size. For nodules with more suspicious imaging characteristics (e.g., hypoechogenicity, microcalcifications, irregular margins), biopsy is recommended when ≥1 cm.


InternalMed_Harrison

InternalMed_Harrison. Most nontoxic MNGs can be managed conservatively. T4 suppression is rarely effective for reducing goiter size and introduces the risk of subclinical or overt thyrotoxicosis, particularly if there is underlying autonomy or if it develops during treatment. If levothyroxine is used, it should be started at low doses (50 μg daily) and advanced gradually while monitoring the TSH level to avoid excessive suppression. Contrast agents and other iodine-containing substances should be avoided because of the risk of inducing the Jod-Basedow effect, characterized by enhanced thyroid hormone production by autonomous nodules. Radioiodine is used with increasing frequency in areas where large goiters are more prevalent because it can decrease goiter size and may selectively ablate regions of autonomy. Dosage of 131I depends on the size of the goiter and radioiodine uptake but is usually about 3.7 MBq (0.1 mCi) per gram of tissue, corrected for uptake (typical dose 370–1070 MBq [10 to 29 mCi]).


InternalMed_Harrison

InternalMed_Harrison. Dosage of 131I depends on the size of the goiter and radioiodine uptake but is usually about 3.7 MBq (0.1 mCi) per gram of tissue, corrected for uptake (typical dose 370–1070 MBq [10 to 29 mCi]). Repeat treatment may be needed and effectiveness may be increased by concurrent administration of low-dose recombinant TSH (0.1 mg IM). It is possible to achieve a 40–50% reduction in goiter size in most patients. Earlier concerns about radiation-induced thyroid swelling and tracheal compression have diminished, as studies have shown this complication to be rare. When acute compression occurs, glucocorticoid treatment or surgery may be needed. Radiation-induced hypothyroidism is less common than after treatment for Graves’ disease. However, posttreatment autoimmune thyrotoxicosis may occur in up to 5% of patients treated for nontoxic MNG. Surgery remains highly effective but is not without risk, particularly in older patients with underlying cardiopulmonary disease.


InternalMed_Harrison

InternalMed_Harrison. The pathogenesis of toxic MNG appears to be similar to that of nontoxic MNG; the major difference is the presence of functional autonomy in toxic MNG. The molecular basis for autonomy in toxic MNG remains unknown. As in nontoxic goiters, many nodules are polyclonal, whereas others are monoclonal and vary in their clonal origins. Genetic abnormalities known to confer functional autonomy, such as activating TSH-R or Gsα mutations (see below), are not usually found in the autonomous regions of toxic MNG goiter.


InternalMed_Harrison

InternalMed_Harrison. In addition to features of goiter, the clinical presentation of toxic MNG includes subclinical hyperthyroidism or mild thyrotoxicosis. The patient is usually elderly and may present with atrial fibrillation or palpitations, tachycardia, nervousness, tremor, or weight loss. Recent exposure to iodine, from contrast dyes or other sources, may precipitate or exacerbate thyrotoxicosis. The TSH level is low. The uncombined T4 level may be normal or minimally increased; T3 is often elevated to a greater degree than T4. Thyroid scan shows heterogeneous uptake with multiple regions of increased and decreased uptake; 24-h uptake of radioiodine may not be increased but is usually in the upper normal range.


InternalMed_Harrison

InternalMed_Harrison. Prior to definitive treatment of the hyperthyroidism, ultrasound imaging should be performed to assess the presence of discrete nodules corresponding to areas of decreased uptake (“cold” nodules). If present, FNA may be indicated based on sonographic features and size cutoffs. The cytology results, if indeterminate or suspicious, may direct the therapy to surgery.


InternalMed_Harrison

InternalMed_Harrison. Antithyroid drugs normalize thyroid function and are particularly useful in the elderly or ill patients with limited lifespan. In contrast to Graves’ disease, spontaneous remission does not occur and so treatment is long-term. Radioiodine is generally the treatment of choice; it treats areas of autonomy as well as decreasing the mass of the goiter. Sometimes, however, a degree of autonomy remains, presumably because multiple autonomous regions emerge as soon as others are treated, and further radioiodine treatment may be necessary. Surgery provides definitive treatment of underlying thyrotoxicosis as well as goiter. Patients should be rendered euthyroid using an antithyroid drug before operation.


InternalMed_Harrison

InternalMed_Harrison. A solitary, autonomously functioning thyroid nodule is referred to as toxic adenoma. The pathogenesis of this disorder has been unraveled by demonstrating the functional effects of mutations that stimulate the TSH-R signaling pathway. Most patients with solitary hyperfunctioning nodules have acquired somatic, activating mutations in the TSH-R (Fig. 405-11). These mutations, located primarily in the receptor transmembrane domain, induce constitutive receptor coupling to GSα, increasing cyclic AMP levels and leading to enhanced thyroid follicular cell proliferation and function. Less commonly, somatic mutations are identified in GSα. These mutations, which are similar to those seen in Transmembrane domains Activating mutations 4 75 6 Cell growth, differentiation Hormone synthesis GS˜AC cyclic AMP TSH-R Extracellular domain


InternalMed_Harrison

InternalMed_Harrison. Transmembrane domains Activating mutations 4 75 6 Cell growth, differentiation Hormone synthesis GS˜AC cyclic AMP TSH-R Extracellular domain FIGURE 405-11 Activating mutations of the thyroid-stimulating hormone receptor (TSH-R). Mutations (*) that activate TSH-R reside mainly in transmembrane 5 and intracellular loop 3, although mutations have occurred in a variety of different locations. The effect of these mutations is to induce conformational changes that mimic TSH binding, thereby leading to coupling to stimulatory G protein (GSα) and activation of adenylate cyclase (AC), an enzyme that generates cyclic AMP. McCune-Albright syndrome (Chap. 412) or in a subset of somatotrope adenomas (Chap. 403), impair guanosine triphosphate (GTP) hydrolysis, causing constitutive activation of the cyclic AMP signaling pathway. In most series, activating mutations in either the TSH-R or the GSα subunit genes are identified in >90% of patients with solitary hyperfunctioning nodules.


InternalMed_Harrison

InternalMed_Harrison. Thyrotoxicosis is usually mild. The disorder is suggested by a subnormal TSH level; the presence of the thyroid nodule, which is generally large enough to be palpable; and the absence of clinical features suggestive of Graves’ disease or other causes of thyrotoxicosis. A thyroid scan provides a definitive diagnostic test, demonstrating focal uptake in the hyperfunctioning nodule and diminished uptake in the remainder of the gland, as activity of the normal thyroid is suppressed.


InternalMed_Harrison

InternalMed_Harrison. Radioiodine ablation is usually the treatment of choice. Because normal thyroid function is suppressed, 131I is concentrated in the hyperfunctioning nodule with minimal uptake and damage to normal thyroid tissue. Relatively large radioiodine doses (e.g., 370–1110 MBq [10–29.9 mCi] 131I) have been shown to correct thyrotoxicosis in about 75% of patients within 3 months. Hypothyroidism occurs in <10% of those patients over the next 5 years. Surgical resection is also effective and is usually limited to enucleation of the adenoma or lobectomy, thereby preserving thyroid function and minimizing risk of hypoparathyroidism or damage to the recurrent laryngeal nerves. Medical therapy using antithyroid drugs and beta blockers can normalize thyroid function but is not an optimal long-term treatment. Using ultrasound guidance, repeated ethanol injections and percutaneous radiofrequency thermal ablation have been used successfully in some centers to ablate hyperfunctioning nodules, and these


InternalMed_Harrison

InternalMed_Harrison. Using ultrasound guidance, repeated ethanol injections and percutaneous radiofrequency thermal ablation have been used successfully in some centers to ablate hyperfunctioning nodules, and these techniques have also been used to reduce the size of nonfunctioning thyroid nodules.


InternalMed_Harrison

InternalMed_Harrison. The various types of benign thyroid nodules are listed in Table 405-10. These lesions are common (5–10% adults), particularly when assessed by sensitive techniques such as ultrasound. The risk of malignancy is very low for macrofollicular adenomas and normofollicular adenomas. Microfollicular, trabecular, and Hürthle cell variants raise greater concern, and the histology is more difficult to interpret. Many are mixed cystic/solid lesions on ultrasound and may appear spongiform reflecting the pathology of macrofollicular structure. However, the majority of solid nodules (whether hypo-, iso-, or hyperechoic) are also benign. FNA, usually performed with ultrasound guidance, is the diagnostic procedure of choice to evaluate thyroid nodules (see the “Approach to the Patient” section on thyroid nodules). Pure thyroid cysts, <2% of all thyroid growths, consist of colloid and are benign as well. Cysts frequently recur, even after repeated aspiration, and may require surgical excision if they


InternalMed_Harrison

InternalMed_Harrison. nodules). Pure thyroid cysts, <2% of all thyroid growths, consist of colloid and are benign as well. Cysts frequently recur, even after repeated aspiration, and may require surgical excision if they are large. Ethanol ablation to sclerose the cyst has been used successfully for patients who are symptomatic.


InternalMed_Harrison

InternalMed_Harrison. TSH suppression with levothyroxine therapy does not decrease thyroid nodule size in iodine-sufficient populations. However, if there is relative iodine deficiency, both iodine and levothyroxine therapy may decrease nodule volume. If levothyroxine is administered in this situation and the nodule has not decreased in size after 6–12 months of suppressive therapy, treatment should be discontinued because little benefit is likely to accrue from long-term treatment; the risk of iatrogenic subclinical thyrotoxicosis should also be considered. Thyroid carcinoma is the most common malignancy of the endocrine system. Malignant tumors derived from the follicular epithelium are classified according to histologic features. Differentiated tumors, such as papillary thyroid cancer (PTC) or follicular thyroid cancer (FTC), are often curable, and the prognosis is good for patients identified with early-stage disease. In contrast, anaplastic thyroid cancer (ATC) Malignant Approximate Prevalence, %


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InternalMed_Harrison. Malignant Approximate Prevalence, % Tall cell, columnar cell variants Others Abbreviation: MEN, multiple endocrine neoplasia. is aggressive, responds poorly to treatment, and is associated with a bleak prognosis.


InternalMed_Harrison

InternalMed_Harrison. Tall cell, columnar cell variants Others Abbreviation: MEN, multiple endocrine neoplasia. is aggressive, responds poorly to treatment, and is associated with a bleak prognosis. The incidence of thyroid cancer is ~12/100,000 per year in the United States and increases with age. Prognosis is worse in older persons (>65 years). Thyroid cancer is twice as common in women as men, but male gender is associated with a worse prognosis. Additional important risk factors include a history of childhood head or neck irradiation, large nodule size (≥4 cm), evidence for local tumor fixation or invasion into lymph nodes, and the presence of metastases (Table 405-11). Several unique features of thyroid cancer facilitate its management: (1) thyroid nodules are amenable to biopsy by FNA; (2) iodine radioisotopes can be used to diagnose (123I) and treat (131I) differentiated thyroid cancer, reflecting the unique uptake of this anion by the thyroid gland; and (3) serum markers allow the detection of


InternalMed_Harrison

InternalMed_Harrison. History of head and neck irradiation, Family history of thyroid cancer, MEN including total-body irradiation for 2, or other genetic syndromes associ bone marrow transplant and brain ated with thyroid malignancy (e.g., radiation for childhood leukemia Cowden’s syndrome, familial polypo sis, Carney complex) Exposure to ionizing radiation from fallout in childhood or adolescence Vocal cord paralysis, hoarse voice Age <20 or >65 years Nodule fixed to adjacent structures Abbreviation: MEN, multiple endocrine neoplasia. Disorders of the Thyroid Gland 2304 residual or recurrent disease, including the use of Tg levels for PTC and FTC, and calcitonin for medullary thyroid cancer (MTC).


InternalMed_Harrison

InternalMed_Harrison. Disorders of the Thyroid Gland 2304 residual or recurrent disease, including the use of Tg levels for PTC and FTC, and calcitonin for medullary thyroid cancer (MTC). Thyroid neoplasms can arise in each of the cell types that populate the gland, including thyroid follicular cells, calcitonin-producing C cells, lymphocytes, and stromal and vascular elements, as well as metastases from other sites (Table 405-10). The American Joint Committee on Cancer (AJCC) has designated a staging system using the tumor, node, metastasis (TNM) classification (Table 405-12). Several other classification and staging systems are also widely used, some of which place greater emphasis on histologic features or risk factors such as age or gender.


InternalMed_Harrison

InternalMed_Harrison. PATHOGENESIS AND GENETIC BASIS Radiation Early studies of the pathogenesis of thyroid cancer focused on the role of external radiation, which predisposes to chromosomal breaks, leading to genetic rearrangements and loss of tumor-suppressor genes. External radiation of the mediastinum, face, head, and neck region was administered in the past to treat an array of conditions, including acne and enlargement of the thymus, tonsils, and adenoids. Radiation exposure increases the risk of benign and malignant thyroid nodules, is associated with multicentric cancers, and shifts the incidence of thyroid cancer to an earlier age group. Radiation from nuclear fallout also increases the risk of thyroid cancer. Children seem more predisposed to the effects of radiation than adults. Of note, radiation derived from 131I therapy appears to contribute minimal increased risk of thyroid cancer.


InternalMed_Harrison

InternalMed_Harrison. TSH and Growth Factors Many differentiated thyroid cancers express TSH receptors and, therefore, remain responsive to TSH. Higher serum TSH levels, even within normal range, are associated with increased thyroid cancer risk in patients with thyroid nodules. These <45 years >45 years Stage I Any T, any N, M0 T1, N0, M0 Stage II Any T, any N, M1 T2, N0, M0 Stage III — T3, N0, M0 T1–T3, N1a, M0 Stage IVA — T4a, any N, M0 T1–T3, N1b, M0 Stage IVB T4b, any N, M0 Stage IVC Any T, any N, M1


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InternalMed_Harrison. T1–T3, N1a, M0 Stage IVA — T4a, any N, M0 T1–T3, N1b, M0 Stage IVB T4b, any N, M0 Stage IVC Any T, any N, M1 Stage IV All cases are stage IV aCriteria include: T, the size and extent of the primary tumor (T1a ≤1 cm; T1b >1 cm but ≤2 cm; T2 >2 cm but ≤4 cm; T3 >4 cm or any tumor with extension into perithyroidal soft tissue or sternothyroid muscle; T4a invasion into subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve; T4b invasion into prevertebral fascia or encasement of carotid artery or mediastinal vessels); N, the absence (N0) or presence (N1a level IV central compartment; N1b levels II–V lateral compartment, upper mediastinal or retro/ parapharyngeal) of regional node involvement; M, the absence (M0) or presence (M1) of distant metastases. Source: American Joint Committee on Cancer staging system for thyroid cancers using the TNM classification, 7th edition.


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InternalMed_Harrison. Source: American Joint Committee on Cancer staging system for thyroid cancers using the TNM classification, 7th edition. observations provide the rationale for T4 suppression of TSH in patients with thyroid cancer. Residual expression of TSH receptors also allows TSH-stimulated uptake of 131I therapy (see below).


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InternalMed_Harrison. observations provide the rationale for T4 suppression of TSH in patients with thyroid cancer. Residual expression of TSH receptors also allows TSH-stimulated uptake of 131I therapy (see below). Oncogenes and Tumor-Suppressor Genes Thyroid cancers are monoclonal in origin, consistent with the idea that they originate as a consequence of mutations that confer a growth advantage to a single cell. In addition to increased rates of proliferation, some thyroid cancers exhibit impaired apoptosis and features that enhance invasion, angiogenesis, and metastasis. Thyroid neoplasms have been analyzed for a variety of genetic alterations, but without clear evidence of an ordered acquisition of somatic mutations as they progress from the benign to the malignant state. On the other hand, certain mutations are relatively specific for thyroid neoplasia, some of which correlate with histologic classification (Table 405-13).


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InternalMed_Harrison. As described above, activating mutations of the TSH-R and the subunit are associated with autonomously functioning nodules. Although these mutations induce thyroid cell growth, this type of nodule is almost always benign.


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InternalMed_Harrison. Activation of the RET-RAS-BRAF signaling pathway is seen in up to 70% of PTCs, although the types of mutations are heterogeneous. A variety of rearrangements involving the RET gene on chromosome 10 bring this receptor tyrosine kinase under the control of other promoters, leading to receptor overexpression. RET rearrangements occur in 20–40% of PTCs in different series and were observed with increased frequency in tumors developing after the Chernobyl radiation accident. Rearrangements in PTC have also been observed for another tyrosine kinase gene, TRK1, which is located on chromosome 1. To date, the identification of PTC with RET or TRK1 rearrangements has not proven useful for predicting prognosis or treatment responses. BRAF V600E mutations appear to be the most common genetic alteration in PTC. These mutations activate the kinase, which stimulates the mitogen-activated protein MAP kinase (MAPK) cascade. RAS mutations, which also stimulate the MAPK cascade, are found in about


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InternalMed_Harrison. in PTC. These mutations activate the kinase, which stimulates the mitogen-activated protein MAP kinase (MAPK) cascade. RAS mutations, which also stimulate the MAPK cascade, are found in about 20–30% of thyroid neoplasms (NRAS > HRAS > KRAS), including both PTC and FTC. Of note, simultaneous RET, BRAF, and RAS mutations rarely occur in the same tumor, suggesting that activation of the MAPK cascade is critical for tumor development, independent of the step that initiates the cascade.


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InternalMed_Harrison. RAS mutations also occur in FTCs. In addition, a rearrangement of the thyroid developmental transcription factor PAX8 with the nuclear receptor PPARγ is identified in a significant fraction of FTCs. Overall, about 70% of follicular cancers have mutations or genetic rearrangements. Loss of heterozygosity of 3p or 11q, consistent with deletions of tumor-suppressor genes, is also common in FTCs. Most of the mutations seen in differentiated thyroid cancers have also been detected in ATCs. BRAF mutations are seen in up to 50% of ATCs. Mutations in CTNNB1, which encodes β-catenin, occur in about two-thirds of ATCs, but not in PTC or FTC. Mutations of the tumor-suppressor P53 also play an important role in the development of ATC. Because P53 plays a role in cell cycle surveillance, DNA repair, and apoptosis, its loss may contribute to the rapid acquisition of genetic instability as well as poor treatment responses (Chap. 102e) (Table 405-13).


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InternalMed_Harrison. The role of molecular diagnostics in the clinical management of thyroid cancer is under investigation. In principle, analyses of specific mutations might aid in classification, prognosis, or choice of treatment. Although BRAF V600E mutations are associated with loss of iodine uptake by tumor cells, there is no clear evidence to date that this information alters clinical decision making. Higher recurrence rates have been variably reported in patients with BRAF-positive PTC, but the impact on survival rates is unclear. Sequencing of thyroid cancers as part of the Cancer Genome Atlas (TCGA) is likely to lead to new classification schemes based on molecular abnormalities in tumors. MTC, when associated with multiple endocrine neoplasia (MEN) type 2, harbors an inherited mutation of the RET gene. Unlike the rearrangements of RET seen in PTC, the mutations in MEN 2 are


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InternalMed_Harrison. Abbreviations: APC, adenomatous polyposis coli; ATC, anaplastic thyroid cancer; BRAF, v-raf homologue, B1; CDKN2A, cyclin-dependent kinase inhibitor 2A; c-MYC, cellular homologue of myelocytomatosis virus protooncogene; ELE1/TK, RET-activating gene ele1/tyrosine kinase; GPCR, G protein–coupled receptor; GSα, G-protein stimulating α-subunit; MEK, mitogen extracellular signal-regulated kinase; MEN 2, multiple endocrine neoplasia-2; MET, met protooncogene (hepatocyte growth factor receptor); MTS, multiple tumor suppressor; p53, p53 tumor suppressor gene; PTC, papillary thyroid cancer; PTEN, phosphatase and tensin homologue; RAS, rat sarcoma protooncogene; RET, rearranged during transfection protooncogene; p21, p21 tumor suppressor; PAX8, paired domain transcription factor; PPARγ1, peroxisome-proliferator activated receptor γ1; TRK, tyrosine kinase receptor; TSH, thyroid-stimulating hormone; WAF, wild-type p53 activated fragment.


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InternalMed_Harrison. Source: Adapted with permission from P Kopp, JL Jameson, in JL Jameson (ed): Principles of Molecular Medicine. Totowa, NJ, Humana Press, 1998. point mutations that induce constitutive activity of the tyrosine kinase spread is debated. Lymph node involvement by thyroid cancer can be (Chap. 408). MTC is preceded by hyperplasia of the C cells, raising well tolerated but appears to increase the risk of recurrence and morthe likelihood that as-yet-unidentified “second hits” lead to cellular tality, particularly in older patients. The staging of PTC by the TNM transformation. A subset of sporadic MTC contains somatic mutations system is outlined in Table 405-12. Most papillary cancers are identithat activate RET. fied in the early stages (>80% stages I or II) and have an excellent prog nosis, with survival curves similar to expected survival (Fig. 405-12).


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InternalMed_Harrison. Mortality is markedly increased in stage IV disease, especially in thePapillary PTC is the most common type of thyroid cancer, accounting presence of distant metastases (stage IVC), but this group comprisesfor 70–90% of well-differentiated thyroid malignancies. Microscopic only about 1% of patients. The treatment of PTC is described below.


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InternalMed_Harrison. PTC is present in up to 25% of thyroid glands at autopsy, but most of these lesions are very small (several millimeters) and are not clinically Follicular The incidence of FTC varies widely in different parts of the significant. Characteristic cytologic features of PTC help make the world; it is more common in iodine-deficient regions. Currently, FTC diagnosis by FNA or after surgical resection; these include psammoma accounts for only about 5% of all thyroid cancers diagnosed in the bodies, cleaved nuclei with an “orphan-Annie” appearance caused by United States. FTC is difficult to diagnose by FNA because the distinclarge nucleoli, and the formation of papillary structures. tion between benign and malignant follicular neoplasms rests largely


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InternalMed_Harrison. PTC tends to be multifocal and to invade locally within the thyroid on evidence of invasion into vessels, nerves, or adjacent structures. gland as well as through the thyroid capsule and into adjacent struc-FTC tends to spread by hematogenous routes leading to bone, lung, tures in the neck. It has a propensity to spread via the lymphatic system and central nervous system metastases. Mortality rates associated with but can metastasize hematogenously as well, particularly to bone and FTC are less favorable than for PTC, in part because a larger proporlung. Because of the relatively slow growth of the tumor, a significant tion of patients present with stage IV disease. Poor prognostic features burden of pulmonary metastases may accumulate, sometimes with include distant metastases, age >50 years, primary tumor size >4 cm, remarkably few symptoms. The prognostic implication of lymph node Hürthle cell histology, and the presence of marked vascular invasion.


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InternalMed_Harrison. Disorders of the Thyroid Gland of papillary cancer. (Adapted with permission from Edge SB, Byrd DR: Thyroid, in Compton CC, Fritz AB, Greene FL, Trotti A [eds]: AJCC Cancer Staging Manual, 7th ed. New York, Springer, 2010, pp 87–92.)


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InternalMed_Harrison. All well-differentiated thyroid cancers should be surgically excised. In addition to removing the primary lesion, surgery allows accurate histologic diagnosis and staging, and multicentric disease is commonly found in the contralateral thyroid lobe. Preoperative sonography should be performed in all patients to assess the central and lateral cervical lymph node compartments for suspicious adenopathy, which if present, can undergo FNA and then be removed at surgery. Bilateral, near-total thyroidectomy has been shown to reduce recurrence rates in all patients except those with T1a tumors (≤1 cm). If cytology is diagnostic for thyroid cancer, bilateral surgery should be done. If malignancy is identified pathologically after lobectomy, completion surgery is recommended unless the tumor is T1a or is a minimally invasive follicular cancer. Bilateral surgery for patients at higher risk allows monitoring of serum Tg levels and administration of radioiodine for remnant ablation and potential


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InternalMed_Harrison. or is a minimally invasive follicular cancer. Bilateral surgery for patients at higher risk allows monitoring of serum Tg levels and administration of radioiodine for remnant ablation and potential treatment of iodine-avid metastases, if indicated. Therefore, near-total thyroidectomy is preferable in almost all patients; complication rates are acceptably low if the surgeon is highly experienced in the procedure.


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InternalMed_Harrison. Because most tumors are still TSH-responsive, levothyroxine suppression of TSH is a mainstay of thyroid cancer treatment. Although TSH suppression clearly provides therapeutic benefit, there are no prospective studies that define the optimal level of TSH suppression. The degree of TSH suppression should be individualized based on a patient’s risk of recurrence. It should be adjusted over time as surveillance blood tests and imaging confirm absence of disease or, alternatively, indicate possible residual/recurrent cancer. For patients at low risk of recurrence, TSH should be suppressed into the low but detectable range (0.1–0.5 mIU/L). If subsequent surveillance testing indicates no evidence of disease, the TSH target may rise to the lower half of the normal range. For patients at high risk of recurrence or with known metastatic disease, TSH levels should be kept to <0.1 mIU/L if there are no strong contraindications to mild thyrotoxicosis. In this instance, unbound T4 must also be


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InternalMed_Harrison. risk of recurrence or with known metastatic disease, TSH levels should be kept to <0.1 mIU/L if there are no strong contraindications to mild thyrotoxicosis. In this instance, unbound T4 must also be monitored to avoid excessive treatment.


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InternalMed_Harrison. After near-total thyroidectomy, substantial thyroid tissue often remains, particularly in the thyroid bed and surrounding the parathyroid glands. Postsurgical radioablation of the remnant thyroid eliminates residual normal thyroid, facilitating the use of Tg determinations and radioiodine scanning for long-term follow-up. In addition, well-differentiated thyroid cancer often incorporates radioiodine, although less efficiently than normal thyroid follicular cells. Radioiodine uptake is determined primarily by expression of the NIS and is stimulated by TSH, requiring expression of the TSH R. The retention time for radioactivity is influenced by the extent to which the tumor retains differentiated functions such as iodide trapping and organification. Consequently, for patients at risk of recurrence and for those with known distant metastatic disease, 131I ablation may also potentially treat residual tumor cells.


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InternalMed_Harrison. Indications Not all patients benefit from radioiodine therapy. Neither recurrence nor survival rates are improved in stage I patients with T1 tumors (≤2 cm) confined to the thyroid. However, in higher risk patients (larger tumors, more aggressive variants of papillary cancer, tumor vascular invasion, presence of large-volume lymph node metastases), radioiodine reduces recurrence and may increase survival.


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InternalMed_Harrison. 131I Thyroid Ablation and Treatment As noted above, the decision to use 131I for thyroid ablation should be coordinated with the surgical approach, because radioablation is much more effective when there is minimal remaining normal thyroid tissue. Radioiodine is administered after iodine depletion (patient follows a low-iodine diet for 1≤2 weeks) and in the presence of elevated serum TSH levels to stimulate uptake of the isotope into both the remnant and potentially any residual tumor. To achieve high serum TSH levels, there are two approaches. A patient may be withdrawn from thyroid hormone so that endogenous TSH is secreted and, ideally, the serum TSH level is >25 mIU/L at the time of 131I therapy. A typical strategy is to treat the patient for several weeks postoperatively with liothyronine (25 μg qd or bid), followed by thyroid hormone withdrawal for 2 weeks. Alternatively, recombinant human TSH (rhTSH) is administered as two daily consecutive injections (0.9 mg) with


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InternalMed_Harrison. with liothyronine (25 μg qd or bid), followed by thyroid hormone withdrawal for 2 weeks. Alternatively, recombinant human TSH (rhTSH) is administered as two daily consecutive injections (0.9 mg) with administration of 131I 24 h after the second injection. The patient can continue to take levothyroxine and remains euthyroid. Both approaches have equal success in achieving remnant ablation.


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InternalMed_Harrison. A pretreatment scanning dose of 131I (usually 111–185 MBq [3–5 mCi]) or 123I (74 MBq [2 mCi]) can reveal the amount of residual tissue and provides guidance about the dose needed to accomplish ablation. However, because of concerns about radioactive “stunning” that impairs subsequent treatment, there is a trend to avoid pretreatment scanning with 131I and use either 123I or proceed directly to ablation, unless there is suspicion that the amount of residual tissue will alter therapy or that there is distant metastatic disease. In the United States, outpatient doses of up to 6475 MBq (175 mCi) can be given at most centers. The administered dose depends on the indication for therapy with lower doses of 1850–2775 MBq (50–75 mCi) given for remnant ablation but higher doses of 3700–5500 MBq (100–150 mCi) used as adjuvant therapy when residual disease may be present. A WBS following radioiodine treatment is used to confirm the 131I uptake in the remnant and to identify possible metastatic


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InternalMed_Harrison. mCi) used as adjuvant therapy when residual disease may be present. A WBS following radioiodine treatment is used to confirm the 131I uptake in the remnant and to identify possible metastatic disease.


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InternalMed_Harrison. Follow-Up Whole-Body Thyroid Scanning and Thyroglobulin Determinations Serum thyroglobulin is a sensitive marker of residual/ recurrent thyroid cancer after ablation of the residual postsurgical thyroid tissue. However, newer Tg assays have functional sensitivities as low as 0.1 ng/mL, as opposed to older assays with functional sensitivities of 1 ng/mL, reducing the number of patients with truly undetectable serum Tg levels. Because the vast majority of papillary thyroid cancer recurrences are in cervical lymph nodes, a neck ultrasound should be performed about 6 months after thyroid ablation; ultrasound has been shown to be more sensitive than WBS in this scenario.


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InternalMed_Harrison. In low-risk patients who have no clinical evidence of residual disease after ablation and a basal Tg <1 ng/mL on levothyroxine, an rhTSH-stimulated Tg level should be obtained 6–12 months after ablation, without WBS. If stimulated Tg levels are low (<1 ng/mL) and, ideally, undetectable, the risk of recurrence is <5% at 5 years. Newer data indicate that rhTSH stimulation may not be required for patients with undetectable basal Tg levels in sensitive assays, if there is documented absence of Tg antibodies. These patients can be followed with unstimulated Tg every 6–12 months and neck ultrasound as indicated. Levothyroxine dosing may then be titrated to a higher TSH level of 0.5–1.5 mIU/L. The use of WBS is reserved for patients with known iodine-avid metastases or those with elevated serum thyroglobulin levels and negative imaging with ultrasound, chest CT, and neck cross-sectional imaging who may require additional 131I therapy.


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InternalMed_Harrison. In addition, most authorities advocate radioiodine treatment for scan-negative, Tg-positive (Tg >5–10 ng/mL) patients, as many derive therapeutic benefit from a large dose of 131I. For such patients, rhTSH preparation is not FDA approved for the treatment of metastatic disease, and the traditional approach of thyroid hormone withdrawal should be followed. This involves switching patients from levothyroxine (T4) to the more rapidly cleared hormone liothyronine (T3), thereby allowing TSH to increase more quickly. Whenever 131I is administered, posttherapy WBS is the gold standard to assess iodine-avid metastases. In addition to radioiodine, external beam radiotherapy is also used to treat specific metastatic lesions, particularly when they cause bone pain or threaten neurologic injury (e.g., vertebral metastases).


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InternalMed_Harrison. New Potential Therapies Kinase inhibitors are being explored as a means to target pathways known to be active in thyroid cancer, including the RAS, BRAF, EGFR, VEGFR, and angiogenesis pathways. A multicenter randomized controlled trial of the multikinase inhibitor sorafenib in 417 patients with progressive metastatic thyroid cancer reported a doubling of progression-free survival to 10.8 months in the treatment group compared with the placebo group. Ongoing trials are exploring whether differentiation protocols with kinase inhibitors or other approaches might enhance radioiodine uptake and efficacy.


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InternalMed_Harrison. ANAPLASTIC AND OTHER FORMS OF THYROID CANCER Anaplastic Thyroid Cancer As noted above, ATC is a poorly differentiated and aggressive cancer. The prognosis is poor, and most patients die within 6 months of diagnosis. Because of the undifferentiated state of these tumors, the uptake of radioiodine is usually negligible, but it can be used therapeutically if there is residual uptake. Chemotherapy has been attempted with multiple agents, including anthracyclines and paclitaxel, but it is usually ineffective. External beam radiation therapy can be attempted and continued if tumors are responsive.


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InternalMed_Harrison. Thyroid Lymphoma Lymphoma in the thyroid gland often arises in the background of Hashimoto’s thyroiditis. A rapidly expanding thyroid mass suggests the possibility of this diagnosis. Diffuse large-cell lymphoma is the most common type in the thyroid. Biopsies reveal sheets of lymphoid cells that can be difficult to distinguish from small-cell lung cancer or ATC. These tumors are often highly sensitive to external radiation. Surgical resection should be avoided as initial therapy because it may spread disease that is otherwise localized to the thyroid. If staging indicates disease outside of the thyroid, treatment should follow guidelines used for other forms of lymphoma (Chap. 134).


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InternalMed_Harrison. MTC can be sporadic or familial and accounts for about 5% of thyroid cancers. There are three familial forms of MTC: MEN 2A, MEN 2B, and familial MTC without other features of MEN (Chap. 408). In general, MTC is more aggressive in MEN 2B than in MEN 2A, and familial MTC is more aggressive than sporadic MTC. Elevated serum calcitonin provides a marker of residual or recurrent disease. All patients with MTC should be tested for RET mutations, because genetic counseling and testing of family members can be offered to those individuals who test positive for mutations. The management of MTC is primarily surgical. Unlike tumors 2307 derived from thyroid follicular cells, these tumors do not take up radioiodine. External radiation treatment and chemotherapy may provide palliation in patients with advanced disease (Chap. 408). APPROACH TO THE PATIENT:


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InternalMed_Harrison. APPROACH TO THE PATIENT: Palpable thyroid nodules are found in about 5% of adults, but the prevalence varies considerably worldwide. Given this high prevalence rate, practitioners commonly identify thyroid nodules either on physical examination or as incidental findings on imaging performed for another indication (e.g., carotid ultrasound, cervical spine MRI). The main goal of this evaluation is to identify, in a cost-effective manner, the small subgroup of individuals with malignant lesions.


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InternalMed_Harrison. Nodules are more common in iodine-deficient areas, in women, and with aging. Most palpable nodules are >1 cm in diameter, but the ability to feel a nodule is influenced by its location within the gland (superficial versus deeply embedded), the anatomy of the patient’s neck, and the experience of the examiner. More sensitive methods of detection, such as CT, thyroid ultrasound, and pathologic studies, reveal thyroid nodules in up to 50% of glands in individuals over the age of 50. The presence of these thyroid incidentalomas has led to much debate about how to detect nodules and which nodules to investigate further.


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InternalMed_Harrison. An approach to the evaluation of a solitary nodule is outlined in Fig. 405-13. Most patients with thyroid nodules have normal thyroid function tests. Nonetheless, thyroid function should be assessed by measuring a TSH level, which may be suppressed by one or more autonomously functioning nodules. If the TSH is suppressed, a radionuclide scan is indicated to determine if the identified nodule is “hot,” as lesions with increased uptake are almost never malignant and FNA is unnecessary. Otherwise, the next step in evaluation is performance of a thyroid ultrasound for three reasons: (1) Ultrasound will confirm if the palpable nodule is indeed a nodule. About 15% of “palpable” nodules are not confirmed on imaging, and therefore, no further evaluation is required. (2) Ultrasound will assess if there are additional nonpalpable nodules for which FNA may be recommended based on imaging features and size. (3) Ultrasound will characterize the imaging features of the nodule, which, combined with


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InternalMed_Harrison. there are additional nonpalpable nodules for which FNA may be recommended based on imaging features and size. (3) Ultrasound will characterize the imaging features of the nodule, which, combined with the nodule’s size, facilitate decision making about FNA.


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InternalMed_Harrison. Evidence-based guidelines from both the American Thyroid Association and the American Association of Clinical Endocrinologists provide recommendations for nodule FNA based on sonographic imaging features and size cut offs, with lower size cut offs for nodules with more suspicious ultrasound characteristics. FNA biopsy, ideally performed with ultrasound guidance, has good sensitivity and specificity when performed by physicians familiar with the procedure and when the results are interpreted by experienced cytopathologists. The technique is particularly useful for detecting PTC. However, the distinction between benign and malignant follicular lesions is often not possible using cytology alone.


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InternalMed_Harrison. In several large studies, FNA biopsies yielded the following findings: 65% benign, 5% malignant or suspicious for malignancy, 10% nondiagnostic or yielding insufficient material for diagnosis, and 20% indeterminate. The Bethesda System is now widely used to provide more uniform terminology for reporting thyroid nodule FNA cytology results. This six-tiered classification system with the respective estimated malignancy rates is shown in Table 405-14. Specifically, the Bethesda System subcategorized cytology specimens previously labeled as indeterminate into three categories: atypia or follicular lesion of undetermined significance (AUS/ FLUS), follicular neoplasm, and suspicious for malignancy. Disorders of the Thyroid Gland


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InternalMed_Harrison. Evaluate and Rx for hyperthyroidism Surgery if indicated with pre-op US for LN assessment Atypia or follicular lesion of undetermined significance (AUS/FLUS) Repeat US-guided FNA or consider molecular testing Surgery if indicated with pre-op US for LN assessment Nondiagnostic NondiagnosticRepeat US-Guided FNA Malignant Suspicious for PTC Follicular neoplasm Consider molecular testing Surgery Benign Follow Pre-op US for LN assessment Close follow-up or surgery Diagnostic US Nodule not functioning Radionuclide scanning Hyperfunctioning nodule Results of FNA cytology History, physical examination, TSH Normal or high TSH Low TSH Bethesda System Cytology Reporting EVALUATION OF THYROID NODULES DETECTED BY PALPATION OR IMAGING Nodule(s) detected on US Do FNA based on US imaging features and size FIGURE 405-13 Approach to the patient with a thyroid nodule. See text and references for details. FNA, fine-needle aspiration; LN, lymph node; PTC, papillary thyroid cancer; TSH, thyroid-stimulating


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InternalMed_Harrison. FIGURE 405-13 Approach to the patient with a thyroid nodule. See text and references for details. FNA, fine-needle aspiration; LN, lymph node; PTC, papillary thyroid cancer; TSH, thyroid-stimulating hormone; US, ultrasound.


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InternalMed_Harrison. Cytology results indicative of malignancy mandate surgery, after performing preoperative sonography to evaluate the cervical lymph nodes. Nondiagnostic cytology specimens generally result from cystic lesions but may also occur in fibrous long-standing nodules. Ultrasound-guided FNA is indicated when a repeat FNA is necessary. Repeat FNA will yield a diagnostic cytology in about 50% of cases. Benign nodules should be monitored by ultrasound for growth, and repeat FNA should be considered if the nodule enlarges. The use of levothyroxine to suppress serum TSH is not effective in shrinking nodules in iodine-replete populations, and therefore, levothyroxine should not be used. The three new cytology classifications introduced by the Bethesda System are associated with different risks of malignancy (Table 405-14). Diagnostic Category Risk of Malignancy Nondiagnostic or unsatisfactory 1–5% Benign 2–4% Atypia or follicular lesion of unknown 15–20%


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InternalMed_Harrison. Diagnostic Category Risk of Malignancy Nondiagnostic or unsatisfactory 1–5% Benign 2–4% Atypia or follicular lesion of unknown 15–20% For nodules with suspicious for malignancy cytology, surgery is recommended after ultrasound assessment of cervical lymph nodes. Options to be discussed with the patient include: (1) lobectomy with intraoperative frozen section; (2) near-total thyroidectomy; and (3) mutational analysis mainly for BRAF V600E, which is virtually diagnostic of PTC, and bilateral rather than unilateral thyroid surgery is required.


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InternalMed_Harrison. On the other hand, the majority of nodules with AUS/FLUS and follicular neoplasm cytology results are benign; only 10–30% are malignant. The traditional approach for these patients is diagnostic lobectomy for histopathologic diagnosis. Therefore, up to 85% of patients undergo surgery for benign nodules. A high-sensitivity (~90%) novel molecular test using gene expression profiling technology may reduce the need for unnecessary surgery in these two groups. In a multicenter trial of over 265 such nodules, a negative gene expression classifier test reduced the risk of malignancy to about 6%, leading to clinical recommendations for follow-up rather than surgery.


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InternalMed_Harrison. The evaluation of a thyroid nodule is stressful for most patients. They are concerned about the possibility of thyroid cancer, whether verbalized or not. It is constructive, therefore, to review the diagnostic approach and to reassure patients when no malignancy is found. When a suspicious lesion or thyroid cancer is identified, the generally favorable prognosis and available treatment options can be reassuring. the result of neoplasia, leading to increased production of adreno-2309 corticotropic hormone (ACTH) by the pituitary or neuroendocrine Disorders of the Adrenal Cortex cells (ectopic ACTH) or increased production of glucocorticoids, mineralocorticoids, or adrenal androgen precursors by adrenal nod ules. Adrenal nodules are increasingly identified incidentally during abdominal imaging performed for other reasons.


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InternalMed_Harrison. The adrenal cortex produces three classes of corticosteroid hormones: glucocorticoids (e.g., cortisol), mineralocorticoids (e.g., aldosterone), and adrenal androgen precursors (e.g., dehydroepiandrosterone [DHEA]) (Fig. 406-1). Glucocorticoids and mineralocorticoids act through specific nuclear receptors, regulating aspects of the physi-ologic stress response as well as blood pressure and electrolyte homeo-stasis. Adrenal androgen precursors are converted in the gonads and peripheral target cells to sex steroids that act via nuclear androgen and estrogen receptors. Disorders of the adrenal cortex are characterized by deficiency or excess of one or several of the three major corticosteroid classes. Hormone deficiency can be caused by inherited glandular or enzy-matic disorders or by destruction of the pituitary or adrenal gland by autoimmune disorders, infection, infarction, or iatrogenic events such as surgery or hormonal suppression. Hormone excess is usually CH3HOH3CH3CH3CH3CHHHH


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InternalMed_Harrison. Disorders of the Adrenal CortexCHAPTER 406OHOHHOH3CH3CHHOH3CCH3H3COHHHHOH3CH3CHHOH3CH3COHHHOCH3OOH3CH3CHHHCH3OOH3CH3CHHHOOOH3CH3CHHHCH3OOHOH3CH3CHHHOHOOHOH3CH3CHHHOOHOHOH3CHOH3CHHHOOHOH3CHHHOOHHOOCHOH3CHHHOOHHOHOHOOOHOH3CH3CHHHOHOHHHHH3CH3CHOHHOH3CH3CHOHHOH3CH3CHOHHHHPregnenolone Cholesterol Mineralocorticoid precursors Glucocorticoid precursors Progesterone HSD17BHSD17B SRD5A HSD11B1 HSD11B217-hydroxy-pregnenolone 17-hydroxy-progesterone (17OHP) 11-Deoxycortisol Cortisol Andro-stenedione Testosterone 5-Dihydrotestosterone Deoxycortico-sterone Cortico-sterone 18OH-Cortico-sterone Aldosterone Cortisone DHEA DHEAS CYP11A1ADXHSD3B2HSD3B2HSD3B2CYP21A2PORCYP17A1PORCYP17A1PORCYP17A1PORSULT2A1PAPSS2CYP17A1PORCYP11B2ADXCYP11B1ADXCYP11B2ADXCYP11B1ADXH6PDHCYP21A2PORCYP11B2ADXFIGURE 406-1 Adrenal steroidogenesis. ADX, adrenodoxin; CYP11A1, side chain cleavage enzyme; CYP11B1, 11β-hydroxylase; CYP11B2, aldosterone synthase; CYP17A1, 17α-hydroxylase/17,20 lyase; CYP21A2, 21-hydroxylase; DHEA,


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InternalMed_Harrison. steroidogenesis. ADX, adrenodoxin; CYP11A1, side chain cleavage enzyme; CYP11B1, 11β-hydroxylase; CYP11B2, aldosterone synthase; CYP17A1, 17α-hydroxylase/17,20 lyase; CYP21A2, 21-hydroxylase; DHEA, dehydroepiandrosterone; DHEAS, dehydro-epiandrosterone sulfate; H6PDH, hexose-6-phosphate dehydrogenase; HSD11B1, 11β-hydroxysteroid dehydrogenase type 1; HSD11B2, 11β-hydroxysteroid dehydrogenase type 2; HSD17B, 17β-hydroxysteroid dehydrogenase; HSD3B2, 3β-hydroxysteroid dehydrogenase type 2; PAPSS2, PAPS synthase type 2; POR, P450 oxidoreductase; SRD5A, 5α-reductase; SULT2A1, DHEA sulfotransferase.


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InternalMed_Harrison. The normal adrenal glands weigh 6–11 g each. They are located above the kidneys and have their own blood supply. Arterial blood flows initially to the subcapsular region and then meanders from the outer cortical zona glomerulosa through the intermediate zona fasciculata to the inner zona reticularis and eventually to the adrenal medulla. The right suprarenal vein drains directly into the vena cava, while the left suprarenal vein drains into the left renal vein. During early embryonic development, the adrenals originate from the urogenital ridge and then separate from gonads and kidneys at about the sixth week of gestation. Concordant with the time of sexual differentiation (seventh to ninth week of gestation, Chap. 410), the adrenal cortex starts to produce cortisol and the adrenal sex steroid 2310 ++Hypothalamus CircadianrhythmStressors(physical, emotional, including fever, hypoglycemia, hypotension) Anterior pituitary Adrenal Cortex CRH Neurotransmitters Circulating Cortisol ACTH


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InternalMed_Harrison. FIGURE 406-2 Regulation of the hypothalamic-pituitary-adrenal the hypothalamus, specifically its suprachiasmatic nucleus (SCN), with additional regulation by a complex network of cell-specific clock genes. Reflecting the pattern of ACTH secretion, adrenal cortisol secretion exhibits a distinct circadian rhythm, starting to rise in the early morning hours prior to awakening, with peak levels in the morning and low levels in the evening (Fig. 406-3). Diagnostic tests assessing the HPA axis make use of the fact that it is regulated by negative feedback. Glucocorticoid excess is diagnosed by employing a dexamethasone suppression test. Dexamethasone, a potent synthetic glucocorticoid, suppresses CRH/ACTH by binding hypothalamic-pituitary glucocorticoid receptors and, therefore, results in downregulation of endogenous cortisol synthesis. Various versions of the dexamethasone suppression test are described in detail in Chap.


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InternalMed_Harrison. 403. If cortisol production is autonomous (e.g., adrenal nodule), ACTH is already suppressed and dexamethasone has little additional effect. If cortisol production is driven by an ACTH-producing pituitary adenoma, dexamethasone suppression is ineffective at low doses but usually induces suppression at high doses. If cortisol production is driven by an ectopic source of ACTH, the tumors are usually resistant to dexamethasone suppression. Thus, the dexamethasone suppression test is useful to establish the diagnosis of Cushing’s syndrome and to assist with the differential diagnosis of cortisol excess.


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InternalMed_Harrison. Conversely, to assess glucocorticoid deficiency, ACTH stimulation of cortisol production is used. The ACTH peptide contains 39 amino acids but the first 24 are sufficient to elicit a physiologic response. The standard ACTH stimulation test involves administration of cosyntropin (ACTH 1-24), 0.25 mg IM or IV, and collection of blood samples at 0, 30, and 60 min for cortisol. A normal response is defined as a cortisol level >20 μg/dL (>550 nmol/L) 30–60 min after cosyntropin stimulation. A low-dose (1 μg cosyntropin IV) version of this test has been advocated; however, it has no superior diagnostic value and is more cumbersome to carry out. Alternatively, an insulin tolerance test (ITT) can be used to assess adrenal function. It involves injection of insulin to induce hypoglycemia, which represents a strong stress signal that triggers hypothalamic CRH release and activation of the entire HPA axis. The ITT involves administration of regular insulin 0.1 U/kg IV (dose (HPA) axis. ACTH,


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InternalMed_Harrison. represents a strong stress signal that triggers hypothalamic CRH release and activation of the entire HPA axis. The ITT involves administration of regular insulin 0.1 U/kg IV (dose (HPA) axis. ACTH, adrenocorticotropic hormone; CRH, corticotropin should be lower if hypopituitarism is likely) and collection of blood releasing hormone.


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InternalMed_Harrison. samples at 0, 30, 60, and 120 min for glucose, cortisol, and growth hormone (GH), if also assessing the GH axis. Oral or IV glucose is precursor DHEA. The orphan nuclear receptors SF1 (steroidogenic administered after the patient has achieved symptomatic hypoglycefactor 1; encoded by the gene NR5A1) and DAX1 (dosage-sensitive sex mia (usually glucose <40 mg/dL). A normal response is defined as a reversal gene 1; encoded by the gene NR0B1), among others, play a cru-cortisol >20 μg/dL and GH >5.1 μg/L. The ITT requires careful clinical cial role during this period of development, as they regulate a multitude of adrenal genes involved in steroidogenesis. 600 Nadir: 0015 h MESOR: 5.25 µg/dl (145 nmol/L) Acrophase: 0830 h Production of glucocorticoids and adrenal androgens is under the control of the hypothalamic-pituitary-adrenal (HPA) axis, whereas mineralocorticoids are regulated by the renin angiotensin-aldosterone (RAA) system.


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InternalMed_Harrison. Glucocorticoid synthesis is under inhibitory feedback control by the hypothalamus and the pituitary (Fig. 406-2). Hypothalamic release of corticotropin-releasing hormone (CRH) occurs in response to endogenous or exogenous stress. CRH stimulates the cleavage of the 241–amino acid polypeptide proopiomelanocortin (POMC) by pituitary-specific prohormone convertase 1 (PC1), yielding the 39–amino acid peptide ACTH. ACTH is released by the corticotrope cells of the anterior pituitary and acts as the pivotal regulator of adrenal cortisol synthesis, with additional short-term effects on mineralocorticoid and adrenal androgen synthesis. The release of CRH, and subsequently ACTH, occurs in a pulsatile fashion that follows a circadian rhythm under the control of


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InternalMed_Harrison. FIGURE 406-3 Physiologic cortisol circadian rhythm. Circulating cortisol concentrations (geometrical mean ± standard deviation values and fitted cosinor) drop under the rhythm-adjusted mean (MESOR) in the early evening hours, with nadir levels around midnight and a rise in the early morning hours; peak levels are observed ~8:30 AM (acrophase). (Modified after M Debono et al: Modified-release hydrocortisone to provide circadian cortisol profiles. J Clin Endocrinol Metab 94:1548, 2009.) Angiotensin II Adrenal Aldosterone release Activation of Angiotensin II receptor type 1 (AT1 receptor) Angiotensin converting enzyme (ACE) Vasoconstriction pressure Juxtaglomerular cells Angiotensin I Angiotensinogen Renin release FIGURE 406-4 Regulation of the renin-angiotensin-aldosterone (RAA) system.


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InternalMed_Harrison. FIGURE 406-4 Regulation of the renin-angiotensin-aldosterone (RAA) system. Disorders of the Adrenal Cortex monitoring and sequential measurements of glucose. It is contraindicated in patients with coronary disease, cerebrovascular disease, or seizure disorders, which has made the short cosyntropin test the commonly accepted first-line test.


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InternalMed_Harrison. Mineralocorticoid production is controlled by the RAA regulatory cycle, which is initiated by the release of renin from the juxtaglomerular cells in the kidney, resulting in cleavage of angiotensinogen to angiotensin I in the liver (Fig. 406-4). Angiotensin-converting enzyme (ACE) cleaves angiotensin I to angiotensin II, which binds and activates the angiotensin II receptor type 1 (AT1 receptor [AT1R]), resulting in increased adrenal aldosterone production and vasoconstriction. Aldosterone enhances sodium retention and potassium excretion, and increases the arterial perfusion pressure, which in turn regulates renin release. Because mineralocorticoid synthesis is primarily under the control of the RAA system, hypothalamic-pituitary damage does not significantly impact the capacity of the adrenal to synthesize aldosterone.


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InternalMed_Harrison. Similar to the HPA axis, the assessment of the RAA system can be used for diagnostic purposes. If mineralocorticoid excess is present, there is a counter-regulatory downregulation of plasma renin (see below for testing). Conversely, in mineralocorticoid deficiency, plasma renin is markedly increased. Physiologically, oral or IV sodium loading results in suppression of aldosterone, a response that is attenuated or absent in patients with autonomous mineralocorticoid excess. STEROID HORMONE SYNTHESIS, METABOLISM, AND ACTION


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InternalMed_Harrison. ACTH stimulation is required for the initiation of steroidogenesis. The ACTH receptor MC2R (melanocortin 2 receptor) interacts with the MC2R-accessory protein MRAP, and the complex is transported to the adrenocortical cell membrane, where it binds to ACTH (Fig. 406-5). ACTH stimulation generates cyclic AMP (cAMP), which upregulates the protein kinase A (PKA) signaling pathway. Inactive PKA is a tetramer of two regulatory and two catalytic subunits that is dissociated by cAMP into a dimer of two regulatory subunits bound to cAMP and two free and active catalytic subunits. PKA activation impacts steroidogenesis in three distinct ways: (1) increases the import of cholesterol esters; (2) increases the activity of hormone-sensitive lipase, which cleaves cholesterol esters to cholesterol for import into the mitochondrion; and (3) increases the availability and phosphorylation of CREB (cAMP response element binding), a transcription factor that enhances transcription of CYP11A1 and other


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InternalMed_Harrison. import into the mitochondrion; and (3) increases the availability and phosphorylation of CREB (cAMP response element binding), a transcription factor that enhances transcription of CYP11A1 and other enzymes required for glucocorticoid synthesis.


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InternalMed_Harrison. Adrenal steroidogenesis occurs in a zone-specific fashion, with mineralocorticoid synthesis occurring in the outer zona glomerulosa, glucocorticoid synthesis in the zona fasciculata, and adrenal androgen synthesis in the inner zona reticularis (Fig. 406-1). All steroidogenic pathways require cholesterol import into the mitochondrion, a process initiated by the action of the steroidogenic acute regulatory (StAR) protein, which shuttles cholesterol from the outer to the inner mitochondrial membrane. The majority of steroidogenic enzymes are cytochrome P450 (CYP) enzymes, which are either located in the mitochondrion (side chain cleavage enzyme, CYP11A1; 11β-hydroxylase, CYP11B1; aldosterone synthase, CYP11B2) or in the endoplasmic reticulum membrane (17α-hydroxylase, CYP17A1; 21-hydroxylase, CYP21A2; aromatase, CYP19A1). These enzymes require electron donation via specific redox cofactor enzymes, P450 oxidoreductase (POR), and adrenodoxin/adrenodoxin reductase (ADX/ADR) for the


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InternalMed_Harrison. CYP21A2; aromatase, CYP19A1). These enzymes require electron donation via specific redox cofactor enzymes, P450 oxidoreductase (POR), and adrenodoxin/adrenodoxin reductase (ADX/ADR) for the microsomal and mitochondrial CYP enzymes, respectively. In addition, the short-chain dehydrogenase 3β-hydroxysteroid dehydrogenase type 2 (3β-HSD2), also termed Δ4,Δ5 isomerase, plays a major role in adrenal steroidogenesis.


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InternalMed_Harrison. The cholesterol side chain cleavage enzyme CYP11A1 generates pregnenolone. Glucocorticoid synthesis requires conversion of pregnenolone to progesterone by 3β-HSD2, followed by conversion to 17-hydroxyprogesterone by CYP17A1, further hydroxylation at carbon 21 by CYP21A2, and eventually, 11β-hydroxylation by CYP11B1 to generate active cortisol (Fig. 406-1). Mineralocorticoid synthesis also requires progesterone, which is first converted to deoxycorticosterone by CYP21A2 and then converted via corticosterone and 18-hydroxycorticosterone to aldosterone in three steps catalyzed by CYP11B2. For adrenal androgen synthesis, pregnenolone undergoes conversion by CYP17A1, which uniquely catalyzes two enzymatic reactions. Via its 17α-hydroxylase activity, CYP17A1 converts pregnenolone to 17-hydroxypregnenolone, followed by generation of the universal sex steroid precursor DHEA via CYP17A1 17,20 lyase activity. The majority of DHEA is secreted by the adrenal in the form of its sulfate ester,


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InternalMed_Harrison. followed by generation of the universal sex steroid precursor DHEA via CYP17A1 17,20 lyase activity. The majority of DHEA is secreted by the adrenal in the form of its sulfate ester, DHEAS, generated by DHEA sulfotransferase (SULT2A1).


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InternalMed_Harrison. FIGURE 406-5 ACTH effects on adrenal steroidogenesis. ACTH, adrenocorticotropic hormone; binding protein; MRAP, MC2R-accessory protein; protein kinase A catalytic subunit (C; PRKACA), PKA regulatory subunit (R; PRKAR1A); StAR, steroidogenic acute regulatory (protein); TSPO, translocator protein.


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InternalMed_Harrison. Following its release from the adrenal, cortisol circulates in the bloodstream mainly bound to cortisol-binding globulin (CBG) and to a lesser extent to albumin, with only a minor fraction circulating as free, unbound hormone. Free cortisol is thought to enter cells directly, not requiring active transport. In addition, in a multitude of peripheral target tissues of glucocorticoid action, including adipose, liver, muscle, and brain, cortisol is generated from inactive cortisone within the cell by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) (Fig. 406-6). Thereby, 11β-HSD1 functions as a tissue-specific prereceptor regulator of glucocorticoid action. For the conversion of inactive cortisone to active cortisol, 11β-HSD1 requires nicotinamide adenine dinucleotide phosphate (NADPH [reduced form]), which is provided by the enzyme hexose-6-phosphate dehydrogenase (H6PDH). Like the catalytic domain of 11β-HSD1, H6PDH is located in the lumen of the endoplasmic reticulum, and


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InternalMed_Harrison. [reduced form]), which is provided by the enzyme hexose-6-phosphate dehydrogenase (H6PDH). Like the catalytic domain of 11β-HSD1, H6PDH is located in the lumen of the endoplasmic reticulum, and converts glucose-6-phosphate (G6P) to 6-phosphogluconate (6PGL), thereby regenerating NADP+ to NADPH, which drives the activation of cortisol from cortisone by 11β-HSD1.


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InternalMed_Harrison. In the cytosol of target cells, cortisol binds and activates the glucocorticoid receptor (GR), which results in dissociation of heat shock FIGURE 406-6 Prereceptor activation of cortisol and glucocorticoid receptor (GR) action. AP-1 activator protein-1; G6P, glucose-6phosphate; GRE, glucocorticoid response elements; HSP, heat shock proteins; NADPH, nicotinamide adenine dinucleotide phosphate (reduced form); 6PGL, 6-phosphogluconate. FIGURE 406-7 Prereceptor inactivation of cortisol and mineralocorticoid receptor action. ENaC, epithelial sodium channel; HRE, hormone response element; NADH, nicotinamide adenine dinucleotide; SGK-1, serum glucocorticoid-inducible kinase-1.


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InternalMed_Harrison. proteins (HSP) from the receptor and subsequent dimerization (Fig. 406-6). Cortisol-bound GR dimers translocate to the nucleus and activate glucocorticoid response elements (GRE) in the DNA sequence, thereby enhancing transcription of glucocorticoid-regulated genes (GR transactivation). However, cortisol-bound GR can also form heterodimers with transcription factors such as AP-1 or NF-κB, resulting in transrepression of proinflammatory genes, a mechanism of major importance for the anti-inflammatory action of glucocorticoids. It is important to note that corticosterone also exerts glucocorticoid activity, albeit much weaker than cortisol itself. However, in rodents, corticosterone is the major glucocorticoid, and in patients with 17-hydroxylase deficiency, lack of cortisol can be compensated for by higher concentrations of corticosterone that accumulates as a consequence of the enzymatic block.


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InternalMed_Harrison. Cortisol is inactivated to cortisone by the microsomal enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) (Fig. 406-7), mainly in the kidney, but also in the colon, salivary glands, and other target tissues. Cortisol and aldosterone bind the mineralocorticoid receptor (MR) with equal affinity; however, cortisol circulates in the bloodstream at about a thousandfold higher concentration. Thus, only rapid inactivation of cortisol to cortisone by 11β-HSD2 prevents MR activation by excess cortisol, thereby acting as a tissue-specific modulator of the MR pathway. In addition to cortisol and aldosterone, deoxycorticosterone (DOC) (Fig. 406-1) also exerts mineralocorticoid activity. DOC accumulation due to 11β-hydroxylase deficiency or due to tumor-related excess production can result in mineralocorticoid excess.


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InternalMed_Harrison. Aldosterone synthesis in the adrenal zona glomerulosa cells is driven by the enzyme aldosterone synthase (CYP11B2). The binding of angiotensin II to the AT1 receptor causes glomerulosa cell membrane depolarization by increasing intracellular sodium through inhibition of sodium potassium (Na+/K+) ATPase enzymes as well as potassium channels. This drives an increase in intracellular calcium by opening of voltage-dependent calcium channels or inhibition of calcium (Ca2+) ATPase enzymes. Consequently, the calcium signaling pathway is triggered, resulting in upregulation of CYP11B2 transcription (Fig. 406-8).


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InternalMed_Harrison. Analogous to cortisol action via the GR, aldosterone (or cortisol) binding to the MR in the kidney tubule cell dissociates the HSP–receptor complex, allowing homodimerization of the MR, and translocation of the hormone-bound MR dimer to the nucleus (Fig. 406-7). The activated MR enhances transcription of the epithelial sodium channel (ENaC) and serum glucocorticoid-inducible kinase 1 (SGK-1). In the cytosol, interaction of ENaC with Nedd4 prevents cell surface expression of ENaC. However, SGK-1 phosphorylates serine residues within the Nedd4 protein, reduces the interaction between Nedd4 and ENaC, and consequently, enhances the trafficking of ENaC to the cell surface, where it mediates sodium retention.


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InternalMed_Harrison. (See also Chap. 403) Cushing’s syndrome reflects a constellation of clinical features that result from chronic exposure to excess glucocorticoids of any etiology. The disorder can be ACTH-dependent (e.g., pituitary corticotrope adenoma, ectopic secretion of ACTH by nonpituitary tumor) or ACTH-independent (e.g., adrenocortical adenoma, adrenocortical carcinoma, nodular adrenal hyperplasia), as well as iatrogenic (e.g., administration of exogenous glucocorticoids to treat various inflammatory conditions). The term Cushing’s disease refers specifically to Cushing’s syndrome caused by a pituitary corticotrope adenoma.


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InternalMed_Harrison. Epidemiology Cushing’s syndrome is generally considered a rare disease. It occurs with an incidence of 1–2 per 100,000 population per year. However, it is debated whether mild cortisol excess may be more prevalent among patients with several features of Cushing’s such as centripetal obesity, type 2 diabetes, and osteoporotic vertebral fractures, recognizing that these are relatively nonspecific and common in the population. In the overwhelming majority of patients, Cushing’s syndrome is caused by an ACTH-producing corticotrope adenoma of the pituitary (Table 406-1), as initially described by Harvey Cushing in 1912. Cushing’s disease more frequently affects women, with the exception of prepubertal cases, where it is more common in boys. By contrast, Disorders of the Adrenal Cortex Na+, K+– Na+, Ca2+ Ca2+ Ca2+–


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InternalMed_Harrison. Disorders of the Adrenal Cortex Na+, K+– Na+, Ca2+ Ca2+ Ca2+– ATPase AT1R Ang II K+ channel exchanger channel ATPase Na+ Depolarization Ca2+ Ca2+ Ca2+ Na+ K+ K+ Nucleus CYP11B2 Aldosterone FIGURE 406-8 Regulation of adrenal aldosterone synthesis. AngII, angiotensin II; AT1R, angiotensin II receptor type 1; CYP11B2, aldosterone synthase. (Modified after F Beuschlein: Regulation of aldosterone secretion: from physiology to disease. Eur J Endocrinol 168:R85, 2013.) ectopic ACTH syndrome is more frequently identified in men. Only 10% of patients with Cushing’s syndrome have a primary, adrenal cause of their disease (e.g., autonomous cortisol excess independent of ACTH), and most of these patients are women. Overall, the medical use of glucocorticoids for immunosuppression, or for the treatment of inflammatory disorders, is the most common cause of Cushing’s syndrome.


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InternalMed_Harrison. Etiology In at least 90% of patients with Cushing’s disease, ACTH excess is caused by a corticotrope pituitary microadenoma, often only a few millimeters in diameter. Pituitary macroadenomas (i.e., tumors >1 cm in size) are found in only 5–10% of patients. Pituitary corticotrope adenomas usually occur sporadically but very rarely can be found in the context of multiple endocrine neoplasia type 1 (MEN 1) (Chap. 408). Ectopic ACTH production is predominantly caused by occult carcinoid tumors, most frequently in the lung, but also in thymus or pancreas. Because of their small size, these tumors are often difficult to locate. Advanced small-cell lung cancer can cause ectopic ACTH production. In rare cases, ectopic CRH and/or ACTH production has been found to originate from medullary thyroid carcinoma or pheochromocytoma, the latter co-secreting catecholamines and ACTH.


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InternalMed_Harrison. The majority of patients with ACTH-independent cortisol excess harbor a cortisol-producing adrenal adenoma; intratumor mutations, i.e., somatic mutations in the PKA catalytic subunit PRKACA, have been identified as cause of disease in 40% of these tumors. Adrenocortical carcinomas may also cause ACTH-independent disease and are often large, with excess production of several corticosteroid classes.


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InternalMed_Harrison. A rare but notable cause of adrenal cortisol excess is macronodular adrenal hyperplasia with low circulating ACTH, but with evidence for autocrine stimulation of cortisol production via intraadrenal ACTH production. These hyperplastic nodules are often also characterized by ectopic expression of G protein–coupled receptors not usually found in the adrenal, including receptors for luteinizing hormone, vasopressin, serotonin, interleukin 1, catecholamines, or gastric inhibitory peptide (GIP), the cause of food-dependent Cushing’s. Activation of these receptors results in upregulation of PKA signaling, as physiologically occurs with ACTH, with a subsequent increase in cortisol production. A combination of germline and somatic mutations in the tumor-suppressor gene ARMC5 have been identified as a prevalent cause of Cushing’s due to macronodular adrenal hyperplasia. Germline mutations in the PKA catalytic subunit PRKACA can represent a rare cause of macronodular adrenal hyperplasia


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InternalMed_Harrison. as a prevalent cause of Cushing’s due to macronodular adrenal hyperplasia. Germline mutations in the PKA catalytic subunit PRKACA can represent a rare cause of macronodular adrenal hyperplasia associated with cortisol excess.


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InternalMed_Harrison. Mutations in one of the regulatory subunits of PKA, PRKAR1A, are found in patients with primary pigmented nodular adrenal disease (PPNAD) as part of Carney’s complex, an autosomal dominant multiple neoplasia condition associated with cardiac myxomas, hyperlentiginosis, Sertoli cell tumors, and PPNAD. PPNAD can present as micronodular or macronodular hyperplasia, or both. Phosphodiesterases can influence intracellular cAMP and can thereby impact PKA activation. Mutations in PDE11A and PDE8B have been identified in patients with bilateral adrenal hyperplasia and Cushing’s, with and without evidence of PPNAD. Another rare cause of ACTH-independent Cushing’s is McCune-Albright syndrome, also associated with polyostotic fibrous dysplasia, unilateral café-au-lait spots, and precocious puberty. McCune-Albright syndrome is caused by activating mutations in the stimulatory Body fat Weight gain, central obesity, rounded face, fat pad on back of neck (“buffalo hump”)


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InternalMed_Harrison. Body fat Weight gain, central obesity, rounded face, fat pad on back of neck (“buffalo hump”) Skin Facial plethora, thin and brittle skin, easy bruising, broad and purple stretch marks, acne, hirsutism Bone Osteopenia, osteoporosis (vertebral fractures), decreased linear growth in children Muscle Weakness, proximal myopathy (prominent atrophy of gluteal and upper leg muscles with difficulty climb Cardiovascular Hypertension, hypokalemia, edema, atherosclerosis system Metabolism Glucose intolerance/diabetes, dyslipidemia Reproductive system Decreased libido, in women amenorrhea (due to cortisol-mediated inhibition of gonadotropin release) Central nervous Irritability, emotional lability, depression, sometimes system cognitive defects; in severe cases, paranoid psychosis Blood and immune Increased susceptibility to infections, increased white system blood cell count, eosinopenia, hypercoagulation with increased risk of deep vein thrombosis and pulmo


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InternalMed_Harrison. Blood and immune Increased susceptibility to infections, increased white system blood cell count, eosinopenia, hypercoagulation with increased risk of deep vein thrombosis and pulmo G protein alpha subunit 1, GNAS-1 (guanine nucleotide binding protein alpha stimulating activity polypeptide 1), and such mutations have also been found in bilateral macronodular hyperplasia without other McCune-Albright features and, in rare instances, also in isolated cortisol-producing adrenal adenomas (Table 406-1; Chap. 426e).


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InternalMed_Harrison. Clinical Manifestations Glucocorticoids affect almost all cells of the body, and thus signs of cortisol excess impact multiple physiologic systems (Table 406-2), with upregulation of gluconeogenesis, lipolysis, and protein catabolism causing the most prominent features. In addition, 2315 excess glucocorticoid secretion overcomes the ability of 11β-HSD2 to rapidly inactivate cortisol to cortisone in the kidney, thereby exerting mineralocorticoid actions, manifest as diastolic hypertension, hypokalemia, and edema. Excess glucocorticoids also interfere with central regulatory systems, leading to suppression of gonadotropins with subsequent hypogonadism and amenorrhea, and suppression of the hypothalamic-pituitary-thyroid axis, resulting in decreased thyroid-stimulating hormone (TSH) secretion.