Endocrine Disorders and the Heart

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Endocrine Disorders and the Heart

Victor R. Lavis, Michalis K. Picolos, and James T. Willerson

Key Points

• Increased mortality from cardiovascular disease among adults with hypopituitarism is perhaps related to growth hormone defi ciency.

• Major cardiovascular manifestations of acromegaly include cardiomegaly, cardiac hypertrophy, hypertension, congestive heart failure, coronary artery disease, and arrhythmias.

• The excess mortality of acromegaly is abolished by suc-cessful treatment of acromegaly.

• The major cardiovascular manifestation of adrenal insuf-fi ciency is arterial hypotension.

• Major cardiovascular manifestations of Cushing’s syn-drome include hypertension, myocardial hypertrophy, and a prothrombotic state.

• The major cardiovascular manifestation of mineralocor-ticoid excess is hypertension, more common than previ-ously thought.

• Hypokalemia is important in mineralocorticoid disor-ders, but most patients are normokalemic.

• Treatment with mineralocorticoid antagonist is benefi -cial following myocardial infarction and in congestive heart failure.

• The major cardiovascular manifestation of pheochromo-cytoma is hypertension.

• In pheochromocytoma, prompt treatment is impor-tant.

• Metabolic syndrome is important as a risk factor for the development of atherosclerotic disease and type 2 diabe-tes mellitus.

• The increased cardiovascular mortality in diabetes mel-litus is reduced by aggressive treatment of multiple risk factors.

• Intensive treatment of hyperglycemia reduces mortality in critical illness.

• There is excess cardiovascular mortality in primary hyperparathyroidism.

• The “euthyroid sick syndrome” results from non-thyroidal illness.

• Major cardiovascular manifestations of hypothyroidism include bradycardia, cardiac enlargement, hypertension, low voltage on the ECG, and sometimes pericardial effusion.

• “Subclinical hypothyroidism” is associated with in -creased lipids, but not yet conclusively linked to excess cardiovascular events.

• Major cardiovascular manifestations of hyperthyroidism include tachycardia and tachyarrhythmias, atrial fi brilla-tion, increased pulse pressure, and increased cardiac con-tractility with decreased reserve.

• Overt and “subclinical” hyperthyroidism are linked to atrial fi brillation.

• Major cardiovascular manifestations of carcinoid syn-drome include tricuspid regurgitation and pulmonic valve damage related to right-sided endocardial plaques.

• In carcinoid syndrome, there is increased morbidity and mortality in patients with carcinoid heart disease.

Hypothalamic-Pituitary Axis

This chapter reviews selected endocrine disorders and their infl uences on the cardiovascular system. The classic hor-mones of the anterior pituitary gland can be divided into three classes of related polypeptides: growth hormone (GH) and prolactin; adrenocorticotropin (ACTH) and other pep-tides derived from the pro-opiomelanocortin precursor; and

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Hypothalamic-Pituitary Axis . . . . . . . . . . . . . . . . . . . . . 2295Somatostatin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2296Prolactin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2296Adult Growth Hormone Defi ciency. . . . . . . . . . . . . . . . 2296Acromegaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2296Adrenal Insuffi ciency . . . . . . . . . . . . . . . . . . . . . . . . . . . 2298Cushing’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2298Disorders of Mineralocorticoids . . . . . . . . . . . . . . . . . . . 2300

Diseases of the Adrenal Medulla: Pheochromocytoma . . . . . . . . . . . . . . . . . . . . . . . . . . 2301

Diabetes Mellitus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2302Disorders of Calcium Metabolism . . . . . . . . . . . . . . . . . 2307Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2309Hyperthyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2312Carcinoid Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2314Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2315

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the glycoprotein hormones thyrotropin (thyroid-stimulating hormone, TSH), luteinizing hormone (LH), and follicle-stim-ulating hormone (FSH). Synthesis and secretion of pituitary hormones are regulated in part by hypothalamic neuropep-tides. These neurohormones are transported from the hypo-thalamus via the pituitary portal circulation, thereby escaping dilution in the systemic circulation. They include growth hormone–releasing hormone (GHRH), somatostatin, thyrotropin-releasing hormone (TRH), dopamine, corticotro-pin-releasing hormone (CRH), and gonadotropin-releasing hormone (GnRH). Adrenocorticotropin and the glycopro-teins have no major cardiovascular effects except those medi-ated by their respective target organs: the adrenal cortex, the thyroid, and the gonads.

Somatostatin

The term somatostatin encompasses a family of homologous peptides with multiple endocrine and paracrine actions. The major sources of somatostatins are the brain, the D cells of the pancreatic islets, and the gastrointestinal mucosa. Soma-tostatin from brain acts via the pituitary portal system to inhibit secretion of thyrotropin and growth hormone.

In the endocrine pancreas, somatostatin inhibits secre-tion of insulin, glucagon, and somatostatin itself. Somatosta-tin also has diverse inhibitory effects on gastric and pancreatic exocrine secretion and on gastrointestinal activity. Soma-tostatin receptors, of which there are fi ve subtypes, are widely distributed throughout the body.1 The various actions of somatostatin appear to be mediated by Gi proteins.

Somatostatin may have a function in cardiac physiology, as it has been reported that cardiac nerves contain soma-tostatin.2 However, to date there has been no description of cardiac symptomatology in states of somatostatin excess. No clinical syndrome of somatostatin defi ciency has yet been recognized.

Uncontrolled studies have shown purported benefi cial effects of treatment with octreotide, an analogue of soma-tostatin, in small numbers of patients with dilated or hyper-trophic cardiomyopathy.3,4 These reports await confi rmation in larger, randomized studies.

Prolactin

There is no established cardiovascular syndrome associated with excessive or defi cient prolactin. One group of investiga-tors has reported an association between hyperprolactinemia and venous thromboembolism,5 and has provided evidence that prolactin promotes adenosine diphosphate (ADP)-induced platelet activation.6 These results await confi rmation.

Adult Growth Hormone Defi ciency

Several studies have shown increased mortality from cardio-vascular disease among adults with hypopituitarism.7 Some of this excess mortality may be related to defi ciency of growth hormone.8,9 There is growing recognition of a syn-

drome of growth hormone defi ciency in adults, the clinical features of which include loss of lean body mass, increased adiposity, muscular weakness, various psychological abnor-malities, dyslipidemia, insulin resistance, abnormal endo-thelial function, osteopenia, bradycardia and impaired left ventricular systolic function.10–13 These features include several recognized cardiovascular risk factors. This problem should be suspected in individuals with known hypotha-lamic-pituitary disease of any etiology. For adults, the stan-dard test for diagnosis of growth hormone defi ciency has been the peak response of serum growth hormone to induced hypoglycemia.14 A synthetic analogue of hypothalamic growth hormone releasing hormone has become available and shows promise as a diagnostic agent that can avoid the risks of hypoglycemia.15

A defi ciency of growth hormone can be treated with injections of recombinant human growth hormone. Treat-ment of adult GH defi ciency increases left ventricular mass and indices of cardiac performance and exercise tolerance, and improves the lipid profi le by increasing high-density lipoprotein (HDL) cholesterol and reducing low-density lipo-protein (LDL) cholesterol.16-18 However, to date there are no data regarding the effect of treatment on cardiovascular mortality.

Acromegaly

Pathophysiology

Acromegaly is the clinical syndrome of excessive circulating GH with onset in adult life. It is nearly always caused by inappropriately high levels of GH secreted by a pituitary adenoma. Very rarely, it may be caused by secretion of GHRH by an extrapituitary tumor.19 Normally, secretion of GH from the anterior pituitary is regulated by the hypothalamic peptides, GHRH and somatostatin. There are several molec-ular variants of circulating GH, of which the relative physi-ologic signifi cance remains to be elucidated.20 GH stimulates the production in various tissues of insulin-like growth factor-I (IGF-I, also known as somatomedin C)21 and, to a lesser extent, IGF-II.22,23 These two peptides are structurally homologous to proinsulin.24 Many of the effects of growth hormone are mediated by the IGFs, especially by IGF-I.25,26

Growth hormone, acting directly or via IGFs, has a number of important metabolic effects. Broadly speaking, it promotes net protein anabolism while stimulating lipolysis and ketogenesis. As a result, lipid-derived fuels (i.e., non-esterifi ed fatty acids and ketone bodies) are used for energy by various tissues, including myocardium. Amino acids are spared for protein synthesis. When GH is administered chronically, uptake and catabolism of glucose by muscle and adipose tissue are diminished, leading to insulin resistance and a tendency toward hyperglycemia.27 Echocardiographic studies indicate that administration of GH to humans increases heart rate and myocardial contractility.28

Clinical Manifestations

The principal manifestations of acromegaly can be classi-fi ed according to the organ systems affected. Growth of


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bone in adults, in whom the epiphyses are closed, leads to broadening of the hands and feet, with increases in shoe, glove, and ring size. There is also enlargement of the man-dible, with prognathism and dental malocclusion. Hypertro-phic bone growth leads to osteoarthritis and nerve entrapment syndromes, which may be major causes of mor-bidity. Manifestations of soft tissue growth include thick-ened, greasy skin, enlargement of abdominal viscera, macroglossia, and goiter. Skin tags are common. An increased incidence of colonic polyps and colon cancer has been reported in patients with acromegaly.29–31 Metabolic manifestations include hypercalciuria and hyperphosphate-mia. Hyperinsulinemia, indicative of insulin resistance, is found in most patients. However, clinical evidence of dia-betes mellitus occurs in only approximately 10% of these individuals. The principal cardiovascular manifestations of acromegaly are cardiac hypertrophy, hypertension, prema-ture coronary artery disease (CAD), congestive heart failure (CHF), and arrhythmias.11,32–37

Acromegaly is a serious disease. The major causes of death and disability are cardiovascular and respiratory disease, neoplasms, and degenerative joint disease.38 Age-specifi c mortality, principally from cardiovascular and respiratory complications, is increased from 1.5 to 3–fold.31

Arterial hypertension occurs in approximately 30% of people with acromegaly,39 especially those with longer dura-tion of disease. The hypertension usually responds to medical treatment.40,41 In patients with acromegaly, there appears to be reduced activity of the renin-angiotensin-aldosterone axis,42,43 confi rmed by pressor responses to angiotensin II antagonists,44 enhanced pressor responsiveness to angioten-sin II,41 and increases in total exchangeable sodium.43 In addition, intravascular volume expansion occurs in many patients. Each of these alterations may contribute to the development of systemic arterial hypertension.41 Successful treatment of acromegaly reduces arterial pressure in many hypertensive acromegalic patients.33,41

Premature atherosclerosis occurs in some patients with acromegaly, but its prevalence is not clear. Virtually all patients with acromegaly have cardiomegaly, especially older individuals. The increase in cardiac mass, including asymmetric septal hypertrophy, is not directly related to hypertension. Some patients have left ventricular (LV) dilatation and reduction of ejection fraction. Clinical evidence of cardiomyopathy includes cardiomegaly, CHF, and occasional arrhythmias.11,34,45,46 Approximately 10% to 20% of patients with acromegaly have CHF, and in perhaps 20% of these there is no obvious predisposing cause. Diastolic dysfunction is found in some patients with acromegaly in the absence of hypertension or atherosclerosis.11,45,46 The CHF may be relatively resistant to conventional medical therapy. At autopsy, lymphocytic infi ltration and small vessel disease of the myocardium34,37 have been found in some patients. Some histologic obser-vations have demonstrated cellular hypertrophy, patchy fi brosis, and myofi brillar degeneration (Fig. 108.1). Autopsy studies of some patients after sudden death have demon-strated degenerative or infl ammatory changes in the sino-atrial (SA) nerve plexus and the atrioventricular (AV) node.37

Diagnosis

Because GH levels are highly variable, it is important to obtain them under standardized conditions. The most useful diagnostic test involves the oral administration of 75 to 100 g of glucose.19 In normal individuals, GH levels are less than 2 ng/mL, 90 to 120 minutes after administration of the test dose.47,48 Serum IGF-I levels, which correlate well with inte-grated measurements of GH,49 are also very helpful in diag-nosis.50 In considering the possible diagnosis of acromegaly, it is also important to determine whether there are other alterations in pituitary or hypothalamic function.

Treatment

Recent surveys of large numbers of patients have shown that those with very low posttreatment GH levels exhibit no increase of mortality compared to the age-adjusted general population,31,51,52 highlighting the importance of reduction of excessive secretion of growth hormone. Criteria for success-ful treatment include normalization of both growth hormone and IGF-I levels.53 The recommended initial treatment in most cases is surgery, usually by the transsphenoidal approach.19,54,55 Reported surgical success rates depend on the size of the adenoma and on the stringency of the defi nition of cure (reviewed elsewhere54). Probably at least 40% of patients require some mode of adjunctive therapy, either drugs or irradiation.56 An effective treatment modality is administration of octreotide, an analogue of somatostatin.54,57 Treatment with octreotide decreases left ventricular mass in acromegalic patients with cardiac hypertrophy.58 Octreotide must be injected several times daily, but longer-acting ana-logues are available.59,60 Pegvisomant is a compound now available for clinical use that acts as an antagonist at the GH receptor. It has been shown to be effective in reducing IGF-I levels and ameliorating the clinical manifestations of acro-megaly.61 Dopaminergic agonists, such as bromocriptine often provide subjective relief of symptoms, but do not sig-nifi cantly reduce GH levels in the majority of patients.19,54

FIGURE 108.1. Histologic appearance of myocardium from a patient with acromegaly, showing hypertrophied fi bers and intersti-tial fi brosis (IF). Mallory-Heidenhain stain, ×120.


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Pituitary irradiation reduces GH levels slowly over several years, during which cardiovascular disease may progress.62 Also, irradiation carries a signifi cant risk of late develop-ment of hypopituitarism, as well as brain damage or devel-opment of brain tumors.54,62,63

Adrenal Insuffi ciency

Pathophysiology

Adrenal insuffi ciency occurs when the secretion of adrenal glucocorticoids or mineralocorticoids is less than is needed by the body. Patients can develop adrenal insuffi ciency for one of several reasons. There may be failure of the pituitary to produce adequate amounts of ACTH, or diminished hypothalamic secretion of CRH, either as the result of hypothalamic disease or as a consequence of long-term treatment with pharmacologic doses of glucocorticoids. Primary failure of the adrenal cortex may be caused by (1) autoimmune disease associated with the development of antiadrenal antibodies, sometimes in association with per-nicious anemia, autoimmune thyroid disease, diabetes mellitus type 1, or hypoparathyroidism; (2) destruction of the adrenal cortex by infection, especially tuberculosis, disseminated mycosis, or opportunistic infection, such as cytomegalovirus in patients with AIDS; (3) infarction or hemorrhagic necrosis associated with anticoagulation, the antiphospholipid syndrome or sepsis, especially meningo-coccemia; (4) rarely, cancer metastatic to the adrenals; or (5) a hereditary defect in organogenesis or the pathway of cor-tisol synthesis.64


Primary adrenal insuffi ciency (Addison’s disease) can occur at any age and affects both sexes equally.65 Its major manifestations are weakness, increased skin or mucosal pigmentation, weight loss, anorexia, nausea, vomiting, and hypotension, often with postural hypotension. Hyponatre-mia, hypochloremia, and hyperkalemia are present in some of these individuals. Hyponatremia is caused by loss of sodium into the urine as the result of aldosterone defi -ciency, coupled with inability to excrete free water. Hyper-kalemia occurs as a result of mineralocorticoid defi ciency and reduction in the glomerular fi ltration rate. Hypercalce-mia, probably related to volume contraction, may also be present.

In patients with impaired secretion of ACTH, there is usually adequate secretion of mineralocorticoids by the adrenal zona glomerulosa, which continues to enjoy trophic stimulation by circulating angiotensins. Consequently, hyperkalemia is not usually a problem. However, because impaired excretion of free water is a consequence of gluco-corticoid defi ciency, hyponatremia may occur.

Arterial hypotension is the most common cardiovascular fi nding in patients with adrenal insuffi ciency. Syncope occurs in many of these individuals. Heart size is normal or small, pulse volume is reduced, and orthostatic hypotension may be present. Echocardiographic studies of limited numbers of patients with Addison’s disease have shown

reduced LV dimensions and mitral valve prolapse, which disappeared with appropriate steroid replacement.66 Rarely, cardiomyopathy and heart failure have been reported as pre-senting manifestations of adrenal insuffi ciency.67,68

Diagnosis

The most convenient screening test for adrenocortical insuf-fi ciency is measurement of plasma cortisol following intra-venous injection of cosyntropin, a synthetic preparation of the 1 to 24 sequence of ACTH.69,70 For determination of the cause of adrenocortical insuffi ciency, there are several useful tests, including measurements of plasma ACTH levels and of plasma cortisol after prolonged infusion of cosyntropin.71

Treatment

Treatment of adrenal insuffi ciency entails replacement of glucocorticoids as well as mineralocorticoids, if necessary. In previously untreated patients who manifest signs of volume depletion, the vascular compartment should be repleted with intravenous saline. Prompt administration of saline solution is especially important in Addisonian crisis, characterized by hypotension and cardiovascular collapse. As myocardial function may be reduced in this situation, one must monitor the patient carefully during volume resuscita-tion, in order to avoid pulmonary edema.72 In acute adrenal insuffi ciency or in patients experiencing physiologic stress, the dosage of glucocorticoid should be several times the usual daily maintenance dose. For treatment of acute adrenal crisis, the recommended dose of hydrocortisone is 100 mg IV q6h. Given in “stress” doses, hydrocortisone, the major natural glucocorticoid, exhibits substantial mineralocorti-coid effects. As soon as the patient’s condition stabilizes, the dose of hydrocortisone should be reduced quickly to a main-tenance dose.

For maintenance therapy, either hydrocortisone or a less costly short-acting synthetic glucocorticoid, such as predni-sone, should be given orally in physiologic replacement dosage (e.g., prednisone 5–7.5 mg daily, or hydrocortisone 15–20 mg in the morning and 5–10 mg in the afternoon). The usual injectable mineralocorticoid is desoxycorticosterone (DOC), and the oral preparation is fl udrocortisone. The replacement dosage for mineralocorticoids should be deter-mined on an individual basis. The usual replacement dosage of fl udrocortisone is 0.05 to 0.2 mg daily, together with a liberal intake of dietary sodium. Hyperkalemia or elevation of plasma renin activity suggests the need for a higher dose of mineralocorticoid.

Cushing’s Syndrome

Pathophysiology

Cushing’s syndrome results from the actions of excessive circulating glucocorticoids. Its most frequent cause is treat-ment with pharmacologic doses of antiinfl ammatory gluco-corticoids for nonendocrine conditions. Most patients with endogenous Cushing’s syndrome have bilateral adrenal hyperplasia with resultant excess production of glucocorti-



coids, mineralocorticoids, and androgens. These patients usually have ACTH-producing tumors of the pituitary (Cushing’s disease) or ectopic ACTH production (e.g., from a lung cancer). Approximately 20% of cases of endogenous Cushing’s syndrome are ACTH-independent and are due to primary adrenal adenoma, carcinoma, or nodular dysplasia. Three times as many women as men have endogenous Cush-ing’s syndrome. Onset usually occurs in the third or fourth decade of life.


Depending on the cause of Cushing’s syndrome, the clinical picture may include the effects of increased androgens or mineralocorticoids in addition to those of glucocorticoids. Major manifestations are truncal obesity, plethora, systolic hypertension, proximal muscle weakness, thinning and fra-gility of the skin with ecchymoses and purple abdominal striae, hyperglycemia, osteoporosis, psychiatric disturbances, and fatigue.73 Many patients experience wide swings in mood, ranging from severe depression to frank psychosis or confusion. Overt diabetes mellitus is present in approxi-mately 20% of patients. Hyperpigmentation, although uncommon, is a clue to hypersecretion of ACTH from the pituitary. In women with endogenous Cushing’s syndrome, hirsutism, a male escutcheon, amenorrhea, and deepening of the voice are due to androgen excess. The major signs of excessive mineralocorticoids are hypertension and hypoka-lemia (see below).

Clinical Cardiovascular Manifestations

Mortality is signifi cantly increased in Cushing’s syndrome, related largely to cardiovascular problems.74 Even people with “subclinical” Cushing’s syndrome, characterized by autonomous cortisol secretion without absolute elevation of circulating cortisol levels, exhibit unfavorable cardiovascu-lar risk profi les.75 The major cardiovascular abnormality is arterial hypertension, occurring in 80% of patients. Possible causes of the hypertension include volume expansion caused by mineralocorticoids and high levels of cortisol, increased production of angiotensin II, and vascular hyperreactivity.74,76 Unlike patients with essential hypertension, hypertensive patients with Cushing’s syndrome of any cause lack the normal nocturnal decline of blood pressure.77–79 As the normal diurnal rhythm of pituitary-adrenal secretion is dis-rupted in Cushing’s syndrome, blood pressure may normally be modulated by physiologic fl uctuations of circulating adrenal steroids.

Hemodynamic, electrocardiographic (ECG), and echocar-diographic manifestations are usually associated with sys-temic arterial hypertension. There may be ECG or echocardiographic evidence of LV hypertrophy, left atrial (LA) enlargement, and, on occasion, evidence of diastolic dysfunction. Recent echocardiographic investigations suggest that increased LV wall thickness and asymmetric septal hypertrophy, with normal LV systolic function and diastolic dysfunction, are common fi ndings in patients with endoge-nous Cushing’s syndrome of any cause.80–82

Chronic excess production of cortisol may also lead to hyperlipidemia, which can promote the development of

atherosclerosis.83 Additionally, Cushing’s syndrome is a pro-thrombotic state, owing to increased circulating clotting factors and decreased fi brinolysis.84

Atrial myxomas and ACTH-independent Cushing’s syn-drome may coexist in the Carney complex, a rare familial syndrome that comprises multiple small pigmented adrenal nodules; spotty cutaneous pigmentation including lentigines and blue nevi; subcutaneous, mammary, or cardiac myxomas; and other endocrine disorders such as acromegaly, thyroid adenomas, and testicular tumors.85

Diagnosis

Dexamethasone, 1 mg given orally late in the evening, with measurement of plasma cortisol between 7 a.m. and 9 a.m. the next morning, serves as a sensitive screening test for endogenous Cushing’s syndrome.86,87 In normal individuals, serum cortisol levels will be less than 1.8 μg/dL with this test. Measurement of 24-hour urinary free cortisol serves as important confi rmatory test.86,87 False-positive responses may occur with obesity, major depression, treatment with estrogen, or alcoholism, among other conditions. Discrimi-nation of these conditions from true Cushing’s syndrome may be aided by measurement of plasma cortisol after sup-pression of ACTH secretion by dexamethasone, followed by stimulation with ovine CRH.88 For discrimination among the several causes of endogenous Cushing’s syndrome, various tests are available, including computed tomographic (CT) and magnetic resonance imaging (MRI) of the adrenal glands and pituitary, and measurement of cortisol levels after administration of ovine CRH, metyrapone, or graded doses of dexamethasone.89,90 In patients with ACTH-dependent endogenous Cushing’s syndrome, the aforementioned tech-niques may not distinguish unequivocally between pituitary and ectopic sources of ACTH. In this circumstance, deter-mination of ACTH levels in the inferior petrosal sinuses after administration of ovine CRH has been reliable.90,91 A recent consensus conference has summarized guidelines for diagnosis and treatment of Cushing’s syndrome.86

Treatment

Treatment of endogenous Cushing’s syndrome is dependent on the cause. For Cushing’s disease, transsphenoidal pitu-itary surgery, with or without irradiation, is most frequently employed. Surgical removal of the causative tumor should be attempted in patients with adrenal neoplasms and those with ectopic secretion of ACTH. Drugs that inhibit adrenal steroid synthesis are available for inoperable patients.92,93 Patients should be given anticoagulant prophylaxis for surgery and procedures.84

Hypertension associated with Cushing’s disease is usually treated with agents that block the effects of angio-tensin II, often angiotensin-converting enzyme (ACE) inhibi-tors. Because hypokalemia is present in some patients with Cushing’s syndrome, diuretics must be prescribed with great care. Efforts should be made to replenish potassium, and if a diuretic is used, potassium-sparing diuretics or potassium supplementation in excess of what might be ordinarily required should be considered. In patients with hypokalemia, cardiac glycosides should be used with caution.


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Disorders of Mineralocorticoids

Pathophysiology

Hyperaldosteronism was once thought to be rare. However, recent epidemiologic data suggest that autonomous secretion of aldosterone with suppression of the renin-angiotensin system is present in up to 30% of individuals with hypertension.94,95 Hyperaldosteronism may arise from an adrenal adenoma or from bilateral adrenal hyperpla-sia.96,97 A similar syndrome caused by an excess of 11-desoxycorticosterone or other mineralocorticoids can develop in patients with functioning adrenal tumors, Cush-ing’s disease, ectopic ACTH syndrome, and the 11β-hydrox-ylase or 17α-hydroxylase varieties of congenital adrenal hyperplasia.96,98,99 Other conditions that produce a similar clinical picture include (1) glucocorticoid-remediable hyper-tension, caused by inappropriate production of mineralocor-ticoids by the adrenal zona fasciculata100; (2) the syndrome of apparent mineralocorticoid excess, caused by action of cortisol on renal mineralocorticoid receptors owing to impaired renal inactivation of cortisol101; and (3) Liddle’s syndrome, owing to excessive renal reabsorption of sodium and excretion of potassium, caused by mutations in the epi-thelial sodium channel.102

In addition to the relationship of aldosterone secretion to hypertension, physiologic levels of mineralocorticoids may play an important role in heart disease. The high affi nity (type 1) mineralocorticoid receptor, which has been identi-fi ed in the heart, binds cortisol and mineralocorticoids with equal affi nity. Hormonal specifi city is provided by local type II 11ß-hydroxysteroid dehydrogenase (11ß-HSD), an enzyme that inactivates cortisol by converting it to cortisone.103,104 As cardiac activity of 11ß-HSD is low, both cortisol and aldosterone can bind to these receptors. In sodium-loaded rats, mineralocorticoids produce myocardial hypertrophy and fi brosis.105,106 Both experimental and clinical evidence suggest that aldosterone has roles in the pathophysiology of hypertension, infl ammation, and endothelial dysfunction (reviewed elsewhere107).


The major clinical consequences of hyperaldosteronism are systemic arterial hypertension, hypokalemia, and metabolic alkalosis. Although not essential for the diagnosis of hyper-aldosteronism, hypokalemia is important because it can predispose to development of frequent and complex ven-tricular arrhythmias. Polyuria and muscular weakness are other signifi cant consequences of hypokalemia. Primary hyperaldosteronism may lead to LV hypertrophy and dia-stolic dysfunction, but malignant arterial hypertension is unusual.

Diagnosis

The most useful screening procedure for primary hyperaldo-steronism is measurement of plasma renin and aldosterone in a patient with systemic arterial hypertension.108,109 An elevated ratio of aldosterone to renin (the exact number

depends on the assay for renin) suggests the diagnosis, which can be confi rmed by lack of suppression of serum or urinary aldosterone during volume expansion or salt loading.110–112 Elevation of both renin activity and circulating aldosterone suggests secondary hyperaldosteronism associated with renal vascular disease, or with renal or cardiac failure.110–112 For the patient with primary hyperaldosteronism, it is impor-tant to discriminate adrenal adenoma from bilateral hyper-plasia. Several tests have been developed for this purpose, including (1) CT of the adrenal glands; (2) measurement of the precursor steroid, 18–hydroxycorticosterone, which is usually markedly elevated in patients with adenoma; (3) response of plasma aldosterone to standing in the morning, with the level declining in patients with adenoma and rising in patients with hyperplasia; and (4) bilateral adrenal vein catheterization, with determination of ratios of aldosterone to cortisol.97,113

Treatment

Surgical removal leads to cure of hypertension only in about 30% to 60% of patients with aldosterone-producing adrenal adenomas.114 Clinical attributes associated with successful surgery include age under 45 years, less than 5 years’ duration of hypertension, absence of a family history of hypertension, preoperative treatment with two or fewer anti-hypertensive drugs, and preoperative response to spironolac-tone.115,116 Medical therapy provides adequate control of hypokalemia and hypertension for patients with bilateral adrenal hyperplasia, and for many individuals with adrenal adenomas. Hyperaldosteronism can be treated with a com-petitive inhibitor of mineralocorticoid action, either spirono-lactone or eplerenone. Spironolactone has antiandrogenic activities that may produce gynecomastia and impotence, especially when doses greater than 200 mg/day are required.117 Eplerenone, which lacks these side effects, has recently been approved for clinical use (reviewed elsewhere118). In patients whose primary hyperaldosteronism is caused by bilateral hyperplasia, surgery is not usually effective. Therefore, treat-ment with spironolactone and other appropriate antihyper-tensive agents is preferred. Every effort should be made to replete serum potassium.

Antagonism of mineralocorticoid action appears to have benefi ts in situations other than primary aldosteronism. In randomized clinical trials, treatment with mineralocorticoid receptor antagonists has reduced mortality in patients with severe CHF treated optimally with diuretics and ACE inhibi-tors,119 and among individuals with left ventricular dysfunc-tion following myocardial infarction.120 The results of these clinical trials suggest that cardiac mineralocorticoid recep-tors are physiologically signifi cant in humans. The role of mineralocorticoid receptor antagonism in treatment of heart disease has recently been reviewed.121–123 Hyperkalemia is a major side effect of treatment with mineralocorticoid antago-nists, particularly when they are used in combination with ACE inhibitors or angiotensin receptor blockers, and in patients with diabetes and impaired renal function. When treating heart disease with mineralocorticoid antagonists, the clinician must remain alert to the risk of potentially dangerous hyperkalemia.124


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Diseases of the Adrenal Medulla: Pheochromocytoma

Pathophysiology

Pheochromocytomas are tumors derived from chromaffi n cells of the sympathetic nervous system, usually in the adrenal medulla (90% in adults and 70% in children). Their most important secretory products are the catechol-amines norepinephrine and epinephrine. Biochemically and physiologically, the adrenal medulla is an integral part of the sympathetic nervous system. The location of adrenal medullary cells is associated with their ability to form epinephrine, as glucocorticoids secreted from the cortex pass in high concentration directly to the me-dulla, inducing the synthesis of phenylethanolamine-N-methyltransferase, the enzyme that converts norepine-phrine into epinephrine.125 Catecholamines stimulate glycogenolysis, gluconeogenesis, and lipolysis, inhibit secre-tion of insulin, increase systemic vascular resistance, and exert positive inotropic and chronotropic actions on the myocardium.

The prevalence of pheochromocytoma was less than 0.05% in an autopsy series from Sydney,126 close to 0.5% in patients tested for hypertension, 1.9% in patients screened biochemically for suspicion of pheochromocy-toma,127 and 4.2% among those with incidentally discovered adrenal nodules.128 In at least 10% of patients, the tumor is discovered incidentally during CT or MRI of the abdomen.129

The prevalence of malignancy in sporadic adrenal pheo-chromocytoma is 9%130; however, up to 36% of pheochro-mocytomas can be malignant depending on the genetic background and location of the tumor. Ten percent of patients have metastatic disease at the time of initial diagnosis.131 Ten percent of pheochromocytomas in adults and 35% in children are bilateral. Pheochromocytomas occur as part of a hereditary syndrome in up to 25% of patients.132 Approximately 5% of pheochromocytomas are inherited as part of one of the multiple endocrine neoplasia type II (MEN-II) syndromes, in which bilateral pheochromo-cytomas and medullary carcinoma of the thyroid coexist. The MEN-IIa syndrome may include hyperparathyroid-ism,133 and the MEN-IIb syndrome includes marfanoid habitus and multiple mucosal neuromas of the tongue, lips, gastrointestinal tract, or conjunctivae, usually without para-thyroid disease.134 In the MEN-II syndromes, bilateral adrenal pheochromocytomas are the rule and mutations in the ret proto-oncogene on chromosome 10 can usually be identifi ed. Pheochromocytomas may also coexist with the phakomatoses, including neurofi bromatosis and von Hippel–Lindau disease, which includes, in addition, cerebellar or retinal hemangioblastomas, and renal and pancreatic tumors.

Extraadrenal pheochromocytomas arising from the sym-pathetic ganglia are also called paragangliomas. About 85% of them are intraabdominal. Cardiac paragangliomas are extremely rare with about 50 cases reported in the literature. They have a characteristic appearance on transesophageal echocardiography.135


Pheochromocytoma is a rare cause of systemic arterial hypertension in humans, but the morbidity and mortality associated with these tumors is signifi cant. These tumors produce paradoxical or sustained hypertension, often with postural hypotension, tachycardia inappropriate to the level of blood pressure, headaches, palpitations, chest pain, arrhythmias, profound sweating, signs of hypermetabolism, glucose intolerance, or hypertension after abdominal trauma or surgery. In a patient with hypertension, the coexistence of headache, sweating, and palpitations is highly suggestive of pheochromocytoma.136 In patients with pheochromocy-toma, systemic arterial hypertension is typically paroxysmal but may be fi xed. Postural hypotension is common, caused by reduction of plasma volume or impairment of sympathetic refl exes.137,138

Electrocardiographic and echocardiographic manifesta-tions in patients with pheochromocytoma are usually the result of systemic arterial hypertension. Electrocardiographic signs include evidence of LV hypertrophy, LA enlargement, left axis deviation, nonspecifi c ST-T wave changes, and ven-tricular and atrial arrhythmias. Occasionally, the ECG sug-gests the presence of myocardial ischemia during attacks of hypertension. The echocardiogram often demonstrates LV hypertrophy with relatively normal LV function. During a hypertensive crisis, the echocardiogram may demonstrate systolic anterior motion of the anterior leafl et of the mitral valve (“SAM pattern”) and paradoxical septal motion.139,140 The most common cardiovascular causes of death are arrhythmias and the consequences of systemic arterial hypertension, including strokes.

Hypertrophic cardiomyopathy or a clinical picture indis-tinguishable from idiopathic dilated cardiomyopathy have been described. The chronic cardiomyopathy seems to depend on persistently high circulating levels of catecholamines because surgical removal of the tumor leads to signifi cant improvement of cardiac function.141–144 Autopsy studies have demonstrated the presence of myocarditis in about half of patients who die from pheochromocytoma.143,145,146 Histologic fi ndings include focal necrosis with infi ltration of infl amma-tory cells, perivascular infl ammation, and contraction band necrosis (Fig. 108.2). Scattered areas of fi brosis are also found.

Diagnosis

Hypertensive patients with any of the clinical problems noted above should be evaluated for pheochromocytoma, as detection may be lifesaving. Tests commonly employed for diagnosis include measurement of urinary catecholamines, vanillylmandelic acid (VMA), fractionated and total meta-nephrines, and measurement of serum catecholamines and plasma free metanephrines (metanephrine and normeta-nephrine). Vanillylmandelic acid and metanephrines are metabolites of catecholamines. Plasma-free metanephrines have sensitivity of 97% and 99% and specifi city of 96% and 82% in detecting hereditary and sporadic disease, respec-tively. Urinary total metanephrines offer slightly higher specifi city but are less sensitive, while fractionated urine metanephrines have sensitivity similar to the plasma-free


2 3 0 2 c h a p t e r 10 8

metanephrines but lower specifi city, especially for the detec-tion of sporadic disease.147 In patients with paroxysmal hypertension, it is helpful to collect the urine and blood samples when blood pressure is elevated. In patients with equivocal results, clonidine suppression testing might be of further help.148

Imaging techniques for localization of pheochromocy-toma include CT, MRI, nuclear scanning with 123I or 131I-metaiodobenzylguanidine (MIBG), somatostatin receptor imaging (SRI), and positron emission tomography (PET). Computed tomography has a sensitivity of 93% to 100% for detecting adrenal pheochromocytomas149 and about 90% for extraadrenal disease.150 Magnetic resonance imaging is supe-rior for the detection of extraadrenal, juxtacardiac, and jux-tavascular tumors.131,151 Both imaging methods have poor specifi city, as low as 50%.152 Therefore, it is critically impor-tant to establish the diagnosis with biochemical tests, before proceeding to imaging studies. MIBG scanning is especially helpful for patients who have already had surgery and those who have malignant pheochromocytoma or tumors at unusual locations. Although not sensitive enough to exclude pheochromocytoma (77–90%), MIBG is highly specifi c (95–100%).149,153–155 SRI has poor sensitivity (25% for adrenal pheo-chromocytoma) but may be particularly helpful for metastatic disease,154 paragangliomas, and MIBG scanning-negative

disease.153,156 PET using 6–[18F]fl uorodopamine is a recently introduced method that offers excellent visualization of primary and metastatic pheochromocytoma.157,158

Treatment

Pharmacologic therapy should be initiated as soon as the diagnosis of pheochromocytoma is made, to minimize the risk of life-threatening hypertensive crisis or arrhythmia. Adequate control of arterial blood pressure is mandatory before initiation of any diagnostic or therapeutic procedures, especially surgery to remove the pheochromocytoma. Tradi-tionally, phenoxybenzamine hydrochloride has been used at an initial dose of 10 mg every 12 hours, which is gradually increased every 2 to 3 days until arterial blood pressure is normalized. Selective α1-receptor antagonists are acceptable alternatives, because they do not produce refl ex tachycardia and have shorter duration of action and reduced duration of postoperative hypotension.130,159 During treatment with α-adrenergic antagonists, sodium intake should be liberalized, as untreated patients are chronically volume depleted. One must be careful to detect postural hypotension associated with hypovolemia.136,160

β-receptor blocking agents may help in patients who have signifi cant tachycardia, palpitations, and catecholamine-induced arrhythmias. However, it is important to establish α-adrenergic blockade before commencement of β-receptor blockade. If β-receptor blockade is begun before establish-ment of adequate α-receptor blockade, severe hypertension may occur as a result of unopposed α-adrenergic stimulation associated with the increase in circulating catecholamines.

Calcium channel antagonists have been shown to control blood pressure and symptoms of pheochromocytoma. They can be used as alternatives to α-receptor antagonists or can be combined with selective α1-receptor antagonists. They reduce catecholamine production161 and inhibit norepineph-rine mediated action on vascular smooth muscle.162 They may prevent catecholamine-induced coronary vasospasm and myocarditis, so they can be especially useful in manag-ing patients with cardiovascular complications. They can be used safely in normotensive patients with episodes of parox-ysmal hypertension.130

Surgical removal of the tumor can be accomplished after adequate blood pressure control is obtained. The anesthesi-ologist should be experienced in the management of these patients, with special regard to treatment of intraoperative tachyarrhythmias. Hypotension after tumor excision should be treated with aggressive volume repletion.

Diabetes Mellitus

Pathophysiology

Diabetes mellitus is not a single disease but rather is a con-stellation of metabolic and pathologic abnormalities, with a variety of causes. Type 1 diabetes is caused by immunologi-cally mediated destruction of the β cells of the pancreatic islets of Langerhans.163–165 Susceptibility to type 1 diabetes is determined by human leukocyte antigen (HLA) genotype,166 with the destructive process being triggered by some envi-

FIGURE 108.2. Histologic appearance of myocardium from a patient with pheochromocytoma, showing myocarditis, nuclear degeneration of myocardial fi bers, edema, and focal histiocytic infi l-tration. Hematoxylin and eosin (H&E) stain, ×285.



ronmental event, perhaps viral infection.164,167,168 Patients with type 1 diabetes mellitus may develop other endocrine manifestations of organ-specifi c autoimmunity, including chronic lymphocytic thyroiditis, Graves’ disease, and idio-pathic adrenal insuffi ciency. Type 1 diabetes exhibits a pre-dilection for Caucasians, and extreme geographic variability of prevalence. Since the peak incidence is during adoles-cence,169,170 type 1 diabetes has been called juvenile diabetes, although new cases occur throughout life, even into old age. Patients with type 1 diabetes usually eventually develop absolute defi ciency of insulin, so they are prone to develop ketoacidosis unless treated regularly with exogenous insulin.

In the United States, over 90% of patients with diabetes are characterized by strong hereditary predisposition unre-lated to HLA type,167,171 and association with aging and obesity. This presentation of diabetes has been termed “type 2” but may be etiologically heterogeneous. Type 2 diabetes is the most common form of diabetes throughout the world. In the United States, it is the most prevalent form of diabetes among white people of European descent. Its prevalence is greater still among Native Americans, African Americans, and Mexican Americans. This form of diabetes is not accom-panied by any detectable immunologic attack on the pan-creas. Because the hyperglycemia is stable and does not lead to metabolic decompensation, type 2 diabetes may be present for a long time prior to diagnosis. Studies of the prevalence of retinopathy suggest that the mean duration of type 2 dia-betes prior to diagnosis is at least 4 to 7 years.172

The pathophysiology of type 2 diabetes includes both insulin resistance, that is, impairment of the action of insulin, and abnormal secretion of insulin, especially in response to hyperglycemia.173–175 However, these patients usually have detectable and often substantial circulating insulin levels, especially early in the course of the disease. Although insulin secretory capability tends to decline over many years, most patients do not require exogenous insulin to prevent metabolic decompensation. Ketoacidosis ordinar-ily occurs only in the context of a stressful event, such as severe infection or infarction of an organ.

The metabolic features of diabetes, which vary in sever-ity from individual to individual, are those that are charac-teristic of inadequacy of insulin action. These abnormalities include (1) inadequately restrained catabolism of stored gly-cogen, triglycerides, and protein; (2) inappropriately increased gluconeogenesis; (3) decreased fractional utilization of circu-lating glucose by skeletal muscle and adipose tissue; and (4) accelerated ketogenesis in patients with absolute defi ciency of insulin. These changes result in hyperglycemia, hyperlip-idemia, and, in severe cases, net catabolism of protein.

People with diabetes are especially prone to develop ath-erosclerotic disease, particularly coronary heart disease. The risk factors for initiation and progression of atherosclerosis are similar to those for development of type 2 diabetes, sug-gesting common pathogenetic mechanisms. The metabolic syndrome, known also as insulin resistance syndrome and syndrome X, consists of a set of physiologic attributes (Table 108.1) that share the property of being risk factors both for atherosclerotic events and for development of type 2 diabetes mellitus.176 These attributes tend to cluster in individuals, suggesting pathophysiologic linkage. For a given person, the

risk of a cardiovascular event is related to the number of components of the metabolic syndrome exhibited by that person.177,178 The metabolic syndrome may be viewed as the set of metabolically related risk factors that predispose to atherosclerotic disease. The primary abnormality has not been identifi ed with certainty, although visceral obesity, insulin resistance, and infl ammation are strong possibilities. Population surveys have shown this cluster of abnormalities to be present in about 85% of people with type 2 diabetes mellitus over the age of 50 years in the United States.179 In type 2 diabetes mellitus, much of the elevated cardiovascular risk seems to be attributable to the high prevalence of the metabolic syndrome.179

Obesity is a key component of the metabolic syndrome. Mounting evidence suggests that adipose tissue plays an important role in linking energy surplus and obesity to car-diovascular disease. Fat cells are not mere repositories for passive storage of excess fuel. They are metabolically highly active, and secrete a variety of mediators, known as adipo-kines, that infl uence the heart and circulation as well as insulin action (reviewed elsewhere180,181). The known adipo-kines include tumor necrosis factor-α (TNF-α), plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6), and mono-cyte chemotactic protein-1 (MCP-1), which may contribute to systemic prothrombosis and generation of infl ammatory mediators that may promote atherosclerosis (reviewed else-where182). Leptin is an adipokine, circulating levels of which are proportional to fat mass and energy surplus. Leptin has major roles in regulation of feeding and reproductive func-tion.183,184 Its relation to cardiovascular disease has not been fully elucidated. Resistin is a secretory product of macro-phages and adipose tissue that promotes insulin resis-tance185,186 and has been shown to infl uence endothelial cell function in vitro.187 Adiponectin, a 30–kd globular protein secreted by fat cells, is of special interest. Although produced by adipose tissue, circulating adiponectin levels are related inversely to obesity and insulin resistance.188,189 Moreover, clinical studies have shown low circulating adiponectin to be correlated with atherosclerotic events,190 suggesting that adiponectin protects against cardiovascular risk. Another recently described secretory product of fat cells is visfatin, which interacts with insulin receptors and mimics some of the actions of insulin; its physiologic role has not been elucidated.191

Premenopausal women with hyperandrogenism tend to be insulin resistant and to exhibit increased numbers of

TABLE 108.1. Components of the metabolic syndrome

Abdominal obesityDyslipidemia Small, dense LDL particles Low HDL-cholesterol HypertriglyceridemiaHypertensionInsulin resistanceHyperglycemiaProinfl ammatory stateProthrombotic state


2 3 0 4 c h a p t e r 10 8

cardiovascular risk factors, including elevated LDL choles-terol, hypertriglyceridemia, hypertension, increased waist circumference, and reduced adiponectin levels.192–194 Some studies have found increased arterial calcifi cation and plaque in such individuals.195,196 Accordingly, hyperandrogenism seems to be linked to the metabolic syndrome. The relation-ship between excessive androgens and insulin resistance is complex. On the one hand, hyperandrogenism is part of the phenotype of impaired insulin receptor function, probably mediated by elevated circulating insulin, and treatments that improve insulin sensitivity tend to reduce androgen levels (reviewed elsewhere197,198). On the other hand, treat-ments that lower circulating androgens tend to improve insulin sensitivity to some extent.199,200


The prevalence of diabetes mellitus is high, and rising. It is estimated that the lifetime risk of developing diabetes mel-litus for an individual born in the United States in 2000 is on the order of 35% to 40%, and higher among women than men.201 The risk is especially high among Hispanic individu-als, 45% and 52% for men and women, respectively.201 More-over, diabetes mellitus is an important cause of death. Current United States mortality data suggest that the diag-nosis of diabetes implies a 30% to 50% reduction of an indi-vidual’s remaining life expectancy.201 The major causes of death and disability in patients with diabetes include (1) atherosclerosis, manifested by occlusive coronary, cerebral, and peripheral vascular disease; (2) glomerulosclerosis leading to chronic renal failure; (3) arterial hypertension, which exacerbates cerebral vascular disease, renal insuffi ciency, and heart failure; (4) congestive heart failure, related to hypertension and ischemic heart disease; (5) peripheral and autonomic neuropathies; (6) proliferative retinopathy, the most common cause of blindness among working-age adults in the United States202; and (7) metabolic decompensation, including ketoacidosis and nonketotic hyperosmolar hyper-glycemia. Microvascular disease produces widening of base-ment membranes of capillaries in the retina, conjunctiva, glomerulus, brain, pancreas, and myocardium.203–206 The clinical signifi cance of these capillary lesions has not yet been fully elucidated. There is considerable evidence that control of hyperglycemia, hypertension, and dyslipidemia can help prevent the ocular, renal, neurologic, and vascular lesions that account for most of the death and disability in patients with both type 1 and type 2 diabetes.207–213

Type 2 diabetes tends to occur in individuals who are already burdened with various cardiovascular risk factors, including central adiposity; dyslipidemia consisting of ele-vated triglycerides, low HDL cholesterol, and small, dense LDL-cholesterol particles; hypertension; systemic infl amma-tion; and a thrombotic tendency as indicated by elevated levels of circulating PAI-1.214–217

A number of potentially atherogenic abnormalities of plasma lipoproteins has been observed among people with diabetes. In poorly controlled type 1 diabetes, typically HDL cholesterol levels are reduced, with mild or no increase in very-low-density lipoprotein (VLDL) and LDL cholesterol. These alterations return to normal when metabolism is nor-malized with intensive insulin therapy.218 Rarely, patients

with long-standing insulin defi ciency may display hyperchy-lomicronemia,219 owing to disappearance of lipoprotein lipase, which depends on insulin for its induction.220 The lipid pattern is different in type 2 diabetes mellitus, which is usually accompanied by obesity and insulin resistance. In this situation, one sees elevations of VLDL cholesterol and triglycerides, with reduced HDL cholesterol levels.218,221 Although LDL cholesterol levels may be normal, there is typically a shift in their size distribution toward smaller, denser particles, which are believed to be more atherogenic than the LDL of nondiabetic individuals.222–224 Control of hyperglycemia may improve LDL and triglyceride levels but is less effective in raising HDL.218

Epidemiologic studies show markedly increased cardio-vascular mortality among persons with diabetes melli-tus.225,226 Coronary artery disease, which leads to premature myocardial infarction (MI), is the leading cause of death among adults with diabetes. The presence of CAD correlates with the duration of diabetes. Additionally, in patients with type 2 diabetes, the level of glycemia is a risk factor for death from cardiovascular disease.227 Individuals with diabetes tend to have larger myocardial infarcts, a higher incidence of CHF, and higher mortality and morbidity rates associated with their infarcts than do nondiabetics.228–230 Survival after MI is reduced in diabetes, with mortality rates as high as 25% during the fi rst year after infarction.228–230 Patients with diabetes mellitus have a higher incidence of painless infarcts than the normal population, with as many as 20% failing to experience pain during MI. Perhaps, because of autonomic neuropathy, many of these patients may experience recurrent myocardial ischemia without symptomatic angina.231,232

In people with diabetes, cardiac anginal threshold may be increased as a consequence of autonomic and sensory neuropathies. In one clinical series, the severity of cardiac dysfunction was related directly to the severity of cardiac autonomic neuropathy.233–235 Autonomic dysfunction some-times results in fi xed heart rates that respond poorly to physiologic and pharmacologic interventions; this limits the ability of the heart to adjust cardiac output physiologically. Cardiovascular autonomic neuropathy is a strong risk factor for mortality in patients with diabetes.236,237

In animal models, experimentally induced diabetes results in ventricular dysfunction that may be at least par-tially corrected by the administration of insulin.238 Diabetic rats or rabbits develop a cardiomyopathy manifested func-tionally by decreased contractility, with slowing of both contraction and relaxation.238,239 These changes occur within a few months of induction of diabetes, and can be reversed by treatment of the diabetic animals with insulin for 4 weeks.238,239 In other experimental models, treatment with insulin does not correct abnormalities of ventricular func-tion. Therefore, the explanation for development of cardio-myopathy in diabetes remains unclear.

There is an increased risk for development of CHF in the diabetic patient, as established in the Framingham Study.240 This increased risk is present even when patients with prior coronary or rheumatic heart disease are excluded and the infl uences of age, blood pressure, weight, and cholesterol are taken into consideration.240 This argues for the existence of a diabetic cardiomyopathy. Noninvasive studies have revealed a variety of abnormalities in diabetic patients, including



increased fractional shortening during systole,241 asynchrony of early diastole,242 and slowed diastolic fi lling.243 These observations suggest that, at least in some individuals, there is a cardiomyopathy not based on the presence of myocardial ischemia.244 In patients with diabetes and cardiomyopathy, common histologic abnormalities are interstitial fi brosis (Fig. 108.3A), arteriolar hyalinization and narrowing of the lumina of intramyocardial arterioles245–249 (Fig. 108.3B). Dia-betic dogs and humans exhibit diastolic dysfunction associ-ated with interstitial deposition of periodic acid-Schiff (PAS)-positive glycoproteins243,250 (Fig. 108.3C).

The combination of diabetes and hypertension seems to promote accelerated development of CAD and cardiomyopa-thy.251 Rats with experimental renovascular hypertension and diabetes develop myocardial fi brosis and hypertrophy,252 as well as microvascular abnormalities.253 These anatomic lesions are not seen in normotensive diabetic animals.253–255 Treatment with diltiazem reduces mortality in hypertensive diabetic rats, suggesting a pathogenic role for intracellular calcium.256 Other factors that may contribute to abnormali-ties in LV function in diabetics include hypertension, increases in GH that develop in patients with diffi cult-to-control diabetes, which may play a role in the increased col-

lagen deposition in the LVs of some diabetics, and an alteration in calcium transport associated with increased sarcolemmal Ca–adenosine triphosphatase (ATPase) activ-ity.257,258 Increases in sarcolemmal Ca-ATPase activity might result in a relative excess of calcium intracellularly, contrib-uting to altered diastolic function and injury to heart muscle cells. Some experimental studies have suggested a benefi cial effect of the slow channel calcium antagonist, verapamil in preventing diabetes-induced myocardial changes in experi-mental models.259 An interesting association with cardiomy-opathy is a high prevalence of either septal hypertrophy or CHF in the infants of diabetic mothers.260 The cardiomyopa-thy in these infants may be transient and secondary to meta-bolic problems.

In patients with diabetes, cardiovascular disease, hyper-tension, and nephropathy are closely interrelated. Nephropa-thy evolves over decades, beginning with glomerular hyperfi ltration, followed by excretion of progressively greater amounts of plasma proteins, and culminating in renal failure.261 Thickening of mesangial matrix is characteristic of diabetic nephropathy, particularly in the glomerular tuft, where nodular glomerulosclerosis may be found.262 Microal-buminuria, defi ned as consistent excretion of more than

A

B

C

FIGURE 108.3. (A) Histologic appearance of myocardium from a patient with diabetes, showing arteriolosclerosis and interstitial fi brosis. (B) Histologic appearance of myocardium from a patient with diabetes, showing hyalinization of a small arteriole. H&E stain, ×300. Inset: Higher magnifi cation of same arteriole (×50). (C)

Histologic appearance of myocardium from a patient with diabetes, showing circumferential periodic acid-Schiff (PAS)-positive mate-rial at the periphery of muscle fi bers shown in cross-section PAS stain, ×210.


2 3 0 6 c h a p t e r 10 8

20 μg of albumin per minute or more than 30 μg of albumin per milligram of creatinine in a random urine specimen,263 is an index of diabetic nephropathy that precedes declining excretory function. The presence of microalbuminuria pre-dicts cardiovascular mortality264,265 as well as development of renal failure.266–269 Arterial hypertension270–272 and dyslip-idemia273,274 are major risk factors for development and pro-gression of diabetic nephropathy.

Peripheral vascular disease is a signifi cant problem for patients with diabetes mellitus (reviewed elsewhere275) and is a major factor leading to lower extremity amputation.276 Arteries in the legs below the knees are more likely to be involved by atherosclerosis in patients with diabetes than in those without diabetes.277 Noninvasive testing with ultra-sound is more sensitive than medical history or physical examination for detection of peripheral arterial insuffi -ciency.278 Cerebral vascular disease and infarction occur more frequently in people with diabetes. The renal vascula-ture may be affected by atherosclerosis in large vessels and by thickening of capillary basement membranes.

Diagnosis

Diabetes mellitus is diagnosed by measurement of circulat-ing glucose levels. The glycemic criteria for diagnosis of diabetes have recently been revised279 (Table 108.2). For example, reproducible fasting plasma glucose levels of greater than 126 mg/dL (7 mM) are considered diagnostic of diabetes. However, the cutoff values should not be interpreted too strictly, as there is no absolute defi nition of diabetes. Serum glucose values are continuously distributed in the popula-tion.280 Epidemiologic studies show an increased burden of cardiovascular risk factors281 as well as increased risk of car-diovascular events including death, among people with glucose levels in the upper part of the “normal” range.282–285 Postchallenge or postprandial glycemia seems to be more closely related to cardiovascular risk than is fasting glucose.286,287 Therefore, the fi nding of borderline hypergly-

cemia or impaired glucose tolerance warrants close attention to all of the patient’s cardiovascular risk factors, even if treat-ment with a hypoglycemic drug is not deemed necessary. The diagnosis of diabetes is strengthened when there is cor-roborative evidence of diabetic retinopathy, peripheral and coronary vascular disease, peripheral neuropathy, or auto-nomic dysfunction.

Prevention and Treatment

The Diabetes Prevention Program showed that intensive life-style modifi cation, including dietary intervention and an exercise program, delayed or prevented onset of type 2 dia-betes in a diverse group of high-risk individuals with impaired glucose tolerance.288 In high-risk individuals with insulin resistance, progression from normoglycemia to overt diabe-tes mellitus appears to be related to declining insulin secre-tory responsiveness. In this situation, drugs that reduce demand for insulin might potentially block the development of hyperglycemia. In the Diabetes Prevention Program, treat-ment with metformin was effective, but less so than the lifestyle program. One study has shown that treatment with a thiazolidinedione seemed to slow the rate of decline of pancreatic insulin secretory capability in some women with a history of gestational diabetes.289 If this observation is confi rmed in other populations, this class of drugs may be helpful for prevention of type 2 diabetes.

Control of blood glucose levels is important for the pre-vention or retardation of the development of long-term mor-bidity and mortality in people with diabetes mellitus.212,213 Randomized clinical trials involving patients with both type 1 and type 2 diabetes have shown convincingly that inten-sive management of glycemia improves outcomes with regard to onset and progression of nephropathy, retinopathy, and neuropathy.208,209 It is less clear whether glycemia is closely related to progression of atherosclerosis.207,208,290

A randomized, prospective study of patients with type 2 diabetes has shown that intensive treatment of blood pres-sure reduced complications related to diabetes.291 A recent study has shown that intensive combined management of blood pressure, albuminuria, lipids, and glycemia reduced the risk of atherosclerotic and microvascular events by about 50%, among patients with type 2 diabetes mellitus and microalbuminuria.211 The relative importance of each of the individual interventions remains to be elucidated.

Observational evidence suggests that hyperglycemia con-tributes to mortality among hospitalized patients.292 One randomized study showed that vigorous treatment of capil-lary glucose levels greater than 110 mg/dL, irrespective of any prior diagnosis of diabetes, reduced mortality in an intensive care unit from 8% to 4.6%.293 A recent meta-analysis implied that treatment with insulin reduces mortality among criti-cally ill patients.294 A randomized, prospective study of patients admitted to the hospital with myocardial infarction, the Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study, showed improved in-hospital and postdischarge survival when hyperglycemia was treated aggressively with insulin and the patients were sent home on insulin, compared with “usual care.”295

In patients with type 1 diabetes mellitus, diet and insulin therapy are critical to management of hyperglycemia. For

TABLE 108.2. Criteria for the diagnosis of diabetes mellitus

Symptoms of diabetes and a casual plasma glucose >200 mg/dL. The classic symptoms of diabetes include polyuria, polydipsia,

and unexplained weight loss. Casual is defi ned as any time of day without regard to time

since last meal.OR

Fasting plasma glucose ≥126 mg/dL. Fasting is defi ned as no caloric intake for at least 8 hours.

ORTwo-hour plasma glucose ≥200 mg/dL during an oral glucose tolerance test. The glucose tolerance test should be performed as described by

the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water. The patient should consume a high-carbohydrate diet for 3 days prior to performance of the test.

In the absence of unequivocal hyperglycemia, these criteria should be confi rmed by repeat testing on a different day.



patients with type 2 diabetes mellitus, diet and regular exer-cise can improve insulin resistance. Several oral agents, including sulfonylureas,296,297 meglitinides,298,299 metfor-min,300,301 α-glucosidase inhibitors,302 and thiazolidinedio-nes303,304 alone or in combination, may be effective in lowering glycemia.305 For reasons unknown, over time there is con-tinuing decline of pancreatic secretory capability in type 2 diabetes,306 so treatment with insulin eventually becomes necessary for many patients. Insulin may be given alone, or combined with oral hypoglycemic agents.307–309

Treatment with thiazolidinediones increases circulating adiponectin and reduces levels of infl ammatory markers, suggesting that these drugs might inhibit progression of atherosclerosis.310–312 A recent study showed a very modest reduction of cardiovascular events, coupled with increased risk of hospitalization for heart failure, in patients treated with pioglitazone.312a Treatment with thiazolidinediones tends to promote fl uid retention, perhaps owing to vasodila-tation or increased vascular permeability.313,314 About 5% of individuals treated with thiazolidinediones alone and about 15% of those treated with thiazolidinediones and insulin develop clinically signifi cant edema.315–317 A recent retro-spective survey found that 4.5% of patients on thiazolidine-diones developed heart failure, versus 2.6% of those not on thiazolidinediones, over 8.5 months’ mean observation.318 The treatments were not assigned randomly, so it is not pos-sible to estimate the risk of heart failure attributable to thia-zolidinediones. However, clearly thiazolidinediones should be given very cautiously to patients at risk for development of heart failure. The American College of Cardiology and American Diabetes Association have recently published joint guidelines concerning this issue.319

Attempts at tight glycemic control entail a substantially increased risk of hypoglycemia, especially among individu-als with type 1 diabetes, or advanced type 2 diabetes with minimal endogenous β-cell function. Patients being treated intensively with insulin may have few or no warning signs of hypoglycemia (hypoglycemic unawareness),320,321 as well as impaired spontaneous recovery from hypoglycemia (hypo-glycemic unresponsiveness),320,322,323 adding to the risk for hypoglycemic brain damage. Much of this problem seems to be related to impairment of the autonomic response to hypo-glycemia by prior episodes of hypoglycemia.324 Clinical studies have shown partial restoration of hypoglycemic awareness and responsiveness by scrupulous avoidance of hypoglycemia.325,326 Hypoglycemia during sleep has been linked to fatal cardiac arrhythmia—the “dead in bed” syn-drome (reviewed elsewhere327). The mechanism of arrhyth-mia has been postulated to be prolongation of the Q-T interval owing to sympathetic activation.328 The electrophysiologic changes can be prevented by infusion of potassium or β-adrenergic blockade.328

It is important to choose antihypertensive drugs care-fully. Guidelines for choosing antihypertensive drugs have been published.329 β-adrenergic blocking agents reduced com-plications in patients with type 2 diabetes330 but may entail special risks for patients with type 1 diabetes who are attempting strict blood sugar control. In such patients these drugs, especially the nonselective beta-blockers such as propranolol, may contribute to hypoglycemic unrespon-siveness.331–334 In patients with preserved hypoglycemic

responsiveness, beta-blockers will blunt the tachycardia but not the diaphoretic response to hypoglycemia.333,334 Further-more, nonspecifi c beta-blockers may diminish pancreatic secretion of insulin,335,336 impair the responsiveness of tissues to insulin,335,336 elevate circulating triglycerides, and reduce plasma levels of HDL cholesterol.335,337,338 One must also be careful with diuretic therapy, which can cause deterioration of insulin resistance in patients with type 2 diabetes mellitus.339

Patients with diabetes should be screened for microal-buminuria, defi ned as consistent excretion of more than 20 μg of albumin per minute or 30 μg of albumin per milli-gram of creatinine in a random urine specimen.263 Cur-rently, many clinicians consider inhibition or blockade of the renin-angiotensin-aldosterone system to be the strategy of fi rst choice for treatment of albuminuria and hyperten-sion in patients with diabetes. Angiotensin-converting enzyme inhibitors reduce albuminuria, prevent or retard the progression of diabetic nephropathy,340,341 and reduce mortality (reviewed elsewhere342,343). Angiotensin II receptor antagonists also reduce albuminuria effectively, and provide further reduction of albuminuria when combined with ACE inhibitors (reviewed elsewhere344,345). It is not yet known whether angiotensin II receptor antagonists confer a sur-vival benefi t.346 Patients started on ACE inhibitors or angiotensin II receptor antagonists should be checked for development of hyperkalemia and deterioration of glomeru-lar fi ltration.347

Among patients with diabetes, hyperlipidemias appear to respond to the same dietary measures and drugs that are appropriate for nondiabetics.348,349 In patients with type 1 diabetes, excellent blood sugar regulation with insulin can produce normal circulating lipoprotein levels.350 Some recently published clinical trials confi rm that reduction of LDL cholesterol levels by treatment with statins reduces the risk of cardiovascular events among people with dia-betes.351–353 Based on this information, an expert panel has recommended an LDL cholesterol goal of <100 mg/dL for individuals with diabetes, with a more stringent goal of <70 mg/dL being a reasonable option for those at very high risk.354 It should be noted that nicotinic acid may exacerbate insulin resistance,355,356 requiring intensifi cation of glycemic management.

Disorders of Calcium Metabolism

Pathophysiology

Maintenance of the concentration of ionized calcium in extracellular fl uid (ECF) within narrow limits is essential for normal neuromuscular excitability and for preservation of skeletal mass. The major hormonal regulator of ECF calcium is parathyroid hormone (PTH), a single-chain polypeptide of 84 amino acids. Its rate of secretion is inversely proportional to the concentration of ionized calcium over the physiologic range of calcium values in ECF.357,358 The relationship between extracellular ionized calcium and secretion of parathyroid hormone is governed by a calcium-sensing receptor protein, which is expressed on the surfaces of parathyroid and renal tubular cells.359–361 The primary physiologic effect of PTH is


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to increase the concentration of ionized calcium in ECF. This is a result of augmentation of bone resorption, reduction of the fractional urinary excretion of fi ltered calcium, and stim-ulation of phosphaturia. In addition, PTH elevates serum calcium concentration by increasing the rate of conversion of 25–hydroxyvitamin D to 1,25–dihydroxyvitamin D, which enhances gastrointestinal absorption of calcium.

Parathyroid hormone has a number of actions on the cardiovascular system, some but not all of which are medi-ated by hypercalcemia. Given in vivo or in vitro, PTH pro-duces an increased heart rate, positive inotropic action, and cardiac hypertrophy.362,363 These changes are believed to result from entry of calcium into cardiac cells and from increased release of endogenous myocardial norepinephrine. Calcium and PTH-mediated activation of the protein kinase C cascade produces hypertrophic and metabolic effects on the cardiomyocyte.364,365 If PTH mediates excessive entry of calcium into cardiac muscle cells, it may also cause necrosis and depressed ventricular function. In addition, PTH has a direct vasodilatory effect on vascular smooth muscle, although it has not been established whether this is a physi-ologically relevant action of the hormone.365,366

The major causes of hypercalcemia include primary hyperparathyroidism, secretion of osteolytic factors (e.g., prostaglandins, cytokines, or PTH-related protein367,368) from a variety of neoplasms, excessive formation of 1,25–dihy-droxyvitamin D by the granulomas of sarcoidosis or chronic infections such as tuberculosis, and the milk-alkali syndrome caused by ingestion of calcium and absorbable alkali.369

Primary hyperparathyroidism involves the excessive pro-duction of PTH. In many patients, primary hyperparathyroid-ism is asymptomatic and is discovered as an incidental result of routine laboratory testing. It is most often caused by a soli-tary parathyroid adenoma. Less frequently, there is general-ized parathyroid hyperplasia or carcinoma of the parathyroid gland. The hypercalcemia associated with MEN-I and -II is usually caused by parathyroid hyperplasia. Germline muta-tions that decrease the sensitivity of the calcium-sensing receptor, also cause hypercalcemia.360,370 Heterozygotes for such mutations have an alteration in the set-point for regula-tion of PTH secretion,358 known as familial hypocalciuric hypercalcemia.360,370 Secondary hyperparathyroidism, most commonly associated with renal disease, gastrointestinal malabsorption, or a disorder of vitamin D economy, arises from chronic hypocalcemic stimulation of PTH secretion, resulting in hyperplasia of the parathyroid glands.

Hypocalcemia most often arises from renal insuffi ciency with hyperphosphatemia, inadequate secretion of PTH (hypoparathyroidism), cellular resistance to the action of PTH (pseudohypoparathyroidism), or some disorder of vitamin D economy. The most important causes of hypo-parathyroidism are surgical removal of the glands, usually as the unintended result of operations on the thyroid, and idio-pathic hypoparathyroidism, often refl ecting immunologi-cally mediated destruction as part of one of the polyglandular autoimmune syndromes.371 Common problems with vitamin D include dietary defi ciency, malabsorption, or some derange-ment in the multiorgan, multienzyme sequence that pro-duces the fi nal active metabolite, 1,25–dihydroxyvitamin D. Hypovitaminosis D is a widespread health problem, particu-larly in the elderly and individuals with darker skin.372–374


The typical manifestations of hypercalcemia include poly-uria, nocturia, nausea, vomiting, constipation, nonspecifi c joint and back pains, renal stones, nephrocalcinosis, and renal failure. There is also decreased neuromuscular excit-ability. In patients with very long-standing or severe hyper-parathyroidism, elevation of serum alkaline phosphatase, osteopenia, localized brown tumors of bone, and spontane-ous fractures may occur, caused by the effects of PTH on bone. In addition, elevation of urinary cyclic adenosine monophosphate refl ects a direct effect of PTH on the kidneys.

Some hypercalcemic patients develop systemic arterial hypertension.375 The precise mechanisms responsible for hypertension in such patients are unclear, as the levels of serum calcium are similar in those who are normotensive and those with hypertension. Increased serum calcium may render vascular smooth muscle more sensitive to agents, such as angiotensin II and norepinephrine. In patients with hypertension and hyperparathyroidism, the hypertension is not always reversible after surgical correction.376,377

Hypercalcemia impairs urinary concentrating ability (nephrogenic diabetes insipidus), leading to volume deple-tion. Deposition of calcium in the renal parenchyma may further impair renal function. Chronic hypercalcemia can lead to ventricular hypertrophy even in the absence of hyper-tension, and to deposition of calcium in the fi brous skeleton of the heart, the valvular tissue, coronary arteries, and myo-cardial fi bers.378,379 The probability of extracellular deposi-tion of calcium salts in the heart, lungs, kidneys, and other organs may be estimated by the product of circulating calcium and phosphorus. When the Ca × P (each in mg/dL) product is greater than 60, there is a risk of metastatic cal-cifi cation; Ca × P products over 75 indicate a severe risk. Increases in extracellular calcium lead to subsequent increases in intracellular calcium and may provoke arrhyth-mias, including fi brillation in isolated cardiac muscle cells.380 Marked hypercalcemia shortens the Q-T interval and may lead to ventricular arrhythmias and sudden death in humans.

Patients with primary hyperparathyroidism are reported to have overrepresentation of cardiovascular death in population studies.381–384 Postulated mediators of this phenomenon385,386 include hypertension,387 disturbances in the renin-angiotensin system,388 cardiac arrhythmias,389,390 structural and functional abnormalities of the vascular wall391–395 and cardiac muscle,396–400 insulin resistance,401 and hyperlipidemia.402 Whether asymptomatic primary hyper-parathyroidism confers increased mortality remains to be determined.386

Hypocalcemia typically produces tetany and other mani-festations of neuromuscular hyperexcitability.403 The ECG effects of hypocalcemia include prolongation of the Q-T interval and arrhythmias, especially torsades de pointes.404 In addition, decreases in gastrointestinal motility are often present. Hypoparathyroidism may cause a dilated cardiomy-opathy, presumably secondary to hypocalcemia.405–410 In these situations, hypomagnesemia and reduced circulating PTH may also contribute.406,411 Hypovitaminosis D causes rickets in children and osteomalacia in adults.412 It has also



been linked with increased risk of hypertension,413,414 conges-tive heart failure,415,416 multiple sclerosis,417 cancer,418–420 and type 1 diabetes mellitus.421

Diagnosis

Evaluation of a hypercalcemic patient should begin with measurement of the ionized fraction of circulating calcium. If ionized hypercalcemia is confi rmed, the next step in dif-ferential diagnosis should be determination of PTH depen-dence by measurement of intact PTH with a second-generation immunoradiometric assay that is highly specifi c for the full length 84-amino-acid peptide.422,423 The combination of hypercalcemia and unequivocally elevated PTH levels most often indicates parathyroid adenoma or hyperplasia. However, one should exclude the diagnosis of familial hypocalciuric hypercalcemia (vide supra)360. This autosomal dominant con-dition is characterized by moderate hypercalcemia with some elevation of PTH levels. Heterozygotes exhibit a benign course, usually without renal or osseous complications,424,425 and require no specifi c treatment. Although the parathyroid glands are usually hyperplastic, parathyroidectomy is of no benefi t in familial hypocalciuric hypercalcemia.424,425 The keys to diagnosis are ascertainment of other affected family members and measurement of urinary calcium excretion. In patients with familial hypocalciuric hypercalcemia, the ratio of calcium to creatinine clearances is less than 0.01.424,425

In a hypocalcemic patient, hypoparathyroidism can be confi rmed by demonstration of inappropriately low serum PTH concentration together with an increased serum phos-phorus level. If the PTH level measured by a full-length second-generation immunoradiometric assay is not low, one should search for another cause of hypocalcemia.

In hypovitaminosis D, serum 25-hydroxyvitamin D con-centration is low,412,426 but circulating 1,25-dihydroxyvitamin D may be normal. Serum calcium usually remains in the normal range due to compensatory elevation of PTH.427,428

Treatment

Owing to the use of multichannel screening tests, hyperpara-thyroidism is frequently discovered in individuals who are relatively asymptomatic. Many of these asymptomatic patients pursue a relatively benign course, without develop-ment of renal insuffi ciency, urinary stones, or signifi cant bone disease. At present there is no reliable criterion for prospective identifi cation of this subset of patients.429 The consensus of experts is that if the patient’s operative risk is reasonable, parathyroidectomy is recommended for patients with any of the following conditions430:

• Serum calcium concentration greater than 1 mg/dL above the upper limits of normal

• Twenty-four-hour urinary calcium greater than 400 mg• Creatinine clearance reduced by more than 30% com-

pared with age-matched subjects• Low bone density of lumbar spine, hip, or radius• Age younger than 50 years• Medical surveillance is not desired or possible

Hyperparathyroid patients who do not undergo surgery should be followed closely, with periodic measurements of

serum calcium and PTH, creatinine clearance, calcium excretion, and bone mineral density.

Calcimimetics are a new class of medications that inter-act with the calcium-sensing receptor on the parathyroid cell. They increase the sensitivity of the receptor to extra-cellular calcium ions and inhibit the release of parathyroid hormone.431,432 Cinacalcet, a second-generation ligand of this class, has been approved for the treatment of hypercalcemia in patients with parathyroid cancer or for dialysis patients with secondary hyperparathyroidism.433–435 A recent double-blind randomized clinical study showed that treatment with cinacalcet maintained normocalcemia over 40 weeks in a group of patients with primary hyperparathy-roidism.436 Drugs of this type may become a useful alter-native to parathyroidectomy in patients with primary hyperparathyroidism.434

The fi rst step in medical treatment of moderate or severe symptomatic hypercalcemia of any cause should be restora-tion of extracellular volume with isotonic fl uids.437,438 After volume expansion, cautious intravenous administration of a loop diuretic such as furosemide will promote excretion of calcium. If these measures do not lower the serum calcium satisfactorily, several effective drugs are available. These include subcutaneous calcitonin and bisphosphonates such as intravenous pamidronate.438–441 Glucocorticoids are employed for treatment of hypercalcemia caused by exces-sive circulating 1,25–dihydroxyvitamin D or by some hema-tologic malignancies.438,442 Hemodialysis remains an option in cases of life-threatening hypercalcemia unresponsive to initial medical management. Treatment of hypertension or edema in patients with hypercalcemia should not include thiazide diuretics, which promote renal reabsorption of calcium and thereby elevate the serum calcium concentration.443,444

In patients with hypoparathyroidism, supplementation of calcium is provided by the administration of calcium, and vitamin D or one of its metabolites to enhance the intestinal absorption of calcium. Hypovitaminosis D can be treated with oral vitamin D (ergocalciferol), 50,000 IU weekly for 8 weeks and maintenance doses after that.445

Hypothyroidism

Pathophysiology

Approximately 90% of normal thyroidal hormone secretion is in the form of thyroxine (T4), which is thought to be a prohormone. About 99.98% of circulating T4 is bound with high affi nity but reversibly to plasma proteins, primarily thyroxine-binding globulin (TBG) and secondarily trans-thyretin (thyroxine-binding prealbumin). Thyroid hormone action is exerted principally by triiodothyronine (T3), which is formed by 5′-deiodination of T4 in the liver and other target tissues. The major actions of T3 are believed to be mediated by interaction with specifi c receptors in cell nuclei. T3 recep-tors, of which several variants have been described, are members of the steroid receptor superfamily.446,447 Initiation of hormonal effects involves a three-way interaction among T3, T3 receptors, and specifi c base sequences of DNA. As a consequence of this binding, alterations occur in gene


2 310 c h a p t e r 10 8

transcription and protein synthesis, leading to many of the biochemical and metabolic effects observed with admini-stration of thyroid hormone.

The actions of thyroid hormones on the cardiovascular system have been extensively studied.448 Thyroid hormones increase cardiac contractility and heart rate. Increased whole-body oxygen consumption, decreased systemic vascular resistance, expansion of blood volume, and direct effects of thyroid hormone on the myocardium all may play roles in mediation of these responses.449–451 Some investigators have reported that thyroid hormone increases cardiac sensitivity to catecholamines, but this effect remains controversial.449 At the cellular level, thyroid hormone increases the activity of plasma membrane Na,K-ATPase, perhaps by stimulation of synthesis of enzyme subunits. This action results in aug-mented hydrolysis of adenosine triphosphate (ATP) at the site of the sarcolemmal sodium pump, which stimulates cellular oxygen consumption. Thyroid hormone also affects other cellular processes, including transport of glucose and calcium and synthesis of myosin. The net effect of thyroid hormone on sarcolemmal calcium transport is to enhance myocardial relaxation.452,453 In rats and rabbits, treatment with thyroid hormone increases the amount of the mobile cardiac myosin isoenzyme (V1), whereas the slower V3 myosin isoform is reduced.454 This effect is less prominent in human myocar-dium. The augmented myosin ATPase activity of the hyper-thyroid heart appears to contribute to the enhanced contractile response, since the activity of this enzyme regu-lates the rate of turnover of actin-myosin cross-bridge link-ages in cardiac muscle. The infl uence of thyroid hormone on myosin isoenzymes appears to be localized primarily in the ventricles. Hypothyroidism induces the opposite effects.454,455

Thyroid hormone also increases peak tension develop-ment while shortening the duration of contraction in ven-tricular muscle. These effects may be related to a more rapid intracellular calcium transient, owing to an increase in the number of slow calcium channels with accelerated reuptake of calcium by the sarcoplasmic reticulum.456–458 Some have suggested that the effects of thyroid hormone on protein synthesis and on myosin isoenzymes in the heart are results of changes in cardiac work rather than direct hormone actions.459,460

Hypothyroidism is caused by reduced secretion of thyroid hormones, usually as a consequence of destruction of the thyroid gland, often mediated by an autoimmune process, and sometimes following thyroidal surgery or treatment with 131I. Occasionally, hypothyroidism results from decreased secre-tion of TSH, owing to pituitary or hypothalamic disease. With secondary hypothyroidism, the signs and symptoms associated with defi ciency of other pituitary hormones are often present. Subclinical hypothyroidism resulting from mild thyroid failure is defi ned as an elevated serum TSH concentration with free T4 in the reference range.461

The antiarrhythmic drug amiodarone has complex effects on pituitary-thyroid physiology.462 Patients who receive it are subjected to an immense pharmacologic overload of iodine, which makes up 37% of the weight of the drug. Amiodarone is stored in adipose tissue, from which iodide is slowly released into the circulation by slow deiodination.463,464 Ami-odarone, in common with other organic iodides, inhibits the

peripheral and pituitary forms of 5′-deiodinase, the enzymes that convert T4 to T3.464,465 This releases TSH secretion from feedback inhibition by circulating T4, and slows the clear-ance of T4 from the circulation. The normal physiologic response to amiodarone includes elevation of circulating T4 levels, as well as increases of plasma TSH, which usually return to normal after about 3 months of treatment. Addi-tionally, amiodarone may produce hypothyroidism or thyro-toxicosis. In countries with abundant environmental iodine, such as the United States, amiodarone-induced hypothyroid-ism is more common than thyrotoxicosis.463 Amiodarone may cause an increase in intrathyroidal Ia-positive T cells, an abnormality found in patients with spontaneous Graves’ disease. T-cell abnormalities disappear after discontinuation of amiodarone. Amiodarone may also produce a syndrome of painful infl ammatory thyroiditis.466


Hypothyroidism is twice as common among women as men. The peak of incidence is between the ages of 30 and 60 years. Characteristic symptoms include cold intolerance, dryness of the skin, weakness, impairment of memory and intellec-tual function, personality change, constipation, hoarseness, and menstrual abnormalities. A case-control study showed that individual symptoms such as fatigability are poor dis-criminators, but combinations of symptoms may identify hypothyroid individuals.467 Typical physical fi ndings include cool, dry skin, slowed mentation and speech, facial puffi ness, and nonpitting edema (myxedema) of the lower extremities. Myxedema refl ects a generalized tendency to accumulation of mucopolysaccharide-rich interstitial fl uid, which may also be manifested as puffi ness of the face and eyes, ascites, pleural or joint effusions, and pericardial effusion (see later). Other classic fi ndings include delayed relaxation of skeletal muscle, as manifested in the Achilles tendon refl ex, and development of a yellowish hue to the skin, resulting from decreased conversion of carotene to vitamin A.

Classical cardiovascular physical fi ndings include brady-cardia, cardiac enlargement, distant heart sounds, weak arterial pulses, and nonpitting peripheral edema. Electrocar-diographic fi ndings include sinus bradycardia, atrioventricu-lar and intraventricular conduction defects, and low voltage. Although hypothyroidism prolongs the cardiac action poten-tial and QT interval, potentially predisposing to cardiac irri-tability, ventricular arrhythmias and in rare cases torsades de pointes468,469 arrhythmias are infrequent in hypothyroid patients.470

Hemodynamically, the hypothyroid state is character-ized by bradycardia, decreased myocardial contractility, and increased total peripheral resistance.471 Blood and plasma volumes are reduced, as are stroke volume and cardiac output. Overt hypothyroidism is associated with higher blood pres-sure in patients with systemic hypertension.472–474 Ten percent to 25% of hypothyroid patients have diastolic hypertension, which combined with the increase in vascular resistance increases cardiac afterload.449,475 Although cardiac enlarge-ment is typical, overt CHF is uncommon.476–479 When it occurs, CHF is caused by dilated cardiomyopathy.471 Another important cause of cardiomegaly in hypothyroidism is peri-cardial effusion, which occurs in up to 30% of hypothyroid


e n d o c r i n e d i s or de r s a n d t h e h e a rt 2 311

patients.471 The effusion is one manifestation of a generalized leakage of protein-rich fl uid into interstitial spaces. Cardiac tamponade is unusual but has on occasion been reported as the presenting sign of hypothyroidism.480 Extensive CAD may be present in hypothyroid patients. Coronary athero-sclerosis occurs with twice the frequency in patients with myxedema compared with age-and sex-matched control subjects.481

Subclinical hypothyroidism has been reported to be asso-ciated with LV diastolic dysfunction at rest and with exer-cise,482–486 impaired fl ow-mediated vasodilatation indicating endothelial dysfunction, and decreased heart rate variability indicating autonomic dysfunction.487 Enhanced risk for ath-erosclerosis and increased cardiovascular risk has been reported,482,488 perhaps related to atherogenic lipid abnormali-ties: mildly increased levels of total cholesterol, LDL choles-terol, and oxidized LDL.448,489–491 However, a recent systematic review did not fi nd adequate evidence linking subclinical hypothyroidism to either cardiac dysfunction or unfavorable cardiovascular outcomes.492

Diagnosis

The typical symptoms and physical examination of a patient with hypothyroidism aid in recognition of the condition. However, as is true for hyperthyroidism, in elderly patients some of the classic clinical manifestations of hypothyroid-ism may be subtle or nonexistent.471 Hyponatremia, hyperprolactinemia, hyperhomocysteinemia, hypoglycemia, hypercholesterolemia, and hypertriglyceridemia may be caused by hypothyroidism.493–495 Hypothyroid patients may also have elevated skeletal muscle enzymes, including cre-atine kinase (CK-MM band), lactic dehydrogenase (LDH), and serum glutamic-oxaloacetic transaminase [SGOT, aspartate aminotransferase (AST)]. The mechanism by which these skeletal muscle enzymes are increased chronically in patients with hypothyroidism is unclear. Measurements of TSH and of serum free T4 index are the most helpful clinically, with the combination of low serum free T4 index and increased TSH concentration being diagnostic of primary hypothyroidism.

Treatment

Patients with hypothyroidism should be treated with T4.496 Precipitation or worsening of myocardial ischemia during treatment of hypothyroidism is a clinically important problem.497 Accordingly, most authors recommend a low starting dose of T4, on the order of 0.025 or even 0.012 mg daily, in elderly patients and those predisposed to ischemic heart disease.496 With such patients, it may be prudent to titrate the dose to less than full replacement levels. For patients at less risk for myocardial ischemia, the starting dose of T4 may be 0.05 mg/day.498,499 The dose may be increased every 4 to 6 weeks until the TSH level is normalized. The usual maintenance dose for adults is about 0.1 to 0.125 mg/day.498,499 During this treatment, the patient’s cardiovascular condition should be monitored carefully. If there is worsen-ing of angina or a marked increase in heart rate or blood pressure, the dose should be reduced to eliminate these effects. In patients with intact pituitary glands, measure-

ment of serum TSH levels provides the most useful marker of the adequacy of replacement therapy.

Whether persons with subclinical hypothyroidism and serum TSH less than 10 mIU/L should be treated remains controversial.492,500 No blinded randomized controlled study has assessed the impact of thyroxine treatment on important clinical cardiac end points.492,501,502

Treating heart failure in the patient with myxedema is somewhat more complicated than in euthyroid individuals, because people with myxedema are often unusually sensitive to the effects of cardiac glycosides. Patients with unstable or limiting angina and untreated myxedema pose a particularly diffi cult clinical problem because angina may be exacerbated or an MI may be caused by too vigorous thyroid hormone replacement. One should replace thyroid hormone very care-fully in such individuals, administering small doses as indi-cated above and initially attempting to make the patient comfortable rather than euthyroid. In the patient with exten-sive CAD and unstable angina, surgical revascularization can be accomplished in association with low-dose thyroid hormone replacement, followed later by full thyroid replace-ment during the postoperative period. Perioperative morbid-ity is only slightly increased for patients with mild to moderate hypothyroidism.503,504 Therefore, necessary cardio-vascular surgery need not be postponed until the euthyroid state is restored. In the patient with CHF and myxedema without CAD, administration of thyroid hormone carefully and in increasing amounts, in association with the use of a diuretic, salt restriction, and digoxin in appropriately small doses, usually leads to the control of CHF in time.

Acutely or chronically ill patients often have low serum T4 and T3 values without elevation of circulating TSH, a situ-ation known as the “euthyroid sick” syndrome.505–510 The thyroid hormone levels are inversely correlated with sur-vival.511 The low T3 values are secondary to decreased extra-thyroidal 5′-deiodinase activity, with reduced conversion of T4 to T3.508,509 The reduced T4 levels are often related to altera-tions in protein binding of circulating T4, causing a decrease in total T4 but only minimal changes in the level of physio-logically active free hormone.508,509,512 There may also be sup-pression of TSH release, owing to severe medical illness or drugs such as dopamine. In the euthyroid sick syndrome, the serum TSH is not elevated, but may increase in the recovery period.508–510 In diffi cult cases, further diagnostic discrimina-tion may be obtained by measurement of serum 3,3′,5′-triiodothyronine (reverse T3), the concentration of which typically rises in the euthyroid sick syndrome but declines in hypothyroidism.508,509 There is controversy regarding whether individuals with the euthyroid sick syndrome are physiologically hypothyroid, but administration of T4 or T3 does not improve prognosis.507,513

Many patients with acute or chronic cardiac disease exhibit the euthyroid sick syndrome. Within 4 hours after acute MI, T3 and T4 levels are reduced by about 20% and 40%, respectively.514 In patients with chronic heart failure, circu-lating thyroid hormone concentration decreases and reverse T3 increases parallel to the degree of functional impair-ment.515 Circulating T3 levels fall signifi cantly in the post-operative period of patients undergoing cardiopulmonary surgery or coronary artery bypass.516–518 This alteration in thyroid status might modify cardiac gene expression and


2 312 c h a p t e r 10 8

contribute to impaired cardiac function.448,519 Although some data imply that the administration of T3 may benefi t some patients with cardiovascular disease, benefi cial effects on major clinical outcome variables have not been conclusively demonstrated.448,449,517,520

Hyperthyroidism

Pathophysiology

Thyrotoxicosis, which is defi ned as the state of excessive circulating thyroid hormone, can have a variety of causes. The most frequent are (1) production of circulating autoanti-bodies that activate TSH receptors, producing diffuse toxic goiter (Graves’ disease); (2) toxic multinodular goiter or hyperfunctioning solitary thyroid adenoma; (3) subacute thy-roiditis; and (4) postpartum and “silent” thyroiditis, probably of autoimmune cause.521 Less common causes include TSH-secreting adenoma of the pituitary, massive overproduction of chorionic gonadotropin or another low-potency thyroid stimulator in patients with hyperemesis gravidarum or tro-phoblastic neoplasm,522,523 and accidental or purposeful inges-tion of thyroid hormone (thyrotoxicosis factitia).

Subclinical hyperthyroidism is characterized by subnor-mal or suppressed serum TSH concentration with circulat-ing thyroid hormones in the reference range.500 It may be due to dysfunction of the thyroid gland (endogenous subclini-cal hyperthyroidism) but more often is the consequence of treatment with l-thyroxine (exogenous subclinical hyperthyroidism).482,492


Patients with thyrotoxicosis typically have heat intolerance; warm, moist skin; brittle nails and hair; tremulousness; irri-tability and emotional lability; increased appetite; weight loss; resting heart rates greater than 90 beats/min; palpita-tions; muscle weakness; and menstrual abnormalities. On physical examination, a thyrotoxic patient typically has a very active precordium with a right ventricular (RV) lift, a palpable pulmonary artery, an enlarged heart, and a systolic ejection murmur. The patient may also have brisk refl exes, a prominent stare, lid lag, a wide pulse pressure, and bound-ing peripheral pulses. Proptosis and paralyses of extraocular muscles, when they occur, point to Graves’ disease as the cause of thyrotoxicosis.

In the young individual, thyrotoxicosis is usually rela-tively easy to identify, but in elderly patients the typical clinical features may be lacking or far more subtle. Palpable thyroid enlargement or a nodule is present in most patients, but these signs may be absent. Therefore, the diagnosis of thyrotoxicosis may be delayed or overlooked for long periods of time.

Excessive thyroid hormone causes increases in heart rate, cardiac contractility, and pulse pressure.524–526 Left ventricu-lar ejection fraction and cardiac output are increased at rest but do not appropriately adapt to exercise due to ineffective and impaired chronotropic, contractile, and vasodilatory car-diovascular reserves. This effect, reversible with restoration of the euthyroid state, can explain the reduced exercise toler-

ance of hyperthyroid patients.451,527,528 Prolonged exposure to even slightly increased amounts of thyroid hormone can lead to cardiac hypertrophy.529 High-output heart failure coexists with thyrotoxicosis in some patients. Cardiac dilatation and hypertrophy, markedly increased cardiac output, and ulti-mately heart failure may develop. The tachycardia of hyper-thyroidism appears to arise from the actions of thyroid hormones on several different ion channels in the cells of the SA node.530 Heart rate variability is attenuated, suggesting impaired autonomic regulation.531 Although many of the car-diovascular manifestations of hyperthyroidism resemble a heightened β-adrenergic state, careful physiologic studies have not shown altered sensitivity of the cardiovascular system to adrenergic stimulation.448,449,451,532–534

Atrial fi brillation with rapid ventricular rate is a particu-lar problem.525,526 It occurs in 5% to 15% of patients with hyperthyroidism and may be the initial reason for medical evaluation.535–537 Although hyperthyroidism is more common in women, atrial fi brillation is more common among men with thyrotoxicosis, and increases in both sexes with advanc-ing age.538 Atrial fi brillation was reported to occur in more than 25% of thyrotoxic individuals older than 60 years.538 The prevalence might be falling because hyperthyroidism is diagnosed now at an earlier stage in its natural history.539 In general, atrial fi brillation is a major risk factor for thrombo-embolism, especially stroke.537,540 About 6% of individuals with thyrotoxicosis and atrial fi brillation have been reported to suffer stroke or transient cerebral ischemia before the thyrotoxicosis is controlled; this is about the same as the risk of cerebral embolism in patients with other causes of atrial fi brillation.540 It is diffi cult to estimate the true risk of thromboembolism in thyrotoxic atrial fi brillation, because the arrhythmia is more prevalent in older persons, and age is itself strongly linked to the risk of stroke.541 The incidence of thromboembolism is highest among patients over 60 years of age and in those with preexisting rheumatic or hyperten-sive heart disease.538

Thyrotoxicosis may provoke or aggravate angina pectoris owing to increased heart rate, or augmented myocardial contractility with attendant increased myocardial oxygen demand. Most patients with angina and thyrotoxicosis have coronary atherosclerosis, but occasionally the coronary arteries are normal on angiography.542

In subclinical hyperthyroidism subtle hyperthyroid symptoms might be present.543 There is growing evidence that subclinical hyperthyroidism has important effects on the heart. A major concern is the increased risk of develop-ment of atrial fi brillation, especially in patients with TSH less than 0.1 mIU/L.492,536,544 A recent meta-analysis has shown that subclinical hyperthyroidism is associated with increased heart rate, atrial arrhythmias, increased LV mass with marginal concentric remodeling, impaired ventricular relaxation, reduced exercise performance, and increased risk for cardiovascular death.482

Diagnosis

A measurement of serum TSH below the limits of detection by a reliable laboratory using “ultrasensitive” immunoradio-metric methodology provides good evidence of thyrotoxico-sis. The diagnosis can be confi rmed by measurement of



circulating thyroid hormones. The serum T3 level is probably a more reliable index of thyrotoxicosis than is the T4 level. Owing to the frequency with which disease or drugs alter binding of T4 and T3 to plasma proteins, one should always obtain an estimate of unbound hormone, such as the free T4 index, free T3 index, or T4 by equilibrium dialysis. If the TSH concentration is low, a high value for one of these indices will confi rm the diagnosis of thyrotoxicosis. Measurements of total T4 and T3 in the serum may be misleading, since patients with heart disease or other serious illnesses may have decreased peripheral conversion of T4 to T3 and decreased plasma protein binding of both hormones.538 As a result, serum total T3 concentration and sometimes total T4 concen-tration are reduced. Indeed, a normal serum T3 concentration in a patient with severe cardiac disease suggests that thyro-toxicosis may be present.538

Treatment

Management of thyrotoxicosis caused by Graves’ disease or toxic nodular goiter ordinarily begins with treatment with an antithyroid drug, either propylthiouracil or methima-zole.538,545 These drugs deplete thyroid stores of T4 and T3 by inhibiting their synthesis. The antithyroid drug should be given for several weeks until a euthyroid state is achieved. For patients with severe cardiac manifestations, such as fl orid CHF, tachyarrhythmia, or unstable angina, more rapid control may be obtained by concurrent treatment with inor-ganic iodide, which blocks the secretion of thyroid hormones. Methimazole or propylthiouracil should be given before administration of iodide, to prevent conversion of the iodide to thyroid hormone. After a few days the iodide can be dis-continued and the patient can be maintained on the antithy-roid drug.

After the patient has been rendered euthyroid with antithyroid drugs, defi nitive therapy should be undertaken. For patients with Graves’ disease and major cardiac problems, thyroidal ablation with radioactive iodine is a pre-ferred defi nitive therapy.538 The antithyroid drug may be resumed several days after administration of radioactive iodine for continued control of symptoms. Ordinarily, several weeks are required for a dose of radioactive iodine to exert its full therapeutic effect. In some patients with Graves’ disease, a prolonged course of antithyroid drug may induce spontaneous remission.545 Surgery is an acceptable alterna-tive therapy for some patients with Graves’ disease and is often the preferred form of defi nitive treatment of toxic nodular goiter. After either radioactive iodine or surgery, hypothyroidism often ensues, eventually requiring treat-ment with T4.

Treatment of subclinical hyperthyroidism is to some degree controversial due to the lack of defi nitive data.492,500,501 There is limited evidence that treatment may facilitate spon-taneous reversion or cardioversion of atrial fi brillation to sinus rhythm.546 In the case of exogenous subclinical hyper-thyroidism, decreasing the levothyroxine dose normalizes the heart rate and results in a nonsignifi cant reduction of LVEF.547 Beta-blockers decrease atrial premature beats, LV mass index, and impaired diastolic fi lling.548

Management of amiodarone-induced thyrotoxicosis is an especially vexing problem, for several reasons: (1) hyperthy-

roidism can exacerbate the patient’s underlying problem with tachyarrhythmias; (2) antithyroid drugs and 131I are fre-quently ineffective; (3) the operative risk of thyroidectomy is often high, owing to underlying ischemic heart disease; and (4) amiodarone is an antiarrhythmic drug of last resort, so its discontinuation may be dangerous. Amiodarone-induced thyrotoxicosis usually appears after months or years of administration of the drug.549 There appear to be at least two mechanisms for development of thyrotoxicosis550: (1) fl ood-ing of iodide into an abnormal gland that has lost its ability to suppress thyroxine production in response to an iodide load; and (2) induction of thyroiditis in a previously normal gland. The former variety of amiodarone-induced thyrotoxi-cosis may be treated with potassium perchlorate together with antithyroid drugs. Patients with amiodarone-induced thyroiditis have been reported to respond to treatment with glucocorticoids.549

The management of CHF with thyrotoxicosis includes reducing volume overload with a diuretic, such as IV furo-semide, and providing control of the heart rate when rapid atrial fi brillation exists. Digoxin or another cardiac glyco-side can be given to slow the rapid ventricular rate, but in the hyperthyroid patient larger doses than usual are often required. This relative resistance has been attributed to increased clearance of the digoxin, but it may also be due to the need to inhibit the increased number of Na,K-ATPase transport units in cardiac muscle. β-adrenergic blockers such as propranolol help to control heart rate and may be useful, especially in patients without CHF. In the patient with CHF, consideration of using a beta-blocker should be carefully reviewed, since such agents may exacerbate heart failure. The decision as to whether to use the agent in a patient with CHF should be based on the extent to which increased heart rate or high-output state is believed to be the cause of the CHF. Esmolol, a rapidly acting beta-blocker, can be given IV to allow one to determine potential benefi -cial or detrimental effects of beta-blocking agents in such patients.551 As an alternative to a beta-blocking agent, a slow calcium channel blocker, such as diltiazem or verapamil, can be used to help control heart rate, although the impor-tant negative inotropic action of verapamil must be kept in mind.

Treatment of atrial fi brillation in patients with thyrotoxicosis should be directed at controlling the ven-tricular rate with cardiac glycosides and often with beta-blockers or the calcium antagonists diltiazem or verapamil. Successful cardioversion with maintenance of sinus rhythm usually cannot be achieved as long as the thyrotoxicosis continues. Spontaneous reversion of the rhythm to sinus usually occurs within 6 weeks after the return of the euthyroid state, although atrial fi brillation may persist in some older patients. One should consider the use of antico-agulant therapy in a patient with hyperthyroidism and atrial fi brillation. Anticoagulant therapy with warfarin reduces the frequency of embolic events in some patients with atrial fi brillation, but it is associated with an increased risk for hemorrhage. Nevertheless, we recommend antico-agulation for patients with atrial fi brillation and thyrotoxi-cosis with a dilated heart or heart failure and for those whose rhythm alternates between sinus rhythm and atrial fi brillation.


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Carcinoid Syndrome

Carcinoid tumors are uncommon neuroendocrine malignan-cies with an estimated incidence of two to three cases per 100,000 people per year.552,553 More often, these tumors are found incidentally at autopsy.554 Carcinoids arise from entero-chromaffi n cells, which are widely distributed throughout the body. Approximately 70% of all carcinoid tumors are located in the digestive system, most often in the terminal ileum, appendix or rectum.552,555 The bronchial tree is the second most frequent location.552 The most malignant carci-noid tumors tend to arise from the terminal ileum.

Pathophysiology

Enterochromaffi n cells, together with other neuroendocrine cells in the thyroid, lung, pancreas, pituitary, and adrenal medulla, constitute the amine precursor uptake and decar-boxylation (APUD) system described by Pearse.556 Depend-ing on their site of origin, carcinoid tumors can have the ability to secrete vasoactive amino acids and peptides. Sero-tonin (5-hydroxytryptamine, 5-HT) is the most prominent secretory product. Once released, serotonin is metabolized by monoamine oxidases in the liver, lungs and brain to 5-hydroxyindoleacetic acid (5-HIAA).557 However, 5-hydroxy-tryptophan, bradykinins, histamine, substance P, ACTH, and several other peptides can also be produced by carcinoids.558,559


Carcinoid tumors are relatively slow growing. Even with metastatic disease, patients can survive for several years. Unless the secretory products are released directly into the systemic circulation, symptoms are usually not present. The carcinoid syndrome develops in about 50% of patients, prin-cipally those with liver metastases or bronchial carcinoids, owing to bypass of fi rst-pass hepatic inactivation of secretory products. The most common clinical elements of the carci-noid syndrome are diarrhea and cutaneous fl ushes.559,560 Wheezing occurs in a few patients, principally those with bronchial carcinoid. Other endocrine manifestations, such as the ectopic ACTH syndrome, may also be present. Pellagra with dermatitis of sun-exposed areas may also be seen, sec-ondary to the high turnover of nicotinic acid by the tumor. It has not been possible to attribute particular symptoms to specifi c secretory products, with the exception of diarrhea, which appears related to serotonin.561,562 Rectal carcinoids do not exhibit secretory activity and do not produce the syn-drome. The severity of the syndrome is generally correlated with the metastatic tumor burden.560

Carcinoid crisis with severe fl ushes, diarrhea leading to dehydration, hypotension, and arrhythmias is a potential life threatening complication. It may be provoked by administra-tion of anesthetics during invasive procedures.

One of the striking endocrine manifestations of the car-cinoid syndrome involves the heart. It occurs in 20% to 70% of patients with metastatic carcinoid tumors.563–565 The typical pathologic lesions are spherical white plaques, attached to the luminal surface of the endocardium of the

right-sided chambers and of the pulmonic and tricuspid valves, as well as the great veins and coronary sinuses (Fig. 108.4). These lesions contain cells embedded in a collagenous stroma, which is rich in glycosaminoglycans but devoid of elastic fi bers.566,567 The secretory product responsible for development of these lesions may well be serotonin itself. There are correlations between the presence and severity of cardiac valvular lesions and levels of circulating serotonin565 as well as excretion of 5–HIAA.557,568 Additionally, treatment of obesity with the serotonin reuptake inhibitors fenfl ura-mine and dexfenfl uramine has been found to be associated with an increased risk of development of valvular regurgita-tion, especially of the aortic valve.569–571 Examination of the affected valves has shown lesions similar to those of the carcinoid syndrome, further strengthening the association between serotonin and valvular disease.572

A

BFIGURE 108.4. (A) View of opened tricuspid valve from a patient with carcinoid syndrome, showing thickening and contraction of leafl ets and chordae tendineae, and thickening of the atrial endocar-dium. (B) View of opened pulmonic valve from the same patient, showing thickened and retracted cusps and constriction of the val-vular ring.



The manifestations of carcinoid heart disease are those typical of tricuspid or pulmonic regurgitation, and pulmonic outfl ow obstruction.565,573 Signs and symptoms are those of RV failure secondary to severe dysfunction of tricuspid and pulmonary valves. Clinical features are often subtle early in the disease course (fatigue, exertional dyspnea) and might be attributed to the primary carcinoid disease. Carcinoid patients may also have labile blood pressure with either pro-nounced hypotension or hypertension, owing to the presence of vasoactive substances in the circulation. Serotonin can lead to tachycardia and hypertensive crisis refractory to con-ventional treatment.563 Left-sided carcinoid heart disease may be present in patients with extensive liver metastases, patent foramen ovale, or bronchial or ovarian carcinoids.574–

576 Cardiac metastases of carcinoid tumors are mainly intra-myocardial but are extremely rare.577

Diagnosis

For patients with suspected carcinoid syndrome, the diagno-sis can best be confi rmed by measurement of excretion of metabolites of serotonin in 24–hour urine collections. For diagnostic purposes, the most important metabolite is 5-HIAA.560 The specifi city of this determination is almost 100% but the sensitivity is reported to be much lower—35%.578 Urinary 5-HIAA levels can be infl uenced by food (e.g., bananas, pineapple) or medications.579 The platelet sero-tonin concentration might be a more sensitive marker of serotonin excess.580,581 Serum chromogranin A, an acidic protein present in the chromaffi n granules of neuroendo-crine cells, can be used for the detection of functioning as well as nonfunctioning tumors. It offers higher sensitivity but the specifi city is lower than urinary 5-HIAA.578

Imaging techniques for localization of carcinoid tumors include 111indium-pentreotide scintigraphy and 131I-MIBG scintigraphy, each with sensitivity of 80% to 90%.582 Com-bination of these tests increases the sensitivity to 95%.582 111Indium-pentreotide is a labeled analogue of octreotide with affi nity for somatostatin receptors located on the cell mem-branes of carcinoid tumors. A positive fi nding with this com-pound predicts response to octreotide therapy.583 131I-MIBG is an analogue of biogenic amine precursors that is taken up by chromaffi n cells and stored in the neurosecretory granules. Larger doses of this compound have been used for treatment of metastatic carcinoid tumors. Positron emission tomogra-phy with [18F]-fl uorodihydroxyphenylalanine (18F-DOPA) is a new imaging technique with promising results.584 Computed tomography scanning can be used for visualization of hepatic and extrahepatic abdominal metastases and mediastinal and pulmonary disease.558,585 Primary tumors in the small bowel can be demonstrated with barium follow through, although small tumors can easily be missed.

Transthoracic echocardiography remains the cornerstone of diagnosis of cardiac involvement. Right atrial and ven-tricular enlargement is present in up to 90% of patients with carcinoid heart disease, and ventricular septal wall motion abnormalities are seen in almost half of the cases.573 The tricuspid valve leafl ets and subvalvular structures are often thickened and retracted, leading to moderate or severe tricus-pid regurgitation.563 Characteristic pulmonary valve involve-ment includes immobility of the pulmonary valve leafl ets.

Pulmonary annular constriction may also occur, resulting in predominant pulmonary outfl ow tract obstruction.586 A new development is the measurement of serum natriuretic peptides for early detection of myocardial damage.587

Treatment

Treatment of carcinoid tumors usually involves surgical removal of accessible tumor, with removal, chemoemboliza-tion, or radiofrequency ablation of hepatic metastases when feasible.555,558,560 Diarrhea can sometimes be controlled with relatively nonspecifi c medications such as loperamide and codeine.558 Supplementation of vitamins and nicotinic acid is recommended.558 Flushes can be reduced by avoiding stress and foods known to provoke them.558 An important recent advance has been the introduction of the somatosta-tin analogues octreotide and lanreotide, which control both diarrhea and fl ushing.588,589 They have also been reported to inhibit tumor growth, but reduction in tumor volume is only occasionally observed. Octreotide is administered sub-cutaneously two to four times daily, whereas lanreotide can be injected less frequently. Long-acting analogues of octreo-tide are now available. The principal side effects of soma-tostatin analogues include malabsorption, hypomotility of the gallbladder and formation of gallstones, and mild glucose intolerance.555 Intravenous octreotide can be used for the preoperative prevention and treatment of carcinoid crisis.590 Interferon-α has been reported to induce biochemical response in 40% of patients.555,558 In general, carcinoid tumors are poorly responsive to standard antineoplastic drugs.558,560

Patients with carcinoid heart disease frequently die as a result of severe tricuspid regurgitation rather than carcino-matosis.563 In one series mean life expectancy was 1.6 years for patients with carcinoid heart disease and 4.6 years in those without cardiac damage.591 Therefore, consideration should be given to the suitability of a patient for valvular surgery even with metastatic disease. It is usually considered preferable to operate early or soon after the onset of cardiac symptoms, as delay can result in worsening of the right ventricular failure and increase the risk of surgery.563,586 Although surgical mortality is high, there is evidence to support an increase in longevity and quality of life after suc-cessful surgery.592,593

Summary

There is increased mortality from cardiovascular disease among adults with hypopituitarism, perhaps related to growth hormone defi ciency, which has been linked to known cardiovascular risk factors. Acromegaly is associated with cardiomegaly, cardiac hypertrophy, hypertension, congestive heart failure, coronary artery disease, and arrhythmias. Suc-cessful treatment of acromegaly abolishes the excess mortal-ity associated with the disease.

Arterial hypotension is the most common cardiovascular fi nding in adrenal insuffi ciency. Acute adrenal crisis should be treated with “stress” doses of intravenous hydrocortisone. Chronic adrenal insuffi ciency may require treatment with mineralocorticoids as well as glucocorticoids.


2 316 c h a p t e r 10 8

The major cardiovascular abnormalities of Cushing’s syndrome are hypertension, myocardial hypertrophy, and a prothrombotic state. Hyperaldosteronism is more commonly linked to hypertension than was previously appreciated. Hypokalemia is an important complication of hyperaldoste-ronism, but most patients are normokalemic.

There are mineralocorticoid receptors in the heart, and treatment with mineralocorticoid antagonists can benefi t individuals following myocardial infarction as well as those with congestive heart failure.

Pheochromocytoma is an uncommon cause of hyperten-sion, but has been found in 4% of individuals with adrenal nodules and hypertension. Once the diagnosis is made, phar-macologic therapy should be started promptly, before inva-sive procedures or surgery are attempted.

The “metabolic syndrome” is a constellation of meta-bolic and constitutional abnormalities that includes obesity, insulin resistance, dyslipidemia, hypertension, and pro-thrombotic and proinfl ammatory states. This syndrome carries a high risk for development of atherosclerotic disease and type 2 diabetes mellitus. There is increased cardiovas-cular mortality among individuals with diabetes mellitus. Aggressive treatment of multiple risk factors, including hyperglycemia, hypertension, and dyslipidemia, can prevent cardiovascular events. For critically ill individuals in the hospital, intensive treatment of hyperglycemia reduces mortality.

Patients with primary hyperparathyroidism have excess cardiovascular mortality.

Patients with nonthyroidal illness have low circulating thyroid hormone levels without elevation of TSH, known as the “euthyroid sick” syndrome. Treatment of this syndrome with thyroid hormone does not improve outcomes.

The major cardiovascular fi ndings of hypothyroidism are bradycardia, cardiac enlargement, hypertension, low voltage on the ECG, and sometimes pericardial effusion. “Subclini-cal hypothyroidism” is associated with increased lipids and cardiac functional abnormalities, but has not yet been con-clusively linked to excess cardiovascular events.

Both overt and subclinical hyperthyroidism are linked to atrial fi brillation, especially in older individuals.

The major clinical cardiovascular manifestations of car-cinoid syndrome are those of pulmonic regurgitation or ste-nosis, or tricuspid regurgitation, related to the presence of endocardial plaques, principally on the right side of the heart.

Acknowledgment

We thank Dr. Carlos Hamilton Jr. for his helpful suggestions.

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Endocrine Disorders and the Heart