Download Endocrine Disorders and the Heart

1
0
8
Endocrine Disorders
and the Heart
Victor R. Lavis, Michalis K. Picolos, and
James T. Willerson
Hypothalamic-Pituitary Axis . . . . . . . . . . . . . . . . . . . . .
Somatostatin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Prolactin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Adult Growth Hormone Deficiency. . . . . . . . . . . . . . . .
Acromegaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Adrenal Insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . .
Cushing’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Disorders of Mineralocorticoids . . . . . . . . . . . . . . . . . . .
2295
2296
2296
2296
2296
2298
2298
2300
Key Points
• Increased mortality from cardiovascular disease among
adults with hypopituitarism is perhaps related to growth
hormone deficiency.
• 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 successful treatment of acromegaly.
• The major cardiovascular manifestation of adrenal insufficiency is arterial hypotension.
• Major cardiovascular manifestations of Cushing’s syndrome include hypertension, myocardial hypertrophy,
and a prothrombotic state.
• The major cardiovascular manifestation of mineralocorticoid excess is hypertension, more common than previously thought.
• Hypokalemia is important in mineralocorticoid disorders, but most patients are normokalemic.
• Treatment with mineralocorticoid antagonist is beneficial following myocardial infarction and in congestive
heart failure.
• The major cardiovascular manifestation of pheochromocytoma is hypertension.
• In pheochromocytoma, prompt treatment is important.
• Metabolic syndrome is important as a risk factor for the
development of atherosclerotic disease and type 2 diabetes mellitus.
• The increased cardiovascular mortality in diabetes mellitus is reduced by aggressive treatment of multiple risk
factors.
Diseases of the Adrenal Medulla:
Pheochromocytoma . . . . . . . . . . . . . . . . . . . . . . . . . .
Diabetes Mellitus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Disorders of Calcium Metabolism . . . . . . . . . . . . . . . . .
Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Hyperthyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Carcinoid Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2301
2302
2307
2309
2312
2314
2315
• Intensive treatment of hyperglycemia reduces mortality
in critical illness.
• There is excess cardiovascular mortality in primary
hyperparathyroidism.
• The “euthyroid sick syndrome” results from nonthyroidal 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 increased lipids, but not yet conclusively linked to excess
cardiovascular events.
• Major cardiovascular manifestations of hyperthyroidism
include tachycardia and tachyarrhythmias, atrial fibrillation, increased pulse pressure, and increased cardiac contractility with decreased reserve.
• Overt and “subclinical” hyperthyroidism are linked to
atrial fibrillation.
• Major cardiovascular manifestations of carcinoid syndrome 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
influences on the cardiovascular system. The classic hormones of the anterior pituitary gland can be divided into
three classes of related polypeptides: growth hormone (GH)
and prolactin; adrenocorticotropin (ACTH) and other peptides derived from the pro-opiomelanocortin precursor; and
2295
CAR108.indd 2295
11/24/2006 10:58:03 AM
2296
chapter
the glycoprotein hormones thyrotropin (thyroid-stimulating
hormone, TSH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Synthesis and secretion of pituitary
hormones are regulated in part by hypothalamic neuropeptides. These neurohormones are transported from the hypothalamus 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, corticotropin-releasing hormone (CRH), and gonadotropin-releasing
hormone (GnRH). Adrenocorticotropin and the glycoproteins have no major cardiovascular effects except those mediated 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. Somatostatin from brain acts via the pituitary portal system to
inhibit secretion of thyrotropin and growth hormone.
In the endocrine pancreas, somatostatin inhibits secretion of insulin, glucagon, and somatostatin itself. Somatostatin also has diverse inhibitory effects on gastric and pancreatic
exocrine secretion and on gastrointestinal activity. Somatostatin receptors, of which there are five 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 somatostatin.2 However, to date there has been no description of
cardiac symptomatology in states of somatostatin excess. No
clinical syndrome of somatostatin deficiency has yet been
recognized.
Uncontrolled studies have shown purported beneficial
effects of treatment with octreotide, an analogue of somatostatin, in small numbers of patients with dilated or hypertrophic cardiomyopathy.3,4 These reports await confirmation
in larger, randomized studies.
Prolactin
There is no established cardiovascular syndrome associated
with excessive or deficient prolactin. One group of investigators 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 confirmation.
Adult Growth Hormone Deficiency
Several studies have shown increased mortality from cardiovascular disease among adults with hypopituitarism.7 Some
of this excess mortality may be related to deficiency of
growth hormone.8,9 There is growing recognition of a syn-
CAR108.indd 2296
10 8
drome of growth hormone deficiency in adults, the clinical
features of which include loss of lean body mass, increased
adiposity, muscular weakness, various psychological abnormalities, dyslipidemia, insulin resistance, abnormal endothelial 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 hypothalamic-pituitary disease of any etiology. For adults, the standard test for diagnosis of growth hormone deficiency 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 deficiency of growth hormone can be treated with
injections of recombinant human growth hormone. Treatment of adult GH deficiency increases left ventricular mass
and indices of cardiac performance and exercise tolerance,
and improves the lipid profile by increasing high-density
lipoprotein (HDL) cholesterol and reducing low-density lipoprotein (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 molecular variants of circulating GH, of which the relative physiologic significance 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., nonesterified 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 classified according to the organ systems affected. Growth of
11/24/2006 10:58:03 AM
en docr in e disor ders a n d the he a rt
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 mandible, with prognathism and dental malocclusion. Hypertrophic bone growth leads to osteoarthritis and nerve
entrapment syndromes, which may be major causes of morbidity. Manifestations of soft tissue growth include thickened, 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 hyperphosphatemia. Hyperinsulinemia, indicative of insulin resistance, is
found in most patients. However, clinical evidence of diabetes mellitus occurs in only approximately 10% of these
individuals. The principal cardiovascular manifestations of
acromegaly are cardiac hypertrophy, hypertension, premature 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-specific 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 duration 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 confirmed by pressor responses to angiotensin II
antagonists,44 enhanced pressor responsiveness to angiotensin 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
infiltration and small vessel disease of the myocardium34,37
have been found in some patients. Some histologic observations have demonstrated cellular hypertrophy, patchy
fibrosis, and myofibrillar degeneration (Fig. 108.1). Autopsy
studies of some patients after sudden death have demonstrated degenerative or inflammatory changes in the sinoatrial (SA) nerve plexus and the atrioventricular (AV)
node.37
CAR108.indd 2297
2297
FIGURE 108.1. Histologic appearance of myocardium from a
patient with acromegaly, showing hypertrophied fibers and interstitial fibrosis (IF). Mallory-Heidenhain stain, ×120.
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 integrated measurements of GH,49 are also very helpful in diagnosis.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 successful 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 analogues 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 acromegaly.61 Dopaminergic agonists, such as bromocriptine
often provide subjective relief of symptoms, but do not significantly reduce GH levels in the majority of patients.19,54
11/24/2006 10:58:03 AM
2298
chapter
Pituitary irradiation reduces GH levels slowly over several
years, during which cardiovascular disease may progress.62
Also, irradiation carries a significant risk of late development of hypopituitarism, as well as brain damage or development of brain tumors.54,62,63
10 8
reduced LV dimensions and mitral valve prolapse, which
disappeared with appropriate steroid replacement.66 Rarely,
cardiomyopathy and heart failure have been reported as presenting manifestations of adrenal insufficiency.67,68
Diagnosis
Adrenal Insufficiency
Pathophysiology
Adrenal insufficiency occurs when the secretion of adrenal
glucocorticoids or mineralocorticoids is less than is needed
by the body. Patients can develop adrenal insufficiency 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 pernicious 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 meningococcemia; (4) rarely, cancer metastatic to the adrenals; or (5)
a hereditary defect in organogenesis or the pathway of cortisol synthesis.64
Clinical Manifestations
Primary adrenal insufficiency (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. Hyponatremia, 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 deficiency, coupled with inability to excrete free water. Hyperkalemia occurs as a result of mineralocorticoid deficiency
and reduction in the glomerular filtration rate. Hypercalcemia, 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 glucocorticoid deficiency, hyponatremia may occur.
Arterial hypotension is the most common cardiovascular
finding in patients with adrenal insufficiency. 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
CAR108.indd 2298
The most convenient screening test for adrenocortical insufficiency is measurement of plasma cortisol following intravenous injection of cosyntropin, a synthetic preparation of
the 1 to 24 sequence of ACTH.69,70 For determination of the
cause of adrenocortical insufficiency, 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 insufficiency 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 resuscitation, in order to avoid pulmonary edema.72 In acute adrenal
insufficiency 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 mineralocorticoid effects. As soon as the patient’s condition stabilizes, the
dose of hydrocortisone should be reduced quickly to a maintenance dose.
For maintenance therapy, either hydrocortisone or a less
costly short-acting synthetic glucocorticoid, such as prednisone, 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 fludrocortisone. The
replacement dosage for mineralocorticoids should be determined on an individual basis. The usual replacement dosage
of fludrocortisone 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 treatment with pharmacologic doses of antiinflammatory glucocorticoids for nonendocrine conditions. Most patients with
endogenous Cushing’s syndrome have bilateral adrenal
hyperplasia with resultant excess production of glucocorti-
11/24/2006 10:58:04 AM
en docr in e disor ders a n d the he a rt
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 Cushing’s syndrome. Onset usually occurs in the third or fourth
decade of life.
Clinical Manifestations
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 fragility 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 approximately 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 hypokalemia (see below).
Clinical Cardiovascular Manifestations
Mortality is significantly 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 cardiovascular risk profiles.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 disrupted in Cushing’s syndrome, blood pressure may normally
be modulated by physiologic fluctuations of circulating
adrenal steroids.
Hemodynamic, electrocardiographic (ECG), and echocardiographic manifestations are usually associated with systemic 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 findings in patients with endogenous Cushing’s syndrome of any cause.80–82
Chronic excess production of cortisol may also lead to
hyperlipidemia, which can promote the development of
CAR108.indd 2299
2299
atherosclerosis.83 Additionally, Cushing’s syndrome is a prothrombotic state, owing to increased circulating clotting
factors and decreased fibrinolysis.84
Atrial myxomas and ACTH-independent Cushing’s syndrome 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 confirmatory test.86,87 False-positive responses
may occur with obesity, major depression, treatment with
estrogen, or alcoholism, among other conditions. Discrimination of these conditions from true Cushing’s syndrome
may be aided by measurement of plasma cortisol after suppression 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 techniques may not distinguish unequivocally between pituitary
and ectopic sources of ACTH. In this circumstance, determination 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 pituitary 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 angiotensin II, often angiotensin-converting enzyme (ACE) inhibitors. 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.
11/24/2006 10:58:04 AM
2300
chapter
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 reninangiotensin system is present in up to 30% of individuals
with hypertension.94,95 Hyperaldosteronism may arise from
an adrenal adenoma or from bilateral adrenal hyperplasia.96,97 A similar syndrome caused by an excess of 11desoxycorticosterone or other mineralocorticoids can
develop in patients with functioning adrenal tumors, Cushing’s disease, ectopic ACTH syndrome, and the 11β-hydroxylase or 17α-hydroxylase varieties of congenital adrenal
hyperplasia.96,98,99 Other conditions that produce a similar
clinical picture include (1) glucocorticoid-remediable hypertension, caused by inappropriate production of mineralocorticoids 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 epithelial 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 affinity
(type 1) mineralocorticoid receptor, which has been identified in the heart, binds cortisol and mineralocorticoids with
equal affinity. Hormonal specificity 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 fibrosis.105,106 Both experimental and clinical evidence
suggest that aldosterone has roles in the pathophysiology of
hypertension, inflammation, and endothelial dysfunction
(reviewed elsewhere107).
Clinical Manifestations
The major clinical consequences of hyperaldosteronism are
systemic arterial hypertension, hypokalemia, and metabolic
alkalosis. Although not essential for the diagnosis of hyperaldosteronism, hypokalemia is important because it can
predispose to development of frequent and complex ventricular arrhythmias. Polyuria and muscular weakness are
other significant consequences of hypokalemia. Primary
hyperaldosteronism may lead to LV hypertrophy and diastolic dysfunction, but malignant arterial hypertension is
unusual.
Diagnosis
The most useful screening procedure for primary hyperaldosteronism 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
CAR108.indd 2300
10 8
depends on the assay for renin) suggests the diagnosis, which
can be confirmed 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 important to discriminate adrenal adenoma from bilateral hyperplasia. 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 antihypertensive drugs, and preoperative response to spironolactone.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 competitive inhibitor of mineralocorticoid action, either spironolactone 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, treatment with spironolactone and other appropriate antihypertensive agents is preferred. Every effort should be made to
replete serum potassium.
Antagonism of mineralocorticoid action appears to have
benefits 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 inhibitors,119 and among individuals with left ventricular dysfunction following myocardial infarction.120 The results of these
clinical trials suggest that cardiac mineralocorticoid receptors are physiologically significant 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 antagonists, 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
11/24/2006 10:58:04 AM
en docr in e disor ders a n d the he a rt
Diseases of the Adrenal Medulla:
Pheochromocytoma
Pathophysiology
Pheochromocytomas are tumors derived from chromaffin
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 catecholamines 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 medulla, inducing the synthesis of phenylethanolamine-Nmethyltransferase, the enzyme that converts norepinephrine into epinephrine.125 Catecholamines stimulate
glycogenolysis, gluconeogenesis, and lipolysis, inhibit secretion 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 pheochromocytoma,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 pheochromocytoma is 9%130 ; however, up to 36% of pheochromocytomas 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 pheochromocytomas and medullary carcinoma of the thyroid coexist.
The MEN-IIa syndrome may include hyperparathyroidism,133 and the MEN-IIb syndrome includes marfanoid
habitus and multiple mucosal neuromas of the tongue, lips,
gastrointestinal tract, or conjunctivae, usually without parathyroid 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
identified. Pheochromocytomas may also coexist with the
phakomatoses, including neurofibromatosis and von Hippel–
Lindau disease, which includes, in addition, cerebellar or
retinal hemangioblastomas, and renal and pancreatic
tumors.
Extraadrenal pheochromocytomas arising from the sympathetic 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
CAR108.indd 2301
2 3 01
Clinical Manifestations
Pheochromocytoma is a rare cause of systemic arterial
hypertension in humans, but the morbidity and mortality
associated with these tumors is significant. 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 pheochromocytoma, 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
reflexes.137,138
Electrocardiographic and echocardiographic manifestations in patients with pheochromocytoma are usually the
result of systemic arterial hypertension. Electrocardiographic
signs include evidence of LV hypertrophy, LA enlargement,
left axis deviation, nonspecific ST-T wave changes, and ventricular and atrial arrhythmias. Occasionally, the ECG suggests 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 leaflet 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 indistinguishable 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 significant
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
findings include focal necrosis with infiltration of inflammatory cells, perivascular inflammation, and contraction band
necrosis (Fig. 108.2). Scattered areas of fibrosis 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 metanephrines, and measurement of serum catecholamines and
plasma free metanephrines (metanephrine and normetanephrine). Vanillylmandelic acid and metanephrines are
metabolites of catecholamines. Plasma-free metanephrines
have sensitivity of 97% and 99% and specificity of 96% and
82% in detecting hereditary and sporadic disease, respectively. Urinary total metanephrines offer slightly higher
specificity but are less sensitive, while fractionated urine
metanephrines have sensitivity similar to the plasma-free
11/24/2006 10:58:04 AM
2302
chapter
10 8
disease.153,156 PET using 6–[18F]fluorodopamine is a recently
introduced method that offers excellent visualization of
primary and metastatic pheochromocytoma.157,158
Treatment
FIGURE 108.2. Histologic appearance of myocardium from a
patient with pheochromocytoma, showing myocarditis, nuclear
degeneration of myocardial fibers, edema, and focal histiocytic infiltration. Hematoxylin and eosin (H&E) stain, ×285.
metanephrines but lower specificity, especially for the detection 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 pheochromocytoma include CT, MRI, nuclear scanning with 123I or 131Imetaiodobenzylguanidine (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 superior for the detection of extraadrenal, juxtacardiac, and juxtavascular tumors.131,151 Both imaging methods have poor
specificity, as low as 50%.152 Therefore, it is critically important 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 specific (95–
100%).149,153–155 SRI has poor sensitivity (25% for adrenal pheochromocytoma) but may be particularly helpful for metastatic
disease,154 paragangliomas, and MIBG scanning-negative
CAR108.indd 2302
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. Traditionally, 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 reflex tachycardia
and have shorter duration of action and reduced duration of
postoperative hypotension.130,159 During treatment with αadrenergic 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
significant tachycardia, palpitations, and catecholamineinduced arrhythmias. However, it is important to establish
α-adrenergic blockade before commencement of β-receptor
blockade. If β-receptor blockade is begun before establishment 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 norepinephrine mediated action on vascular smooth muscle.162 They
may prevent catecholamine-induced coronary vasospasm
and myocarditis, so they can be especially useful in managing patients with cardiovascular complications. They can be
used safely in normotensive patients with episodes of paroxysmal hypertension.130
Surgical removal of the tumor can be accomplished after
adequate blood pressure control is obtained. The anesthesiologist 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 constellation of metabolic and pathologic abnormalities, with a
variety of causes. Type 1 diabetes is caused by immunologically 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-
11/24/2006 10:58:04 AM
en docr in e disor ders a n d the he a rt
ronmental event, perhaps viral infection.164,167,168 Patients
with type 1 diabetes mellitus may develop other endocrine
manifestations of organ-specific autoimmunity, including
chronic lymphocytic thyroiditis, Graves’ disease, and idiopathic adrenal insufficiency. Type 1 diabetes exhibits a predilection for Caucasians, and extreme geographic variability
of prevalence. Since the peak incidence is during adolescence,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 deficiency 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 unrelated 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 accompanied by any detectable immunologic attack on the pancreas. 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 diabetes 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 ordinarily 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 severity from individual to individual, are those that are characteristic of inadequacy of insulin action. These abnormalities
include (1) inadequately restrained catabolism of stored glycogen, triglycerides, and protein; (2) inappropriately increased
gluconeogenesis; (3) decreased fractional utilization of circulating glucose by skeletal muscle and adipose tissue; and (4)
accelerated ketogenesis in patients with absolute deficiency
of insulin. These changes result in hyperglycemia, hyperlipidemia, and, in severe cases, net catabolism of protein.
People with diabetes are especially prone to develop atherosclerotic disease, particularly coronary heart disease. The
risk factors for initiation and progression of atherosclerosis
are similar to those for development of type 2 diabetes, suggesting 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
CAR108.indd 2303
2303
TABLE 108.1. Components of the metabolic syndrome
Abdominal obesity
Dyslipidemia
Small, dense LDL particles
Low HDL-cholesterol
Hypertriglyceridemia
Hypertension
Insulin resistance
Hyperglycemia
Proinflammatory state
Prothrombotic state
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 identified with certainty, although visceral obesity,
insulin resistance, and inflammation 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 cardiovascular 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 adipokines, that influence the heart and circulation as well as
insulin action (reviewed elsewhere180,181). The known adipokines include tumor necrosis factor-α (TNF-α), plasminogen
activator inhibitor-1 (PAI-1), interleukin-6 (IL-6), and monocyte chemotactic protein-1 (MCP-1), which may contribute
to systemic prothrombosis and generation of inflammatory
mediators that may promote atherosclerosis (reviewed elsewhere182). 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 function.183,184 Its relation to cardiovascular disease has not been
fully elucidated. Resistin is a secretory product of macrophages and adipose tissue that promotes insulin resistance185,186 and has been shown to influence 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
11/24/2006 10:58:04 AM
2304
chapter
cardiovascular risk factors, including elevated LDL cholesterol, hypertriglyceridemia, hypertension, increased waist
circumference, and reduced adiponectin levels.192–194 Some
studies have found increased arterial calcification and plaque
in such individuals.195,196 Accordingly, hyperandrogenism
seems to be linked to the metabolic syndrome. The relationship 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, treatments that lower circulating androgens tend to improve
insulin sensitivity to some extent.199,200
Clinical Manifestations
The prevalence of diabetes mellitus is high, and rising. It is
estimated that the lifetime risk of developing diabetes mellitus 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 individuals, 45% and 52% for men and women, respectively.201 Moreover, diabetes mellitus is an important cause of death.
Current United States mortality data suggest that the diagnosis of diabetes implies a 30% to 50% reduction of an individual’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 insufficiency,
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 hyperglycemia. Microvascular disease produces widening of basement membranes of capillaries in the retina, conjunctiva,
glomerulus, brain, pancreas, and myocardium.203–206 The
clinical significance 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 elevated triglycerides, low HDL cholesterol, and small, dense
LDL-cholesterol particles; hypertension; systemic inflammation; 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 normalized with intensive insulin therapy.218 Rarely, patients
CAR108.indd 2304
10 8
with long-standing insulin deficiency may display hyperchylomicronemia,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 cardiovascular mortality among persons with diabetes mellitus.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 first 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 sometimes 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 partially corrected by the administration of insulin.238 Diabetic
rats or rabbits develop a cardiomyopathy manifested functionally 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 function. Therefore, the explanation for development of cardiomyopathy 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
influences 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
11/24/2006 10:58:05 AM
2305
en docr in e disor ders a n d the he a rt
increased fractional shortening during systole,241 asynchrony
of early diastole,242 and slowed diastolic filling.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 fibrosis
(Fig. 108.3A), arteriolar hyalinization and narrowing of the
lumina of intramyocardial arterioles245–249 (Fig. 108.3B). Diabetic dogs and humans exhibit diastolic dysfunction associated 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 cardiomyopathy.251 Rats with experimental renovascular hypertension
and diabetes develop myocardial fibrosis 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 abnormalities in LV function in diabetics include hypertension,
increases in GH that develop in patients with difficult-tocontrol 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) activity.257,258 Increases in sarcolemmal Ca-ATPase activity might
result in a relative excess of calcium intracellularly, contributing to altered diastolic function and injury to heart muscle
cells. Some experimental studies have suggested a beneficial
effect of the slow channel calcium antagonist, verapamil in
preventing diabetes-induced myocardial changes in experimental models.259 An interesting association with cardiomyopathy is a high prevalence of either septal hypertrophy or
CHF in the infants of diabetic mothers.260 The cardiomyopathy in these infants may be transient and secondary to metabolic problems.
In patients with diabetes, cardiovascular disease, hypertension, and nephropathy are closely interrelated. Nephropathy evolves over decades, beginning with glomerular
hyperfiltration, 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 Microalbuminuria, defined as consistent excretion of more than
A
C
B
FIGURE 108.3. (A) Histologic appearance of myocardium from a
patient with diabetes, showing arteriolosclerosis and interstitial
fibrosis. (B) Histologic appearance of myocardium from a patient
with diabetes, showing hyalinization of a small arteriole. H&E
stain, ×300. Inset: Higher magnification of same arteriole (×50). (C)
CAR108.indd 2305
Histologic appearance of myocardium from a patient with diabetes,
showing circumferential periodic acid-Schiff (PAS)-positive material at the periphery of muscle fibers shown in cross-section PAS
stain, ×210.
11/24/2006 10:58:05 AM
2306
chapter
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 predicts cardiovascular mortality264,265 as well as development
of renal failure.266–269 Arterial hypertension270–272 and dyslipidemia273,274 are major risk factors for development and progression of diabetic nephropathy.
Peripheral vascular disease is a significant 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 ultrasound is more sensitive than medical history or physical
examination for detection of peripheral arterial insufficiency.278 Cerebral vascular disease and infarction occur
more frequently in people with diabetes. The renal vasculature may be affected by atherosclerosis in large vessels and
by thickening of capillary basement membranes.
Diagnosis
Diabetes mellitus is diagnosed by measurement of circulating glucose levels. The glycemic criteria for diagnosis of
diabetes have recently been revised 279 (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 population.280 Epidemiologic studies show an increased burden of
cardiovascular risk factors281 as well as increased risk of cardiovascular 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 finding of borderline hypergly-
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.
OR
Two-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.
CAR108.indd 2306
10 8
cemia or impaired glucose tolerance warrants close attention
to all of the patient’s cardiovascular risk factors, even if treatment with a hypoglycemic drug is not deemed necessary.
The diagnosis of diabetes is strengthened when there is corroborative evidence of diabetic retinopathy, peripheral and
coronary vascular disease, peripheral neuropathy, or autonomic dysfunction.
Prevention and Treatment
The Diabetes Prevention Program showed that intensive lifestyle modification, including dietary intervention and an
exercise program, delayed or prevented onset of type 2 diabetes 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 diabetes mellitus appears to be related to declining insulin secretory responsiveness. In this situation, drugs that reduce
demand for insulin might potentially block the development
of hyperglycemia. In the Diabetes Prevention Program, treatment 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
confirmed 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 prevention or retardation of the development of long-term morbidity 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 intensive 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 pressure 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 contributes to mortality among hospitalized patients.292 One
randomized study showed that vigorous treatment of capillary 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 critically 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
11/24/2006 10:58:05 AM
en docr in e disor ders a n d the he a rt
patients with type 2 diabetes mellitus, diet and regular exercise can improve insulin resistance. Several oral agents,
including sulfonylureas,296,297 meglitinides,298,299 metformin,300,301 α-glucosidase inhibitors, 302 and thiazolidinediones303,304 alone or in combination, may be effective in lowering
glycemia.305 For reasons unknown, over time there is continuing 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 inflammatory 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 fluid retention, perhaps owing to vasodilatation 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 significant edema.315–317 A recent retrospective survey found that 4.5% of patients on thiazolidinediones 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 possible to estimate the risk of heart failure attributable to thiazolidinediones. 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 individuals 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 (hypoglycemic 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 hypoglycemia 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” syndrome (reviewed elsewhere 327). The mechanism of arrhythmia 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 βadrenergic blockade.328
It is important to choose antihypertensive drugs carefully. Guidelines for choosing antihypertensive drugs have
been published.329 β-adrenergic blocking agents reduced complications 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 unresponsiveness.331–334 In patients with preserved hypoglycemic
CAR108.indd 2307
2307
responsiveness, beta-blockers will blunt the tachycardia but
not the diaphoretic response to hypoglycemia.333,334 Furthermore, nonspecific 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 microalbuminuria, defined as consistent excretion of more than
20 μg of albumin per minute or 30 μg of albumin per milligram of creatinine in a random urine specimen.263 Currently, many clinicians consider inhibition or blockade of
the renin-angiotensin-aldosterone system to be the strategy
of first choice for treatment of albuminuria and hypertension in patients with diabetes. Angiotensin-converting
enzyme inhibitors reduce albuminuria, prevent or retard
the progression of diabetic nephropathy,340,341 and reduce
mortality (reviewed elsewhere 342,343). Angiotensin II receptor
antagonists also reduce albuminuria effectively, and provide
further reduction of albuminuria when combined with ACE
inhibitors (reviewed elsewhere 344,345). It is not yet known
whether angiotensin II receptor antagonists confer a survival benefit.346 Patients started on ACE inhibitors or
angiotensin II receptor antagonists should be checked for
development of hyperkalemia and deterioration of glomerular filtration.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 confirm that reduction of
LDL cholesterol levels by treatment with statins reduces
the risk of cardiovascular events among people with diabetes.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 intensification of glycemic
management.
Disorders of Calcium Metabolism
Pathophysiology
Maintenance of the concentration of ionized calcium in
extracellular fluid (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
11/24/2006 10:58:05 AM
2308
chapter
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 filtered calcium, and stimulation 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 mediated by hypercalcemia. Given in vivo or in vitro, PTH produces 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 physiologically 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–dihydroxyvitamin 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 production of PTH. In many patients, primary hyperparathyroidism is asymptomatic and is discovered as an incidental result
of routine laboratory testing. It is most often caused by a solitary parathyroid adenoma. Less frequently, there is generalized parathyroid hyperplasia or carcinoma of the parathyroid
gland. The hypercalcemia associated with MEN-I and -II is
usually caused by parathyroid hyperplasia. Germline mutations 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 regulation 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 insufficiency
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 hypoparathyroidism are surgical removal of the glands, usually as
the unintended result of operations on the thyroid, and idiopathic hypoparathyroidism, often reflecting immunologically mediated destruction as part of one of the polyglandular
autoimmune syndromes.371 Common problems with vitamin
D include dietary deficiency, malabsorption, or some derangement in the multiorgan, multienzyme sequence that produces the fi nal active metabolite, 1,25–dihydroxyvitamin D.
Hypovitaminosis D is a widespread health problem, particularly in the elderly and individuals with darker skin.372–374
CAR108.indd 2308
10 8
Clinical Manifestations
The typical manifestations of hypercalcemia include polyuria, nocturia, nausea, vomiting, constipation, nonspecific
joint and back pains, renal stones, nephrocalcinosis, and
renal failure. There is also decreased neuromuscular excitability. In patients with very long-standing or severe hyperparathyroidism, elevation of serum alkaline phosphatase,
osteopenia, localized brown tumors of bone, and spontaneous fractures may occur, caused by the effects of PTH on
bone. In addition, elevation of urinary cyclic adenosine
monophosphate reflects 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 depletion. Deposition of calcium in the renal parenchyma may
further impair renal function. Chronic hypercalcemia can
lead to ventricular hypertrophy even in the absence of hypertension, and to deposition of calcium in the fibrous skeleton
of the heart, the valvular tissue, coronary arteries, and myocardial fibers.378,379 The probability of extracellular deposition 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 calcification; Ca × P products over 75 indicate a severe risk.
Increases in extracellular calcium lead to subsequent
increases in intracellular calcium and may provoke arrhythmias, including fibrillation 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 hyperparathyroidism confers increased mortality remains to be
determined.386
Hypocalcemia typically produces tetany and other manifestations 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 cardiomyopathy, 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
11/24/2006 10:58:05 AM
en docr in e disor ders a n d the he a rt
been linked with increased risk of hypertension,413,414 congestive 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 confirmed, the next step in differential diagnosis should be determination of PTH dependence by measurement of intact PTH with a second-generation
immunoradiometric assay that is highly specific 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 condition 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 specific treatment. Although the parathyroid
glands are usually hyperplastic, parathyroidectomy is of no
benefit 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
confirmed by demonstration of inappropriately low serum
PTH concentration together with an increased serum phosphorus 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 concentration 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, hyperparathyroidism is frequently discovered in individuals who are
relatively asymptomatic. Many of these asymptomatic
patients pursue a relatively benign course, without development of renal insufficiency, urinary stones, or significant
bone disease. At present there is no reliable criterion for
prospective identification 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% compared 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
CAR108.indd 2309
2309
serum calcium and PTH, creatinine clearance, calcium
excretion, and bone mineral density.
Calcimimetics are a new class of medications that interact with the calcium-sensing receptor on the parathyroid
cell. They increase the sensitivity of the receptor to extracellular 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 doubleblind randomized clinical study showed that treatment
with cinacalcet maintained normocalcemia over 40
weeks in a group of patients with primary hyperparathyroidism.436 Drugs of this type may become a useful alternative to parathyroidectomy in patients with primary
hyperparathyroidism.434
The first step in medical treatment of moderate or severe
symptomatic hypercalcemia of any cause should be restoration of extracellular volume with isotonic fluids.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 excessive circulating 1,25–dihydroxyvitamin D or by some hematologic 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 affinity but reversibly to plasma proteins, primarily
thyroxine-binding globulin (TBG) and secondarily transthyretin (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 specific receptors in cell nuclei. T3 receptors, 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 specific base sequences of DNA. As a
consequence of this binding, alterations occur in gene
11/24/2006 10:58:06 AM
2 310
chapter
transcription and protein synthesis, leading to many of the
biochemical and metabolic effects observed with administration 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 wholebody 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 augmented 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 myocardium. The augmented myosin ATPase activity of the hyperthyroid heart appears to contribute to the enhanced
contractile response, since the activity of this enzyme regulates the rate of turnover of actin-myosin cross-bridge linkages in cardiac muscle. The influence 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 development while shortening the duration of contraction in ventricular 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 secretion of TSH, owing to pituitary or hypothalamic disease.
With secondary hypothyroidism, the signs and symptoms
associated with deficiency 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 Amiodarone, in common with other organic iodides, inhibits the
CAR108.indd 2310
10 8
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 clearance 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. Additionally, amiodarone may produce hypothyroidism or thyrotoxicosis. In countries with abundant environmental iodine,
such as the United States, amiodarone-induced hypothyroidism 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 inflammatory thyroiditis.466
Clinical Manifestations
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 intellectual function, personality change, constipation, hoarseness,
and menstrual abnormalities. A case-control study showed
that individual symptoms such as fatigability are poor discriminators, but combinations of symptoms may identify
hypothyroid individuals.467 Typical physical findings include
cool, dry skin, slowed mentation and speech, facial puffiness,
and nonpitting edema (myxedema) of the lower extremities.
Myxedema reflects a generalized tendency to accumulation
of mucopolysaccharide-rich interstitial fluid, which may also
be manifested as puffiness of the face and eyes, ascites,
pleural or joint effusions, and pericardial effusion (see later).
Other classic findings include delayed relaxation of skeletal
muscle, as manifested in the Achilles tendon reflex, and
development of a yellowish hue to the skin, resulting from
decreased conversion of carotene to vitamin A.
Classical cardiovascular physical findings include bradycardia, cardiac enlargement, distant heart sounds, weak
arterial pulses, and nonpitting peripheral edema. Electrocardiographic findings include sinus bradycardia, atrioventricular and intraventricular conduction defects, and low voltage.
Although hypothyroidism prolongs the cardiac action potential and QT interval, potentially predisposing to cardiac irritability, ventricular arrhythmias and in rare cases torsades
de pointes468,469 arrhythmias are infrequent in hypothyroid
patients.470
Hemodynamically, the hypothyroid state is characterized 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 pressure 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 enlargement 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 pericardial effusion, which occurs in up to 30% of hypothyroid
11/24/2006 10:58:06 AM
en docr in e disor ders a n d the he a rt
patients.471 The effusion is one manifestation of a generalized
leakage of protein-rich fluid 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 atherosclerosis 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 associated with LV diastolic dysfunction at rest and with exercise,482–486 impaired flow-mediated vasodilatation indicating
endothelial dysfunction, and decreased heart rate variability
indicating autonomic dysfunction.487 Enhanced risk for atherosclerosis and increased cardiovascular risk has been
reported,482,488 perhaps related to atherogenic lipid abnormalities: mildly increased levels of total cholesterol, LDL cholesterol, and oxidized LDL.448,489–491 However, a recent systematic
review did not find 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 hypothyroidism 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 creatine 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 worsening 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-
CAR108.indd 2311
2 311
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
difficult 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 carefully in such individuals, administering small doses as indicated above and initially attempting to make the patient
comfortable rather than euthyroid. In the patient with extensive CAD and unstable angina, surgical revascularization
can be accomplished in association with low-dose thyroid
hormone replacement, followed later by full thyroid replacement during the postoperative period. Perioperative morbidity is only slightly increased for patients with mild to
moderate hypothyroidism.503,504 Therefore, necessary cardiovascular 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 situation known as the “euthyroid sick” syndrome.505–510 The
thyroid hormone levels are inversely correlated with survival.511 The low T3 values are secondary to decreased extrathyroidal 5′-deiodinase activity, with reduced conversion of
T4 to T3.508,509 The reduced T4 levels are often related to alterations in protein binding of circulating T4, causing a decrease
in total T4 but only minimal changes in the level of physiologically active free hormone.508,509,512 There may also be suppression 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 difficult cases, further diagnostic discrimination 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, circulating thyroid hormone concentration decreases and reverse
T3 increases parallel to the degree of functional impairment.515 Circulating T3 levels fall significantly in the postoperative period of patients undergoing cardiopulmonary
surgery or coronary artery bypass.516–518 This alteration in
thyroid status might modify cardiac gene expression and
11/24/2006 10:58:06 AM
2 312
chapter
contribute to impaired cardiac function.448,519 Although some
data imply that the administration of T3 may benefit some
patients with cardiovascular disease, beneficial effects on
major clinical outcome variables have not been conclusively
demonstrated.448,449,517,520
Hyperthyroidism
Pathophysiology
Thyrotoxicosis, which is defined as the state of excessive
circulating thyroid hormone, can have a variety of causes.
The most frequent are (1) production of circulating autoantibodies that activate TSH receptors, producing diffuse toxic
goiter (Graves’ disease); (2) toxic multinodular goiter or
hyperfunctioning solitary thyroid adenoma; (3) subacute thyroiditis; and (4) postpartum and “silent” thyroiditis, probably
of autoimmune cause.521 Less common causes include TSHsecreting adenoma of the pituitary, massive overproduction
of chorionic gonadotropin or another low-potency thyroid
stimulator in patients with hyperemesis gravidarum or trophoblastic neoplasm,522,523 and accidental or purposeful ingestion of thyroid hormone (thyrotoxicosis factitia).
Subclinical hyperthyroidism is characterized by subnormal or suppressed serum TSH concentration with circulating thyroid hormones in the reference range.500 It may be
due to dysfunction of the thyroid gland (endogenous subclinical hyperthyroidism) but more often is the consequence
of treatment with l-thyroxine (exogenous subclinical
hyperthyroidism).482,492
Clinical Manifestations
Patients with thyrotoxicosis typically have heat intolerance;
warm, moist skin; brittle nails and hair; tremulousness; irritability and emotional lability; increased appetite; weight
loss; resting heart rates greater than 90 beats/min; palpitations; 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 reflexes,
a prominent stare, lid lag, a wide pulse pressure, and bounding 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 relatively 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 ventricular 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 cardiovascular reserves. This effect, reversible with restoration
of the euthyroid state, can explain the reduced exercise toler-
CAR108.indd 2312
10 8
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 ultimately heart failure may develop. The tachycardia of hyperthyroidism 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 cardiovascular 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 fibrillation with rapid ventricular rate is a particular 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 fibrillation is more common among men
with thyrotoxicosis, and increases in both sexes with advancing age.538 Atrial fibrillation 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 fibrillation is a major risk factor for thromboembolism, especially stroke.537,540 About 6% of individuals
with thyrotoxicosis and atrial fibrillation 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
fibrillation.540 It is difficult to estimate the true risk of
thromboembolism in thyrotoxic atrial fibrillation, 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 hypertensive 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 development of atrial fibrillation, 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” immunoradiometric methodology provides good evidence of thyrotoxicosis. The diagnosis can be confirmed by measurement of
11/24/2006 10:58:06 AM
en docr in e disor ders a n d the he a rt
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 confirm 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 concentration are reduced. Indeed, a normal serum T3 concentration
in a patient with severe cardiac disease suggests that thyrotoxicosis 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 methimazole.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
florid CHF, tachyarrhythmia, or unstable angina, more rapid
control may be obtained by concurrent treatment with inorganic 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 discontinued and the patient can be maintained on the antithyroid drug.
After the patient has been rendered euthyroid with
antithyroid drugs, definitive therapy should be undertaken.
For patients with Graves’ disease and major cardiac
problems, thyroidal ablation with radioactive iodine is a preferred 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 alternative 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 treatment 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 spontaneous reversion or cardioversion of atrial fibrillation to
sinus rhythm.546 In the case of exogenous subclinical hyperthyroidism, decreasing the levothyroxine dose normalizes
the heart rate and results in a nonsignificant reduction of
LVEF.547 Beta-blockers decrease atrial premature beats, LV
mass index, and impaired diastolic filling.548
Management of amiodarone-induced thyrotoxicosis is an
especially vexing problem, for several reasons: (1) hyperthy-
CAR108.indd 2313
2 313
roidism can exacerbate the patient’s underlying problem
with tachyarrhythmias; (2) antithyroid drugs and 131I are frequently 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) flooding 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 thyrotoxicosis 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 furosemide, and providing control of the heart rate when rapid
atrial fibrillation exists. Digoxin or another cardiac glycoside 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 beneficial 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 important negative inotropic action of verapamil must be kept in
mind.
Treatment of atrial fibrillation in patients with
thyrotoxicosis should be directed at controlling the ventricular rate with cardiac glycosides and often with betablockers 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 fibrillation may persist in
some older patients. One should consider the use of anticoagulant therapy in a patient with hyperthyroidism and
atrial fibrillation. Anticoagulant therapy with warfarin
reduces the frequency of embolic events in some patients
with atrial fibrillation, but it is associated with an increased
risk for hemorrhage. Nevertheless, we recommend anticoagulation for patients with atrial fibrillation and thyrotoxicosis with a dilated heart or heart failure and for those
whose rhythm alternates between sinus rhythm and atrial
fibrillation.
11/24/2006 10:58:06 AM
2 314
chapter
Carcinoid Syndrome
Carcinoid tumors are uncommon neuroendocrine malignancies 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 enterochromaffin 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 carcinoid tumors tend to arise from the terminal ileum.
Pathophysiology
Enterochromaffin cells, together with other neuroendocrine
cells in the thyroid, lung, pancreas, pituitary, and adrenal
medulla, constitute the amine precursor uptake and decarboxylation (APUD) system described by Pearse.556 Depending on their site of origin, carcinoid tumors can have the
ability to secrete vasoactive amino acids and peptides. Serotonin (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 5hydroxyindoleacetic acid (5-HIAA).557 However, 5-hydroxytryptophan, bradykinins, histamine, substance P, ACTH,
and several other peptides can also be produced by
carcinoids.558,559
10 8
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 fibers.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 fenfluramine and dexfenfluramine has been found to be associated
with an increased risk of development of valvular regurgitation, 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
Clinical Manifestations
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, principally those with liver metastases or bronchial carcinoids,
owing to bypass of first-pass hepatic inactivation of secretory
products. The most common clinical elements of the carcinoid syndrome are diarrhea and cutaneous flushes.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, secondary to the high turnover of nicotinic acid by the tumor.
It has not been possible to attribute particular symptoms to
specific 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 syndrome. The severity of the syndrome is generally correlated
with the metastatic tumor burden.560
Carcinoid crisis with severe flushes, diarrhea leading to
dehydration, hypotension, and arrhythmias is a potential life
threatening complication. It may be provoked by administration of anesthetics during invasive procedures.
One of the striking endocrine manifestations of the carcinoid 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
CAR108.indd 2314
A
B
FIGURE 108.4. (A) View of opened tricuspid valve from a patient
with carcinoid syndrome, showing thickening and contraction of
leaflets and chordae tendineae, and thickening of the atrial endocardium. (B) View of opened pulmonic valve from the same patient,
showing thickened and retracted cusps and constriction of the valvular ring.
11/24/2006 10:58:07 AM
en docr in e disor ders a n d the he a rt
The manifestations of carcinoid heart disease are those
typical of tricuspid or pulmonic regurgitation, and pulmonic
outflow 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 pronounced hypotension or hypertension, owing to the presence
of vasoactive substances in the circulation. Serotonin can
lead to tachycardia and hypertensive crisis refractory to conventional 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 intramyocardial but are extremely rare.577
Diagnosis
For patients with suspected carcinoid syndrome, the diagnosis can best be confirmed by measurement of excretion of
metabolites of serotonin in 24–hour urine collections. For
diagnostic purposes, the most important metabolite is 5HIAA.560 The specificity of this determination is almost
100% but the sensitivity is reported to be much lower—
35%.578 Urinary 5-HIAA levels can be influenced by food (e.
g., bananas, pineapple) or medications.579 The platelet serotonin concentration might be a more sensitive marker of
serotonin excess.580,581 Serum chromogranin A, an acidic
protein present in the chromaffin granules of neuroendocrine cells, can be used for the detection of functioning as
well as nonfunctioning tumors. It offers higher sensitivity
but the specificity 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 Combination of these tests increases the sensitivity to 95%.582
111
Indium-pentreotide is a labeled analogue of octreotide with
affinity for somatostatin receptors located on the cell membranes of carcinoid tumors. A positive fi nding with this compound predicts response to octreotide therapy.583 131I-MIBG is
an analogue of biogenic amine precursors that is taken up by
chromaffin cells and stored in the neurosecretory granules.
Larger doses of this compound have been used for treatment
of metastatic carcinoid tumors. Positron emission tomography with [18F]-fluorodihydroxyphenylalanine (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 ventricular 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 leaflets and subvalvular structures are often
thickened and retracted, leading to moderate or severe tricuspid regurgitation.563 Characteristic pulmonary valve involvement includes immobility of the pulmonary valve leaflets.
CAR108.indd 2315
2 315
Pulmonary annular constriction may also occur, resulting
in predominant pulmonary outflow 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, chemoembolization, or radiofrequency ablation of hepatic metastases when
feasible.555,558,560 Diarrhea can sometimes be controlled with
relatively nonspecific 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 somatostatin analogues octreotide and lanreotide, which control both
diarrhea and flushing.588,589 They have also been reported to
inhibit tumor growth, but reduction in tumor volume is
only occasionally observed. Octreotide is administered subcutaneously two to four times daily, whereas lanreotide can
be injected less frequently. Long-acting analogues of octreotide are now available. The principal side effects of somatostatin 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 carcinomatosis.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 successful surgery.592,593
Summary
There is increased mortality from cardiovascular disease
among adults with hypopituitarism, perhaps related to
growth hormone deficiency, 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. Successful treatment of acromegaly abolishes the excess mortality associated with the disease.
Arterial hypotension is the most common cardiovascular
finding in adrenal insufficiency. Acute adrenal crisis should
be treated with “stress” doses of intravenous hydrocortisone.
Chronic adrenal insufficiency may require treatment with
mineralocorticoids as well as glucocorticoids.
11/24/2006 10:58:07 AM
2 316
chapter
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 hyperaldosteronism, but most patients are normokalemic.
There are mineralocorticoid receptors in the heart, and
treatment with mineralocorticoid antagonists can benefit
individuals following myocardial infarction as well as those
with congestive heart failure.
Pheochromocytoma is an uncommon cause of hypertension, but has been found in 4% of individuals with adrenal
nodules and hypertension. Once the diagnosis is made, pharmacologic therapy should be started promptly, before invasive procedures or surgery are attempted.
The “metabolic syndrome” is a constellation of metabolic and constitutional abnormalities that includes obesity,
insulin resistance, dyslipidemia, hypertension, and prothrombotic and proinflammatory states. This syndrome
carries a high risk for development of atherosclerotic disease
and type 2 diabetes mellitus. There is increased cardiovascular 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. “Subclinical hypothyroidism” is associated with increased lipids and
cardiac functional abnormalities, but has not yet been conclusively linked to excess cardiovascular events.
Both overt and subclinical hyperthyroidism are linked to
atrial fibrillation, especially in older individuals.
The major clinical cardiovascular manifestations of carcinoid syndrome are those of pulmonic regurgitation or stenosis, 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.
References
1. Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol 1999;20:157–198.
2. Day SM, Gu J, Polak JM, et al. Somatostatin in the human heart
and comparison with guinea pig and rat heart. Br Heart J
1985;53:153–157.
3. Eryol NK, Guven M, Topsakal R, et al. The effects of octreotide
in dilated cardiomyopathy: an open-label trial in 12 patients.
Jpn Heart J 2004;45:613–621.
CAR108.indd 2316
10 8
4. Gunal AI, Isik A, Celiker H, et al. Short term reduction of left
ventricular mass in primary hypertrophic cardiomyopathy by
octreotide injections. Heart 1996;76:418–421.
5. Wallaschofski H, Donne M, Eigenthaler M, et al. PRL as a novel
potent cofactor for platelet aggregation. J Clin Endocrinol
Metab 2001;86:5912–5919.
6. Wallaschofski H, Kobsar A, Koksch M, et al. Prolactin receptor
signaling during platelet activation. Horm Metab Res 2003;
35:228–235.
7. McCallum RW, Petrie JR, Dominiczak AF, et al. Growth
hormone deficiency and vascular risk. Clin Endocrinol (Oxf)
2002;57:11–24.
8. Bates AS, Van’t Hoff W, Jones PJ, et al. The effect of hypopituitarism on life expectancy. J Clin Endocrinol Metab 1996;
81:1169–1172.
9. Rosen T, Bengtsson BA. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 1990;336:285–288.
10. de Boer H, Blok GJ, Van der Veen EA. Clinical aspects of growth
hormone deficiency in adults. Endocr Rev 1995;16:63–86.
11. Colao A, Vitale G, Pivonello R, et al. The heart: an end-organ
of GH action. Eur J Endocrinol 2004;151(suppl 1):S93–101.
12. Carroll PV, Christ ER, Bengtsson BA, et al. Growth hormone
deficiency in adulthood and the effects of growth hormone
replacement: a review. Growth Hormone Research Society Scientific Committee. J Clin Endocrinol Metab 1998;83:382–395.
13. Sacca L, Cittadini A, Fazio S. Growth hormone and the heart.
Endocr Rev 1994;15:555–573.
14. Shalet SM, Toogood A, Rahim A, et al. The diagnosis of growth
hormone deficiency in children and adults. Endocr Rev 1998;
19:203–223.
15. Aimaretti G, Corneli G, Razzore P, et al. Comparison between
insulin-induced hypoglycemia and growth hormone (GH)releasing hormone + arginine as provocative tests for the diagnosis of GH deficiency in adults. J Clin Endocrinol Metab
1998;83:1615–1618.
16. Maison P, Chanson P. Cardiac effects of growth hormone in
adults with growth hormone deficiency: a meta-analysis. Circulation 2003;108:2648–2652.
17. Elgzyri T, Castenfors J, Hagg E, et al. The effects of GH replacement therapy on cardiac morphology and function, exercise
capacity and serum lipids in elderly patients with GH deficiency. Clin Endocrinol (Oxf) 2004;61:113–122.
18. Colao A, di Somma C, Pivonello R, et al. The cardiovascular
risk of adult GH deficiency (GHD) improved after GH replacement and worsened in untreated GHD: a 12-month prospective
study. J Clin Endocrinol Metab 2002;87:1088–1093.
19. Melmed S. Acromegaly. N Engl J Med 1990;322:966–977.
20. Baumann G. Growth hormone heterogeneity: genes, isohormones, variants, and binding proteins. Endocr Rev 1991;12:
424–449.
21. Klapper DG, Svoboda ME, Van Wyk JJ. Sequence analysis of
somatomedin-C: confi rmation of identity with insulin-like
growth factor I. Endocrinology 1983;112:2215–2217.
22. LeRoith D, Werner H, Beitner-Johnson D, et al. Molecular and
cellular aspects of the insulin-like growth factor I receptor.
Endocr Rev 1995;16:143–163.
23. Le Roith D, Butler AA. Insulin-like growth factors in pediatric
health and disease. J Clin Endocrinol Metab 1999;84:4355–
4361.
24. Rinderknecht E, Humbel RE. The amino acid sequence of
human insulin-like growth factor I and its structural homology
with proinsulin. J Biol Chem 1978;253:2769–2776.
25. Daughaday WH, Rotwein P. Insulin-like growth factors I and
II. Peptide, messenger ribonucleic acid and gene structures,
serum, and tissue concentrations. Endocr Rev 1989;10:68–91.
26. Isaksson O. GH, IGF-I, and growth. J Pediatr Endocrinol Metab
2004;17(suppl 4):1321–1326.
11/24/2006 10:58:07 AM
en docr in e disor ders a n d the he a rt
27. Davidson MB. Effect of growth hormone on carbohydrate and
lipid metabolism. Endocr Rev 1987;8:115–131.
28. Thuesen L, Christiansen JS, Sorensen KE, et al. Increased myocardial contractility following growth hormone administration
in normal man. An echocardiographic study. Dan Med Bull
1988;35:193–196.
29. Ezzat S, Melmed S. Clinical review 18: Are patients with acromegaly at increased risk for neoplasia? J Clin Endocrinol Metab
1991;72:245–249.
30. Ezzat S, Strom C, Melmed S. Colon polyps in acromegaly. Ann
Intern Med 1991;114:754–755.
31. Orme SM, McNally RJ, Cartwright RA, et al. Mortality and
cancer incidence in acromegaly: a retrospective cohort study.
United Kingdom Acromegaly Study Group. J Clin Endocrinol
Metab 1998;83:2730–2734.
32. McGuffi n WL Jr, Sherman BM, Roth F, et al. Acromegaly and
cardiovascular disorders. A prospective study. Ann Intern Med
1974;81:11–18.
33. Baldwin A, Cundy T, Butler J, et al. Progression of cardiovascular disease in acromegalic patients treated by external
pituitary irradiation. Acta Endocrinol (Copenh) 1985;108:
26–30.
34. Lie JT. Pathology of the heart in acromegaly: anatomic fi ndings
in 27 autopsied patients. Am Heart J 1980;100:41–52.
35. Mather HM, Boyd MJ, Jenkins JS. Heart size and function in
acromegaly. Br Heart J 1979;41:697–701.
36. Csanady M, Gaspar L, Hogye M, et al. The heart in acromegaly:
an echocardiographic study. Int J Cardiol 1983;2:349–361.
37. Rossi L, Thiene G, Caragaro L, et al. Dysrhythmias and sudden
death in acromegalic heart disease. A clinicopathologic study.
Chest 1977;72:495–498.
38. Colao A, Ferone D, Marzullo P, et al. Systemic complications
of acromegaly: epidemiology, pathogenesis, and management.
Endocr Rev 2004;25:102–152.
39. Molitch ME. Clinical manifestations of acromegaly. Endocrinol Metab Clin North Am 1992;21:597–614.
40. Souadjian JV, Schirger A. Hypertension in acromegaly. Am J
Med Sci 1967;254:629–633.
41. Moore TJ, Thein-Wai W, Dluhy RG, et al. Abnormal adrenal
and vascular responses to angiotensin II and an angiotensin
antagonist in acromegaly. J Clin Endocrinol Metab 1980;51:
215–222.
42. Cain JP, Williams GH, Dluhy RG. Plasma renin activity and
aldosterone secretion in patients with acromegaly. J Clin Endocrinol Metab 1972;34:73–81.
43. Snow MH, Piercy DA, Robson V, et al. An investigation into
the pathogenesis of hypertension in acromegaly. Clin Sci Mol
Med 1977;53:87–91.
44. Ogihara T, Hata T, Maruyama A, et al. Blood pressure response
to an angiotensin II antagonist in patients with acromegaly. J
Clin Endocrinol Metab 1979;48:159–162.
45. Colao A, Marzullo P, Di Somma C, et al. Growth hormone and
the heart. Clin Endocrinol (Oxf) 2001;54:137–154.
46. Clayton RN. Cardiovascular function in acromegaly. Endocr
Rev 2003;24:272–277.
47. Stewart PM, Smith S, Seth J, et al. Normal growth hormone
response to the 75 g oral glucose tolerance test measured by
immunoradiometric assay. Ann Clin Biochem 1989;26(pt 2):
205–206.
48. Freda PU. Current concepts in the biochemical assessment of
the patient with acromegaly. Growth Horm IGF Res 2003;13:
171–184.
49. Chang-DeMoranville BM, Jackson IM. Diagnosis and endocrine testing in acromegaly. Endocrinol Metab Clin North Am
1992;21:649–668.
50. Biochemical assessment and long-term monitoring in patients
with acromegaly: statement from a joint consensus conference
CAR108.indd 2317
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
2 317
of the Growth Hormone Research Society and the Pituitary
Society. J Clin Endocrinol Metab 2004;89:3099–3102.
Swearingen B, Barker FG, 2nd, Katznelson L, et al. Long-term
mortality after transsphenoidal surgery and adjunctive therapy
for acromegaly. J Clin Endocrinol Metab 1998;83:3419–3426.
Holdaway IM, Rajasoorya RC, Gamble GD. Factors influencing
mortality in acromegaly. J Clin Endocrinol Metab 2004;89:
667–674.
Giustina A, Barkan A, Casanueva FF, et al. Criteria for cure of
acromegaly: a consensus statement. J Clin Endocrinol Metab
2000;85:526–529.
Melmed S, Jackson I, Kleinberg D, et al. Current treatment
guidelines for acromegaly. J Clin Endocrinol Metab 1998;83:
2646–2652.
Melmed S, Casanueva FF, Cavagnini F, et al. Guidelines for
acromegaly management. J Clin Endocrinol Metab 2002;87:
4054–4058.
Clemmons DR, Chihara K, Freda PU, et al. Optimizing control
of acromegaly: integrating a growth hormone receptor antagonist into the treatment algorithm. J Clin Endocrinol Metab
2003;88:4759–4767.
Ezzat S, Snyder PJ, Young WF, et al. Octreotide treatment of
acromegaly. A randomized, multicenter study. Ann Intern Med
1992;117:711–718.
Lim MJ, Barkan AL, Buda AJ. Rapid reduction of left ventricular
hypertrophy in acromegaly after suppression of growth hormone
hypersecretion. Ann Intern Med 1992;117:719–726.
Ayuk J, Stewart SE, Stewart PM, et al. Long-term safety and
efficacy of depot long-acting somatostatin analogs for the treatment of acromegaly. J Clin Endocrinol Metab 2002;87:4142–
4146.
Ayuk J, Stewart SE, Stewart PM, et al. Efficacy of Sandostatin
LAR (long-acting somatostatin analogue) is similar in patients
with untreated acromegaly and in those previously treated with
surgery and/or radiotherapy. Clin Endocrinol (Oxf) 2004;60:
375–381.
Muller AF, Kopchick JJ, Flyvbjerg A, et al. Clinical review 166:
Growth hormone receptor antagonists. J Clin Endocrinol Metab
2004;89:1503–1511.
Williams GH, Braunwald E. Endocrine and nutritional disorders and heart disease. In: Braunwald E, ed. Heart Disease:
A Textbook of Cardiovascular Medicine. Philadelphia: WB
Saunders, 1992:1827–1830.
Molitch M. Acromegaly. In: Collu R, Brown GM, Vanloon GR,
eds. Clinical Neuroendocrinology. Boston: Blackwell Scientific
Publications, 1988:189–227.
Oelkers W. Adrenal insufficiency. N Engl J Med 1996;335:
1206–1212.
Knowlton AI, Baer L. Cardiac failure in Addison’s disease. Am
J Med 1983;74:829–836.
Fallo F, Betterle C, Budano S, et al. Regression of cardiac abnormalities after replacement therapy in Addison’s disease. Eur J
Endocrinol 1999;140:425–428.
Eto K, Koga T, Sakamoto A, et al. Adult reversible cardiomyopathy with pituitary adrenal insufficiency caused by empty
sella—a case report. Angiology 2000;51:319–323.
Afzal A, Khaja F. Reversible cardiomyopathy associated with
Addison’s disease. Can J Cardiol 2000;16:377–379.
May ME, Carey RM. Rapid adrenocorticotropic hormone test
in practice. Retrospective review. Am J Med 1985;79:679–684.
Thaler LM, Blevins LS Jr. The low dose (1–microg) adrenocorticotropin stimulation test in the evaluation of patients with
suspected central adrenal insufficiency. J Clin Endocrinol
Metab 1998;83:2726–2729.
Rose LI, Williams GH, Jagger PI, et al. The 48–hour adrenocorticotrophin infusion test for adrenocortical insufficiency. Ann
Intern Med 1970;73:49–54.
11/24/2006 10:58:07 AM
2 318
chapter
72. Conwell LS, Gray LM, Delbridge RG, et al. Reversible cardiomyopathy in paediatric Addison’s disease—a cautionary tale. J
Pediatr Endocrinol Metab 2003;16:1191–1195.
73. Cushing H. The basophil adenomas of the pituitary body and
their clinical manifestations (pituitary basophilism). Bull
Johns Hopkins Hosp 1932;50:137.
74. Baid S, Nieman LK. Glucocorticoid excess and hypertension.
Curr Hypertens Rep 2004;6:493–499.
75. Tauchmanova L, Rossi R, Biondi B, et al. Patients with subclinical Cushing’s syndrome due to adrenal adenoma have increased
cardiovascular risk. J Clin Endocrinol Metab 2002;87:4872–
4878.
76. Saruta T, Suzuki H, Handa M, et al. Multiple factors contribute
to the pathogenesis of hypertension in Cushing’s syndrome. J
Clin Endocrinol Metab 1986;62:275–279.
77. Munakata M, Imai Y, Abe K, et al. Involvement of the hypothalamo-pituitary-adrenal axis in the control of circadian
blood pressure rhythm. J Hypertens Suppl 1988;6:S44–46.
78. Piovesan A, Panarelli M, Terzolo M, et al. 24–hour profiles of
blood pressure and heart rate in Cushing’s syndrome: relationship between cortisol and cardiovascular rhythmicities. Chronobiol Int 1990;7:263–265.
79. Zelinka T, Strauch B, Pecen L, et al. Diurnal blood pressure
variation in pheochromocytoma, primary aldosteronism and
Cushing’s syndrome. J Hum Hypertens 2004;18:107–111.
80. Fallo F, Budano S, Sonino N, et al. Left ventricular structural
characteristics in Cushing’s syndrome. J Hum Hypertens
1994;8:509–513.
81. Muiesan ML, Lupia M, Salvetti M, et al. Left ventricular structural and functional characteristics in Cushing’s syndrome. J
Am Coll Cardiol 2003;41:2275–2279.
82. Sugihara N, Shimizu M, Kita Y, et al. Cardiac characteristics
and postoperative courses in Cushing’s syndrome. Am J Cardiol
1992;69:1475–1480.
83. Krieger DT. Physiopathology of Cushing’s disease. Endocr Rev
1983;4:22–43.
84. Boscaro M, Sonino N, Scarda A, et al. Anticoagulant prophylaxis
markedly reduces thromboembolic complications in Cushing’s
syndrome. J Clin Endocrinol Metab 2002;87:3662–3626.
85. Stratakis CA, Kirschner LS, Carney JA. Clinical and molecular
features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab
2001;86:4041–4046.
86. Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing’s syndrome: a consensus statement. J
Clin Endocrinol Metab 2003;88:5593–5602.
87. Nieman LK. Diagnostic tests for Cushing’s syndrome. Ann N
Y Acad Sci 2002;970:112–118.
88. Yanovski JA, Cutler GB Jr, Chrousos GP, et al. Corticotropinreleasing hormone stimulation following low-dose dexamethasone administration. A new test to distinguish Cushing’s
syndrome from pseudo-Cushing’s states. JAMA 1993;269:
2232–2238.
89. Kaye TB, Crapo L. The Cushing syndrome: an update on diagnostic tests. Ann Intern Med 1990;112:434–444.
90. Loriaux DL, Nieman L. Corticotropin-releasing hormone
testing in pituitary disease. Endocrinol Metab Clin North Am
1991;20:363–369.
91. Oldfield EH, Doppman JL, Nieman LK, et al. Petrosal sinus
sampling with and without corticotropin-releasing hormone
for the differential diagnosis of Cushing’s syndrome. N Engl J
Med 1991;325:897–905.
92. Boggan JE, Tyrrell JB, Wilson CB. Transsphenoidal microsurgical management of Cushing’s disease. Report of 100 cases. J
Neurosurg 1983;59:195–200.
93. Nolan PM, Sheeler LR, Hahn JF, et al. Therapeutic problems
with transsphenoidal pituitary surgery for Cushing’s disease.
Cleve Clin Q 1982;49:199–207.
CAR108.indd 2318
10 8
94. Olivieri O, Ciacciarelli A, Signorelli D, et al. Aldosterone to
renin ratio in a primary care setting: the Bussolengo study. J
Clin Endocrinol Metab 2004;89:4221–4226.
95. Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of
primary aldosteronism, including surgically correctable forms,
in centers from five continents. J Clin Endocrinol Metab
2004;89:1045–1050.
96. White PC. Disorders of aldosterone biosynthesis and action. N
Engl J Med 1994;331:250–258.
97. Blumenfeld JD, Sealey JE, Schlussel Y, et al. Diagnosis and
treatment of primary hyperaldosteronism. Ann Intern Med
1994;121:877–885.
98. White PC, Speiser PW. Steroid 11 beta-hydroxylase deficiency
and related disorders. Endocrinol Metab Clin North Am 1994;
23:325–339.
99. Kater CE, Biglieri EG. Disorders of steroid 17 alpha-hydroxylase
deficiency. Endocrinol Metab Clin North Am 1994;23:341–357.
100. Dluhy RG, Lifton RP. Glucocorticoid-remediable aldosteronism. Endocrinol Metab Clin North Am 1994;23:285–297.
101. Walker BR, Edwards CR. Licorice-induced hypertension and
syndromes of apparent mineralocorticoid excess. Endocrinol
Metab Clin North Am 1994;23:359–377.
102. Shimkets RA, Warnock DG, Bositis CM, et al. Liddle’s syndrome: heritable human hypertension caused by mutations in
the beta subunit of the epithelial sodium channel. Cell 1994;
79:407–414.
103. Krozowski ZS, Provencher PH, Smith RE, et al. Isozymes of 11
beta-hydroxysteroid dehydrogenase: which enzyme endows
mineralocorticoid specificity? Steroids 1994;59:116–120.
104. White PC, Mune T, Agarwal AK. 11 beta-Hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid
excess. Endocr Rev 1997;18:135–156.
105. Brilla CG, Matsubara LS, Weber KT. Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and
secondary hyperaldosteronism. J Mol Cell Cardiol 1993;25:
563–575.
106. Young M, Fullerton M, Dilley R, et al. Mineralocorticoids,
hypertension, and cardiac fibrosis. J Clin Invest 1994;93:2578–
2583.
107. Struthers AD. Aldosterone blockade in cardiovascular disease.
Heart 2004;90:1229–1234.
108. Stowasser M, Gordon RD. Primary aldosteronism. Best Pract
Res Clin Endocrinol Metab 2003;17:591–605.
109. Montori VM, Young WF Jr. Use of plasma aldosterone concentration-to-plasma renin activity ratio as a screening test for
primary aldosteronism. A systematic review of the literature.
Endocrinol Metab Clin North Am 2002;31:619–632, xi.
110. Kater CE, Biglieri EG, Brust N, et al. Stimulation and suppression of the mineralocorticoid hormones in normal subjects and
adrenocortical disorders. Endocr Rev 1989;10:149–164.
111. Young WF Jr. Pheochromocytoma and primary aldosteronism:
diagnostic approaches. Endocrinol Metab Clin North Am 1997;
26:801–827.
112. Bravo EL. Primary aldosteronism. Issues in diagnosis and management. Endocrinol Metab Clin North Am 1994;23:271–283.
113. Espiner EA, Ross DG, Yandle TG, et al. Predicting surgically
remedial primary aldosteronism: role of adrenal scanning,
posture testing, and adrenal vein sampling. J Clin Endocrinol
Metab 2003;88:3637–3644.
114. Young WF Jr. Minireview: primary aldosteronism—changing
concepts in diagnosis and treatment. Endocrinology 2003;144:
2208–2213.
115. Sawka AM, Young WF, Thompson GB, et al. Primary aldosteronism: factors associated with normalization of blood pressure after surgery. Ann Intern Med 2001;135:258–261.
116. Celen O, O’Brien MJ, Melby JC, et al. Factors influencing
outcome of surgery for primary aldosteronism. Arch Surg
1996;131:646–650.
11/24/2006 10:58:08 AM
en docr in e disor ders a n d the he a rt
117. Rose LI, Underwood RH, Newmark SR, et al. Pathophysiology
of spironolactone-induced gynecomastia. Ann Intern Med
1977;87:398–403.
118. Weinberger MH. Eplerenone: a new selective aldosterone receptor antagonist. Drugs Today (Barc) 2004;40:481–485.
119. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone
on morbidity and mortality in patients with severe heart
failure. Randomized Aldactone Evaluation Study Investigators.
N Engl J Med 1999;341:709–717.
120. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction
after myocardial infarction. N Engl J Med 2003;348:1309–
1321.
121. Tan LB, Schlosshan D, Barker D. Fiftieth anniversary of aldosterone: from discovery to cardiovascular therapy. Int J Cardiol
2004;96:321–333.
122. Meier DJ, Pitt B, Rajagopalan S. Eplerenone: will it have a role
in the treatment of acute coronary syndromes? Curr Cardiol
Rep 2004;6:259–263.
123. Davis KL, Nappi JM. The cardiovascular effects of eplerenone,
a selective aldosterone-receptor antagonist. Clin Ther
2003;25:2647–2668.
124. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004;351:543–551.
125. Wurtman RJ, Axelrod J. Control of enzymatic synthesis of
adrenaline in the adrenal medulla by adrenal cortical steroids.
J Biol Chem 1966;241:2301–2305.
126. McNeil AR, Blok BH, Koelmeyer TD, et al. Phaeochromocytomas discovered during coronial autopsies in Sydney, Melbourne
and Auckland. Aust N Z J Med 2000;30:648–652.
127. Smythe GA, Edwards G, Graham P, et al. Biochemical diagnosis of pheochromocytoma by simultaneous measurement of
urinary excretion of epinephrine and norepinephrine. Clin
Chem 1992;38:486–492.
128. Mantero F, Terzolo M, Arnaldi G, et al. A survey on adrenal
incidentaloma in Italy. Study Group on Adrenal Tumors of the
Italian Society of Endocrinology. J Clin Endocrinol Metab
2000;85:637–644.
129. Baguet JP, Hammer L, Mazzuco TL, et al. Circumstances
of discovery of phaeochromocytoma: a retrospective study
of 41 consecutive patients. Eur J Endocrinol 2004;150:681–
686.
130. Bravo EL, Tagle R. Pheochromocytoma: state-of-the-art and
future prospects. Endocr Rev 2003;24:539–553.
131. Goldstein RE, O’Neill JA Jr, Holcomb GW 3rd, et al. Clinical
experience over 48 years with pheochromocytoma. Ann Surg
1999;229:755–764; discussion 764–766.
132. Neumann HP, Bausch B, McWhinney SR, et al. Germ-line
mutations in nonsyndromic pheochromocytoma. N Engl J Med
2002;346:1459–1466.
133. Steiner AL, Goodman AD, Powers SR. Study of a kindred with
pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing’s disease: multiple endocrine neoplasia, type 2. Medicine (Baltimore) 1968;47:371–409.
134. Khairi MR, Dexter RN, Burzynski NJ, et al. Mucosal neuroma,
pheochromocytoma and medullary thyroid carcinoma: multiple endocrine neoplasia type 3. Medicine (Baltimore) 1975;
54:89–112.
135. Osranek M, Bursi F, Gura GM, et al. Echocardiographic features of pheochromocytoma of the heart. Am J Cardiol 2003;
91:640–643.
136. Bravo EL, Gifford RW Jr. Current concepts. Pheochromocytoma: diagnosis, localization and management. N Engl J Med
1984;311:1298–1303.
137. Levenson JA, Safar ME, London GM, et al. Haemodynamics in
patients with phaeochromocytoma. Clin Sci (Lond) 1980;58:
349–356.
CAR108.indd 2319
2 319
138. McManus BM, Fleury TA, Roberts WC. Fatal catecholamine
crisis in pheochromocytoma: curable cause of cardiac arrest.
Am Heart J 1981;102:930–932.
139. Cueto L, Arriaga J, Zinser J. Echocardiographic changes in
pheochromocytoma. Chest 1979;76:600–601.
140. Shub C, Cueto-Garcia L, Sheps SG, et al. Echocardiographic
fi ndings in pheochromocytoma. Am J Cardiol 1986;57:971–
975.
141. Brilakis ES, Young WF Jr, Wilson JW, et al. Reversible catecholamine-induced cardiomyopathy in a heart transplant candidate
without persistent or paroxysmal hypertension. J Heart Lung
Transplant 1999;18:376–380.
142. Dalby MC, Burke M, Radley-Smith R, et al. Pheochromocytoma presenting after cardiac transplantation for dilated cardiomyopathy. J Heart Lung Transplant 2001;20:773–775.
143. Imperato-McGinley J, Gautier T, Ehlers K, et al. Reversibility
of catecholamine-induced dilated cardiomyopathy in a child
with a pheochromocytoma. N Engl J Med 1987;316:793–797.
144. Goldstein DS, Eisenhofer G, Flynn JA, et al. Diagnosis and
localization of pheochromocytoma. Hypertension 2004;43:
907–910.
145. Van Vliet PD, Burchell HB, Titus JL. Focal myocarditis associated with pheochromocytoma. N Engl J Med 1966;274:1102–
1108.
146. Scott I, Parkes R, Cameron DP. Phaeochromocytoma and cardiomyopathy. Med J Aust 1988;148:94–96.
147. Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis
of pheochromocytoma: which test is best? JAMA 2002;287:
1427–1434.
148. Eisenhofer G, Goldstein DS, Walther MM, et al. Biochemical
diagnosis of pheochromocytoma: how to distinguish true- from
false-positive test results. J Clin Endocrinol Metab 2003;88:
2656–2666.
149. Pacak K, Linehan WM, Eisenhofer G, et al. Recent advances in
genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med 2001;134:315–329.
150. Mannelli M, Ianni L, Cilotti A, et al. Pheochromocytoma in
Italy: a multicentric retrospective study. Eur J Endocrinol 1999;
141:619–624.
151. Francis IR, Korobkin M. Pheochromocytoma. Radiol Clin
North Am 1996;34:1101–1112.
152. Maurea S, Cuocolo A, Reynolds JC, et al. Iodine-131–metaiodobenzylguanidine scintigraphy in preoperative and postoperative evaluation of paragangliomas: comparison with CT and
MRI. J Nucl Med 1993;34:173–179.
153. Ilias I, Pacak K. Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J
Clin Endocrinol Metab 2004;89:479–491.
154. van der Harst E, de Herder WW, Bruining HA, et al. [(123)I]me
taiodobenzylguanidine and [(111)In]octreotide uptake in benign
and malignant pheochromocytomas. J Clin Endocrinol Metab
2001;86:685–693.
155. Sisson JC, Shulkin BL. Nuclear medicine imaging of pheochromocytoma and neuroblastoma. Q J Nucl Med 1999;43:217–
223.
156. Limouris GS, Giannakopoulos V, Stavraka A, et al. Comparison of In-111 pentetreotide, Tc-99m (V)DMSA and I-123 mIBG
scintimaging in neural crest tumors. Anticancer Res 1997;17:
1589–1592.
157. Pacak K, Eisenhofer G, Carrasquillo JA, et al. 6–
[18F]fluorodopamine positron emission tomographic (PET)
scanning for diagnostic localization of pheochromocytoma.
Hypertension 2001;38:6–8.
158. Ilias I, Yu J, Carrasquillo JA, et al. Superiority of 6-[18F]fluorodopamine positron emission tomography versus [131I]metaiodobenzylguanidine scintigraphy in the localization of
metastatic pheochromocytoma. J Clin Endocrinol Metab
2003;88:4083–4087.
11/24/2006 10:58:08 AM
2320
chapter
159. Hoffman B. Catecholamines, sympathomimetic drugs and
adrenergic receptor antagonists. In: Hardman JG, Lombard LE,
eds. Goodman and Gillman’s The Pharmacological Basis of
Therapeutics. Philadelphia: McGaw-Hill, 2001:215–268.
160. Bravo EL. Pheochromocytoma: an approach to antihypertensive management. Ann N Y Acad Sci 2002;970:1–10.
161. Serfas D, Shoback DM, Lorell BH. Phaeochromocytoma and
hypertrophic cardiomyopathy: apparent suppression of symptoms and noradrenaline secretion by calcium-channel blockade. Lancet 1983;2:711–713.
162. Lehmann HU, Hochrein H, Witt E, et al. Hemodynamic
effects of calcium antagonists. Review. Hypertension 1983;5:
II66–73.
163. Nerup J, Mandrup-Poulsen T, Molvig J, et al. Mechanisms of
pancreatic beta-cell destruction in type I diabetes. Diabetes
Care 1988;11(suppl 1):16–23.
164. Cahill GF Jr, McDevitt HO. Insulin-dependent diabetes mellitus: the initial lesion. N Engl J Med 1981;304:1454–1465.
165. Atkinson MA, Maclaren NK. The pathogenesis of insulindependent diabetes mellitus. N Engl J Med 1994;331:1428–
1436.
166. Todd JA, Bell JI, McDevitt HO. HLA-DQ beta gene contributes
to susceptibility and resistance to insulin-dependent diabetes
mellitus. Nature 1987;329:599–604.
167. Barnett AH, Eff C, Leslie RD, et al. Diabetes in identical twins.
A study of 200 pairs. Diabetologia 1981;20:87–93.
168. Nerup J, Mandrup-Poulsen T, Molvig J. The HLA-IDDM association: implications for etiology and pathogenesis of IDDM.
Diabetes Metab Rev 1987;3:779–802.
169. Christau B, Kromann H, Andersen OO, et al. Incidence, seasonal and geographical patterns of juvenile-onset insulindependent diabetes mellitus in Denmark. Diabetologia
1977;13:281–284.
170. LaPorte RE, Fishbein HA, Drash AL, et al. The Pittsburgh
insulin-dependent diabetes mellitus (IDDM) registry. The incidence of insulin-dependent diabetes mellitus in Allegheny
County, Pennsylvania (1965–1976). Diabetes 1981;30:279–284.
171. Newman B, Selby JV, King MC, et al. Concordance for type 2
(non-insulin-dependent) diabetes mellitus in male twins. Diabetologia 1987;30:763–768.
172. Harris MI, Klein R, Welborn TA, et al. Onset of NIDDM occurs
at least 4–7 yr before clinical diagnosis. Diabetes Care
1992;15:815–819.
173. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med
Clin North Am 2004;88:787–835, ix.
174. Dickson LM, Rhodes CJ. Pancreatic beta-cell growth and survival in the onset of type 2 diabetes: a role for protein kinase
B in the Akt? Am J Physiol Endocrinol Metab 2004;287:
E192–198.
175. Bouche C, Serdy S, Kahn CR, et al. The cellular fate of glucose
and its relevance in type 2 diabetes. Endocr Rev 2004;25:807–
830.
176. Grundy SM, Hansen B, Smith SC Jr, et al. Clinical management
of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association conference on scientific issues related to
management. Circulation 2004;109:551–556.
177. Sattar N, Gaw A, Scherbakova O, et al. Metabolic syndrome
with and without C-reactive protein as a predictor of coronary
heart disease and diabetes in the West of Scotland Coronary
Prevention Study. Circulation 2003;108:414–419.
178. Ridker PM, Buring JE, Cook NR, et al. C-reactive protein, the
metabolic syndrome, and risk of incident cardiovascular events:
an 8-year follow-up of 14,719 initially healthy American
women. Circulation 2003;107:391–397.
179. Alexander CM, Landsman PB, Teutsch SM, et al. NCEP-defi ned
metabolic syndrome, diabetes, and prevalence of coronary
CAR108.indd 2320
10 8
heart disease among NHANES III participants age 50 years and
older. Diabetes 2003;52:1210–1214.
180. Ritchie SA, Ewart MA, Perry CG, et al. The role of insulin and
the adipocytokines in regulation of vascular endothelial function. Clin Sci (Lond) 2004;107:519–532.
181. Pittas AG, Joseph NA, Greenberg AS. Adipocytokines and
insulin resistance. J Clin Endocrinol Metab 2004;89:447–452.
182. Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004;92:347–355.
183. Friedman JM. The function of leptin in nutrition, weight, and
physiology. Nutr Rev 2002;60:S1–14; discussion S68–84,85–87.
184. Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin
in women with hypothalamic amenorrhea. N Engl J Med
2004;351:987–997.
185. Wolf G. Insulin resistance and obesity: resistin, a hormone
secreted by adipose tissue. Nutr Rev 2004;62:389–394.
186. Rea R, Donnelly R. Resistin: an adipocyte-derived hormone.
Has it a role in diabetes and obesity? Diabetes Obes Metab
2004;6:163–170.
187. Verma S, Li SH, Wang CH, et al. Resistin promotes endothelial
cell activation: further evidence of adipokine-endothelial interaction. Circulation 2003;108:736–740.
188. Goldstein BJ, Scalia R. Adiponectin: A novel adipokine linking
adipocytes and vascular function. J Clin Endocrinol Metab
2004;89:2563–2568.
189. Matsuzawa Y, Funahashi T, Kihara S, et al. Adiponectin and
metabolic syndrome. Arterioscler Thromb Vasc Biol 2004;24:
29–33.
190. Pischon T, Girman CJ, Hotamisligil GS, et al. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA
2004;291:1730–1737.
191. Fukuhara A, Matsuda M, Nishizawa M, et al. Visfatin: a protein
secreted by visceral fat that mimics the effects of insulin.
Science 2005307:426–430.
192. Talbott E, Clerici A, Berga SL, et al. Adverse lipid and coronary
heart disease risk profiles in young women with polycystic
ovary syndrome: results of a case-control study. J Clin Epidemiol 1998;51:415–422.
193. Wild S, Pierpoint T, McKeigue P, et al. Cardiovascular disease
in women with polycystic ovary syndrome at long-term followup: a retrospective cohort study. Clin Endocrinol (Oxf) 2000;
52:595–600.
194. Sieminska L, Marek B, Kos-Kudla B, et al. Serum adiponectin
in women with polycystic ovarian syndrome and its relation to
clinical, metabolic and endocrine parameters. J Endocrinol
Invest 2004;27:528–534.
195. Talbott EO, Guzick DS, Sutton-Tyrrell K, et al. Evidence for
association between polycystic ovary syndrome and premature
carotid atherosclerosis in middle-aged women. Arterioscler
Thromb Vasc Biol 2000;20:2414–2421.
196. Talbott EO, Zborowski JV, Rager JR, et al. Evidence for an
association between metabolic cardiovascular syndrome and
coronary and aortic calcification among women with polycystic ovary syndrome. J Clin Endocrinol Metab 2004;89:5454–
5461.
197. Dunaif A, Thomas A. Current concepts in the polycystic ovary
syndrome. Annu Rev Med 2001;52:401–419.
198. Sam S, Dunaif A. Polycystic ovary syndrome: syndrome XX?
Trends Endocrinol Metab 2003;14:365–370.
199. Moghetti P, Tosi F, Castello R, et al. The insulin resistance in
women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin
action in women. J Clin Endocrinol Metab 1996;81:952–960.
200. Ganie MA, Khurana ML, Eunice M, et al. Comparison of efficacy of spironolactone with metformin in the management of
polycystic ovary syndrome: an open-labeled study. J Clin Endocrinol Metab 2004;89:2756–2762.
11/24/2006 10:58:08 AM
en docr in e disor ders a n d the he a rt
201. Narayan KM, Boyle JP, Thompson TJ, et al. Lifetime risk for
diabetes mellitus in the United States. JAMA 2003;290:
1884–1890.
202. Klein R, Klein BE, Moss SE. Visual impairment in diabetes.
Ophthalmology 1984;91:1–9.
203. Tsilibary EC. Microvascular basement membranes in diabetes
mellitus. J Pathol 2003;200:537–546.
204. Raptis AE, Viberti G. Pathogenesis of diabetic nephropathy.
Exp Clin Endocrinol Diabetes 2001;109(suppl 2):S424–437.
205. Williamson JR, Kilo C. Capillary basement membranes in diabetes. Diabetes 1983;32(suppl 2):96–100.
206. Factor SM, Okun EM, Minase T. Capillary microaneurysms in
the human diabetic heart. N Engl J Med 1980;302:384–388.
207. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin
therapy prevents the progression of diabetic microvascular
complications in Japanese patients with non-insulin-dependent
diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995;28:103–117.
208. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. The Diabetes Control and
Complications Trial Research Group. N Engl J Med 1993;329:
977–986.
209. Intensive blood-glucose control with sulphonylureas or insulin
compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837–
853.
210. Effect of intensive blood-glucose control with metformin on
complications in overweight patients with type 2 diabetes
(UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group.
Lancet 1998;352:854–865.
211. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention
and cardiovascular disease in patients with type 2 diabetes. N
Engl J Med 2003;348:383–393.
212. Klein R, Klein BE, Moss SE. The Wisconsin epidemiological
study of diabetic retinopathy: a review. Diabetes Metab Rev
1989;5:559–570.
213. Rosenstock J, Raskin P. Diabetes and its complications: blood
glucose control vs. genetic susceptibility. Diabetes Metab Rev
1988;4:417–435.
214. Stern MP. Diabetes and cardiovascular disease. The “common
soil” hypothesis. Diabetes 1995;44:369–374.
215. Stern MP. Do non-insulin-dependent diabetes mellitus and cardiovascular disease share common antecedents? Ann Intern
Med 1996;124:110–116.
216. D’Agostino RB Jr, Hamman RF, Karter AJ, et al. Cardiovascular
disease risk factors predict the development of type 2 diabetes:
the insulin resistance atherosclerosis study. Diabetes Care
2004;27:2234–2240.
217. Festa A, D’Agostino R Jr, Tracy RP, et al. Elevated levels of
acute-phase proteins and plasminogen activator inhibitor-1
predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes 2002;51:1131–1137.
218. Dunn FL. Hyperlipidemia in diabetes mellitus. Diabetes Metab
Rev 1990;6:47–61.
219. Bagdade JD, Porte D Jr, Bierman EL. Diabetic lipemia. A form
of acquired fat-induced lipemia. N Engl J Med 1967;276:
427–433.
220. Taskinen MR. Lipoprotein lipase in diabetes. Diabetes Metab
Rev 1987;3:551–570.
221. Garg A, Grundy SM. Treatment of dyslipidemia in noninsulin-dependent diabetes mellitus with lovastatin. Am J
Cardiol 1988;62:44J–49J.
222. Kissebah AH. Low density lipoprotein metabolism in noninsulin-dependent diabetes mellitus. Diabetes Metab Rev 1987;
3:619–651.
CAR108.indd 2321
2 3 21
223. Fisher WR. Heterogeneity of plasma low density lipoproteins
manifestations of the physiologic phenomenon in man. Metabolism 1983;32:283–291.
224. Carr MC, Brunzell JD. Abdominal obesity and dyslipidemia in
the metabolic syndrome: importance of type 2 diabetes and
familial combined hyperlipidemia in coronary artery disease
risk. J Clin Endocrinol Metab 2004;89:2601–2607.
225. Gu K, Cowie CC, Harris MI. Mortality in adults with and
without diabetes in a national cohort of the U.S. population,
1971–1993. Diabetes Care 1998;21:1138–1145.
226. Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in
nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229–234.
227. Wei M, Gaskill SP, Haffner SM, et al. Effects of diabetes and
level of glycemia on all-cause and cardiovascular mortality.
The San Antonio Heart Study. Diabetes Care 1998;21:1167–
1172.
228. Stone PH, Muller JE, Hartwell T, et al. The effect of diabetes
mellitus on prognosis and serial left ventricular function after
acute myocardial infarction: contribution of both coronary
disease and diastolic left ventricular dysfunction to the adverse
prognosis. The MILIS Study Group. J Am Coll Cardiol 1989;14:
49–57.
229. Herlitz J, Malmberg K, Karlson BW, et al. Mortality and morbidity during a five-year follow-up of diabetics with myocardial
infarction. Acta Med Scand 1988;224:31–38.
230. Abbott RD, Donahue RP, Kannel WB, et al. The impact of
diabetes on survival following myocardial infarction in men
vs women. The Framingham Study. JAMA 1988;260:3456–
3460.
231. Nesto RW, Phillips RT, Kett KG, et al. Angina and exertional
myocardial ischemia in diabetic and nondiabetic patients:
assessment by exercise thallium scintigraphy. Ann Intern Med
1988;108:170–175.
232. Roy TM, Peterson HR, Snider HL, et al. Autonomic influence
on cardiovascular performance in diabetic subjects. Am J Med
1989;87:382–388.
233. Zola B, Kahn JK, Juni JE, et al. Abnormal cardiac function in
diabetic patients with autonomic neuropathy in the absence of
ischemic heart disease. J Clin Endocrinol Metab 1986;63:
208–214.
234. Pfeifer MA, Cook D, Brodsky J, et al. Quantitative evaluation
of cardiac parasympathetic activity in normal and diabetic
man. Diabetes 1982;31:339–345.
235. Ambepityia G, Kopelman PG, Ingram D, et al. Exertional myocardial ischemia in diabetes: a quantitative analysis of anginal
perceptual threshold and the influence of autonomic function.
J Am Coll Cardiol 1990;15:72–77.
236. Ewing DJ, Campbell IW, Clarke BF. The natural history of diabetic autonomic neuropathy. Q J Med 1980;49:95–108.
237. Maser RE, Mitchell BD, Vinik AI, et al. The association between
cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care 2003;26:
1895–1901.
238. Fein FS, Strobeck JE, Malhotra A, et al. Reversibility of diabetic
cardiomyopathy with insulin in rats. Circ Res 1981;49:1251–
1261.
239. Fein FS, Miller-Green B, Zola B, et al. Reversibility of diabetic
cardiomyopathy with insulin in rabbits. Am J Physiol 1986;250:
H108–113.
240. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in
congestive heart failure: the Framingham study. Am J Cardiol
1974;34:29–34.
241. Thuesen L, Christiansen JS, Mogensen CE, et al. Cardiac
hyperfunction in insulin-dependent diabetic patients developing microvascular complications. Diabetes 1988;37:851–856.
11/24/2006 10:58:08 AM
2322
chapter
242. Sanderson JE, Brown DJ, Rivellese A, et al. Diabetic cardiomyopathy? An echocardiographic study of young diabetics. Br Med
J 1978;1:404–407.
243. Ruddy TD, Shumak SL, Liu PP, et al. The relationship of cardiac
diastolic dysfunction to concurrent hormonal and metabolic
status in type I diabetes mellitus. J Clin Endocrinol Metab
1988;66:113–118.
244. Crepaldi G, Nosadini R. Diabetic cardiopathy: is it a real
entity? Diabetes Metab Rev 1988;4:273–288.
245. Sutherland CG, Fisher BM, Frier BM, et al. Endomyocardial
biopsy pathology in insulin-dependent diabetic patients with
abnormal ventricular function. Histopathology 1989;14:593–
602.
246. Rubler S, Dlugash J, Yuceoglu YZ, et al. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J
Cardiol 1972;30:595–602.
247. Fischer VW, Barner HB, Leskiw ML. Capillary basal laminar
thickness in diabetic human myocardium. Diabetes 1979;28:
713–719.
248. Fisher BM, Gillen G, Lindop GB, et al. Cardiac function and
coronary arteriography in asymptomatic type 1 (insulin-dependent) diabetic patients: evidence for a specific diabetic heart
disease. Diabetologia 1986;29:706–712.
249. Zoneraich S. Diabetes and the Heart. Charles C. Thomas,
Springfield, IL: 1978.
250. Regan TJ, Lyons MM, Ahmed SS, et al. Evidence for cardiomyopathy in familial diabetes mellitus. J Clin Invest 1977;60:
884–899.
251. Grossman E, Messerli FH. Diabetic and hypertensive heart
disease. Ann Intern Med 1996;125:304–310.
252. Fein FS, Capasso JM, Aronson RS, et al. Combined renovascular hypertension and diabetes in rats: a new preparation
of congestive cardiomyopathy. Circulation 1984;70:318–
330.
253. Factor SM, Minase T, Cho S, et al. Coronary microvascular
abnormalities in the hypertensive-diabetic rat. A primary
cause of cardiomyopathy? Am J Pathol 1984;116:9–20.
254. Factor SM, Minase T, Bhan R, et al. Hypertensive diabetic cardiomyopathy in the rat: ultrastructural features. Virchows
Arch A Pathol Anat Histopathol 1983;398:305–317.
255. Factor SM, Bhan R, Minase T, et al. Hypertensive-diabetic
cardiomyopathy in the rat: an experimental model of human
disease. Am J Pathol 1981;102:219–228.
256. Fein FS, Cho S, Malhotra A, et al. Beneficial effects of diltiazem
on the natural history of hypertensive diabetic cardiomyopathy
in rats. J Am Coll Cardiol 1991;18:1406–1417.
257. Schaffer SW, Mozaffari MS, Artman M, et al. Basis for myocardial mechanical defects associated with non-insulin-dependent
diabetes. Am J Physiol 1989;256:E25–30.
258. Borda E, Pascual J, Wald M, et al. Hypersensitivity to calcium
associated with an increased sarcolemmal Ca2+-ATPase activity in diabetic rat heart. Can J Cardiol 1988;4:97–101.
259. Afzal N, Ganguly PK, Dhalla KS, et al. Beneficial effects of
verapamil in diabetic cardiomyopathy. Diabetes 1988;37:936–
942.
260. Deorari AK, Saxena A, Singh M, et al. Echocardiographic
assessment of infants born to diabetic mothers. Arch Dis Child
1989;64:721–724.
261. Nelson RG, Bennett PH, Beck GJ, et al. Development and progression of renal disease in Pima Indians with non-insulindependent diabetes mellitus. Diabetic Renal Disease Study
Group. N Engl J Med 1996;335:1636–1642.
262. Mauer SM, Steffes MW, Brown DM. The kidney in diabetes.
Am J Med 1981;70:603–612.
263. Supplement 1. American Diabetes Association: clinical practice recommendations 2000. Diabetic nephropathy. Diabetes
Care 2000;23(suppl 1):S69–72.
CAR108.indd 2322
10 8
264. Messent JW, Elliott TG, Hill RD, et al. Prognostic significance
of microalbuminuria in insulin-dependent diabetes mellitus: a
twenty-three year follow-up study. Kidney Int 1992;41:836–
839.
265. Neil A, Hawkins M, Potok M, et al. A prospective populationbased study of microalbuminuria as a predictor of mortality in
NIDDM. Diabetes Care 1993;16:996–1003.
266. Stehouwer CD, Nauta JJ, Zeldenrust GC, et al. Urinary albumin
excretion, cardiovascular disease, and endothelial dysfunction
in non-insulin-dependent diabetes mellitus. Lancet 1992;340:
319–323.
267. Mogensen CE. Microalbuminuria predicts clinical proteinuria
and early mortality in maturity-onset diabetes. N Engl J Med
1984;310:356–360.
268. Borch-Johnsen K, Kreiner S. Proteinuria: value as predictor of
cardiovascular mortality in insulin dependent diabetes mellitus. Br Med J (Clin Res Ed) 1987;294:1651–1654.
269. Jensen T, Borch-Johnsen K, Kofoed-Enevoldsen A, et al. Coronary heart disease in young type 1 (insulin-dependent) diabetic
patients with and without diabetic nephropathy: incidence and
risk factors. Diabetologia 1987;30:144–148.
270. Parving HH. Impact of blood pressure and antihypertensive
treatment on incipient and overt nephropathy, retinopathy, and
endothelial permeability in diabetes mellitus. Diabetes Care
1991;14:260–269.
271. Rossing P, Hommel E, Smidt UM, et al. Impact of arterial blood
pressure and albuminuria on the progression of diabetic
nephropathy in IDDM patients. Diabetes 1993;42:715–719.
272. Viberti GC, Walker JD. Diabetic nephropathy: etiology and
prevention. Diabetes Metab Rev 1988;4:147–162.
273. Ravid M, Brosh D, Ravid-Safran D, et al. Main risk factors for
nephropathy in type 2 diabetes mellitus are plasma cholesterol
levels, mean blood pressure, and hyperglycemia. Arch Intern
Med 1998;158:998–1004.
274. Krolewski AS, Warram JH, Christlieb AR. Hypercholesterolemia—a determinant of renal function loss and deaths in
IDDM patients with nephropathy. Kidney Int Suppl 1994;45:
S125–131.
275. Peripheral arterial disease in people with diabetes. Diabetes
Care 2003;26:3333–3341.
276. Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb
amputation. Basis for prevention. Diabetes Care 1990;13:513–
521.
277. Jude EB, Oyibo SO, Chalmers N, et al. Peripheral arterial
disease in diabetic and nondiabetic patients: a comparison of
severity and outcome. Diabetes Care 2001;24:1433–1437.
278. Teodorescu VJ, Chen C, Morrissey N, et al. Detailed protocol
of ischemia and the use of noninvasive vascular laboratory
testing in diabetic foot ulcers. Am J Surg 2004;187:75S–80S.
279. Supplement 1. American Diabetes Association: clinical practice recommendations 2000. Diabetes Care 2000;23(suppl 1):
S5–10.
280. Hayner NS, Kjelsberg MO, Epstein FH, et al. Carbohydrate tolerance and diabetes in a total community, Tecumseh, Michigan. 1. Effects of age, sex, and test conditions on one-hour
glucose tolerance in adults. Diabetes 1965;14:413–423.
281. Piche ME, Arcand-Bosse JF, Despres JP, et al. What is a normal
glucose value? Differences in indexes of plasma glucose homeostasis in subjects with normal fasting glucose. Diabetes Care
2004;27:2470–2477.
282. Balkau B, Shipley M, Jarrett RJ, et al. High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men: 20-year follow-up in the Whitehall Study, the Paris
Prospective Study, and the Helsinki Policemen Study. Diabetes
Care 1998;21:360–367.
283. Meigs JB, Nathan DM, Wilson PW, et al. Metabolic risk factors
worsen continuously across the spectrum of nondiabetic
11/24/2006 10:58:09 AM
en docr in e disor ders a n d the he a rt
glucose tolerance. The Framingham Offspring Study. Ann
Intern Med 19(8;128:524–533.
284. Hu G. Gender difference in all-cause and cardiovascular mortality related to hyperglycaemia and newly-diagnosed diabetes.
Diabetologia 2003;46:608–617.
285. Qiao Q, Tuomilehto J, Borch-Johnsen K. Post-challenge hyperglycaemia is associated with premature death and macrovascular complications. Diabetologia 2003;46(suppl 1):M17–21.
286. Barrett-Connor E, Ferrara A. Isolated postchallenge hyperglycemia and the risk of fatal cardiovascular disease in older
women and men. The Rancho Bernardo Study. Diabetes Care
1998;21:1236–1239.
287. Glucose tolerance and cardiovascular mortality: comparison of
fasting and 2-hour diagnostic criteria. Arch Intern Med
2001;161:397–405.
288. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in
the incidence of type 2 diabetes with lifestyle intervention or
metformin. N Engl J Med 2002;346:393–403.
289. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of
pancreatic beta-cell function and prevention of type 2 diabetes
by pharmacological treatment of insulin resistance in high-risk
Hispanic women. Diabetes 2002;51:2796–2803.
290. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia
with macrovascular and microvascular complications of type
2 diabetes (UKPDS 35): prospective observational study. BMJ
2000;321:405–412.
291. Tight blood pressure control and risk of macrovascular and
microvascular complications in type 2 diabetes: UKPDS 38.
UK Prospective Diabetes Study Group. BMJ 1998;317:703–
713.
292. Umpierrez GE, Isaacs SD, Bazargan N, et al. Hyperglycemia:
an independent marker of in-hospital mortality in patients
with undiagnosed diabetes. J Clin Endocrinol Metab 2002;87:
978–982.
293. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin
therapy in the critically ill patients. N Engl J Med 2001;
345:1359–1367.
294. Pittas AG, Siegel RD, Lau J. Insulin therapy for critically ill
hospitalized patients: a meta-analysis of randomized controlled
trials. Arch Intern Med 2004;164:2005–2011.
295. Malmberg K. Prospective randomised study of intensive insulin
treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes
Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. BMJ 1997;314:1512–1515.
296. Groop LC. Sulfonylureas in NIDDM. Diabetes Care 1992;
15:737–754.
297. Melander A, Bitzen PO, Faber O, et al. Sulphonylurea antidiabetic drugs. An update of their clinical pharmacology and rational therapeutic use. Drugs 1989;37:58–72.
298. Dornhorst A. Insulinotropic meglitinide analogues. Lancet
2001;358:1709–1716.
299. Standl E, Fuchtenbusch M. The role of oral antidiabetic agents:
why and when to use an early-phase insulin secretion agent
in Type II diabetes mellitus. Diabetologia 2003;46(suppl 1):
M30–36.
300. DeFronzo RA, Goodman AM. Efficacy of metformin in patients
with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med 1995;333:
541–549.
301. Stumvoll M, Nurjhan N, Perriello G, et al. Metabolic effects of
metformin in non-insulin-dependent diabetes mellitus. N Engl
J Med 1995;333:550–554.
302. Chiasson JL, Josse RG, Hunt JA, et al. The efficacy of acarbose
in the treatment of patients with non-insulin-dependent diabetes mellitus. A multicenter controlled clinical trial. Ann Intern
Med 1994;121:928–935.
CAR108.indd 2323
2323
303. Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of
insulin resistance and type II diabetes. Diabetes 1996;45:
1661–1669.
304. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med 2004;351:
1106–1118.
305. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 2002;287:360–372.
306. U.K. prospective diabetes study 16. Overview of 6 years’ therapy
of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes 1995;44:1249–1258.
307. Schwartz S, Raskin P, Fonseca V, et al. Effect of troglitazone in
insulin-treated patients with type II diabetes mellitus. Troglitazone and Exogenous Insulin Study Group. N Engl J Med
1998;338:861–866.
308. Turner RC, Holman RR. Insulin use in NIDDM. Rationale
based on pathophysiology of disease. Diabetes Care 1990;13:
1011–1020.
309. Galloway JA. Treatment of NIDDM with insulin agonists or
substitutes. Diabetes Care 1990;13:1209–1239.
310. Miyazaki Y, Mahankali A, Wajcberg E, et al. Effect of pioglitazone on circulating adipocytokine levels and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab
2004;89:4312–4319.
311. Tiikkainen M, Hakkinen AM, Korsheninnikova E, et al. Effects
of rosiglitazone and metformin on liver fat content, hepatic
insulin resistance, insulin clearance, and gene expression in
adipose tissue in patients with type 2 diabetes. Diabetes
2004;53:2169–2176.
312. Tonelli J, Li W, Kishore P, et al. Mechanisms of early insulinsensitizing effects of thiazolidinediones in type 2 diabetes.
Diabetes 2004;53:1621–1629.
312a. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary
prevention of macrovascular events in patients with type 2
diabetes in the Proactive Study. Prospective pioglitazone clinical trial in macrovascular events: a randomised controlled
trial. Lancet 2005;366:1279–1289.
313. Idris I, Gray S, Donnelly R. Rosiglitazone and pulmonary
oedema: an acute dose-dependent effect on human endothelial
cell permeability. Diabetologia 2003;46:288–290.
314. Zanchi A, Chiolero A, Maillard M, et al. Effects of the peroxisomal proliferator-activated receptor-gamma agonist pioglitazone on renal and hormonal responses to salt in healthy men.
J Clin Endocrinol Metab 2004;89:1140–1145.
315. Avandia (rosiglitazone maleate) package insert. Philadelphia:
GlaxoSmithKline Pharmaceuticals, 2000.
316. Actos (pioglitazone hydrochloride) package insert. Lincolnshire, IL: Takeda Pharmaceuticals America, 2002.
317. Raskin P, Rendell M, Riddle MC, et al. A randomized trial of
rosiglitazone therapy in patients with inadequately controlled
insulin-treated type 2 diabetes. Diabetes Care 2001;24:1226–
1232.
318. Delea TE, Edelsberg JS, Hagiwara M, et al. Use of thiazolidinediones and risk of heart failure in people with type 2 diabetes:
a retrospective cohort study. Diabetes Care 2003;26:2983–
2989.
319. Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use,
fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American
Diabetes Association. Diabetes Care 2004;27:256–263.
320. Gerich JE, Campbell PJ. Overview of counterregulation and its
abnormalities in diabetes mellitus and other conditions. Diabetes Metab Rev 1988;4:93–111.
321. Clarke WL, Gonder-Frederick LA, Richards FE, et al.
Multifactorial origin of hypoglycemic symptom unawareness in IDDM. Association with defective glucose counterregulation and better glycemic control. Diabetes 1991;40:680–
685.
11/24/2006 10:58:09 AM
2324
chapter
322. Amiel SA, Tamborlane WV, Sacca L, et al. Hypoglycemia and
glucose counterregulation in normal and insulin-dependent
diabetic subjects. Diabetes Metab Rev 1988;4:71–89.
323. Lingenfelser T, Renn W, Sommerwerck U, et al. Compromised
hormonal counterregulation, symptom awareness, and neurophysiological function after recurrent short-term episodes of
insulin-induced hypoglycemia in IDDM patients. Diabetes
1993;42:610–618.
324. Cryer PE. Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med 2004;350:2272–2279.
325. Fanelli CG, Epifano L, Rambotti AM, et al. Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and
magnitude of most of neuroendocrine responses to, symptoms
of, and cognitive function during hypoglycemia in intensively
treated patients with short-term IDDM. Diabetes 1993;42:
1683–1689.
326. Cranston I, Lomas J, Maran A, et al. Restoration of hypoglycaemia awareness in patients with long-duration insulindependent diabetes. Lancet 1994;344:283–287.
327. Allen KV, Frier BM. Nocturnal hypoglycemia: clinical manifestations and therapeutic strategies toward prevention. Endocr
Pract 2003;9:530–543.
328. Robinson RT, Harris ND, Ireland RH, et al. Mechanisms of
abnormal cardiac repolarization during insulin-induced hypoglycemia. Diabetes 2003;52:1469–1474.
329. Arauz-Pacheco C, Parrott MA, Raskin P. Hypertension management in adults with diabetes. Diabetes Care 2004;27(suppl
1):S65–67.
330. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes:
UKPDS 39. UK Prospective Diabetes Study Group. BMJ
1998;317:713–720.
331. De Feo P, Bolli G, Perriello G, et al. The adrenergic contribution
to glucose counterregulation in type I diabetes mellitus.
Dependency on A-cell function and mediation through beta
2–adrenergic receptors. Diabetes 1983;32:887–893.
332. Newman RJ. Comparison of propranolol, metoprolol, and acebutolol on insulin-induced hypoglycaemia. Br Med J 1976;2:
447–449.
333. Lager I, Blohme G, Smith U. Effect of cardioselective and nonselective beta-blockade on the hypoglycaemic response in
insulin-dependent diabetics. Lancet 1979;1:458–462.
334. Deacon SP, Barnett D. Comparison of atenolol and propranolol
during insulin-induced hypoglycaemia. Br Med J 1976;2:
272–273.
335. Lithell HO. Effect of antihypertensive drugs on insulin, glucose,
and lipid metabolism. Diabetes Care 1991;14:203–209.
336. Pollare T, Lithell H, Selinus I, et al. Sensitivity to insulin during
treatment with atenolol and metoprolol: a randomised, double
blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients. BMJ 1989;298:1152–1157.
337. Stein PP, Black HR. Drug treatment of hypertension in patients
with diabetes mellitus. Diabetes Care 1991;14:425–448.
338. Weidmann P, Ferrier C, Saxenhofer H, et al. Serum lipoproteins
during treatment with antihypertensive drugs. Drugs 1988;
35(suppl 6):118–134.
339. Pollare T, Lithell H, Berne C. A comparison of the effects of
hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl J Med 1989;321:
868–873.
340. Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.
The Collaborative Study Group. N Engl J Med 1993;329:
1456–1462.
341. Mogensen CE, Keane WF, Bennett PH, et al. Prevention of diabetic renal disease with special reference to microalbuminuria.
Lancet 1995;346:1080–1084.
CAR108.indd 2324
10 8
342. Toto RD. Lessons learned from recent clinical trials in hypertensive diabetics: what’s good for the kidney is good for the
heart and brain. Am J Hypertens 2004;17:7S–10S; quiz A2–4.
343. de Zeeuw D. Should albuminuria be a therapeutic target in
patients with hypertension and diabetes? Am J Hypertens
2004;17:11S–15S; quiz A2–4.
344. Andersen NH, Mogensen CE. Dual blockade of the renin angiotensin system in diabetic and nondiabetic kidney disease. Curr
Hypertens Rep 2004;6:369–376.
345. Sowers JR. Treatment of hypertension in patients with diabetes. Arch Intern Med 2004;164:1850–1857.
346. Strippoli GF, Craig M, Deeks JJ, et al. Effects of angiotensin
converting enzyme inhibitors and angiotensin II receptor
antagonists on mortality and renal outcomes in diabetic
nephropathy: systematic review. BMJ 2004;329:828.
347. Toto RD. Renal insufficiency due to angiotensin-converting
enzyme inhibitors. Miner Electrolyte Metab 1994;20:193–200.
348. Garg A. Treatment of diabetic dyslipidemia. Am J Cardiol
1998;81:47B–51B.
349. Haffner SM. Dyslipidemia management in adults with diabetes. Diabetes Care 2004;27(suppl 1):S68–71.
350. Sosenko JM, Breslow JL, Miettinen OS, et al. Hyperglycemia
and plasma lipid levels: a prospective study of young insulindependent diabetic patients. N Engl J Med 1980;302:650–654.
351. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary
prevention of cardiovascular disease with atorvastatin in type
2 diabetes in the Collaborative Atorvastatin Diabetes Study
(CARDS): multicentre randomised placebo-controlled trial.
Lancet 2004;364:685–696.
352. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus
moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495–1504.
353. MRC/BHF Heart Protection Study of cholesterol lowering with
simvastatin in 20,536 high-risk individuals: a randomised
placebo-controlled trial. Lancet 2002;360:7–22.
354. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent
clinical trials for the National Cholesterol Education Program
Adult Treatment Panel III guidelines. Circulation 2004;110:227–
239.
355. Garg A, Grundy SM. Management of dyslipidemia in NIDDM.
Diabetes Care 1990;13:153–169.
356. Molnar GD, Berge KG, Rosevear JW, et al. The Effect of Nicotinic Acid in Diabetes Mellitus. Metabolism 1964;13:181–190.
357. Pocotte SL, Ehrenstein G, Fitzpatrick LA. Regulation of parathyroid hormone secretion. Endocr Rev 1991;12:291–301.
358. Khosla S, Ebeling PR, Firek AF, et al. Calcium infusion suggests a “set-point” abnormality of parathyroid gland function
in familial benign hypercalcemia and more complex disturbances in primary hyperparathyroidism. J Clin Endocrinol
Metab 1993;76:715–720.
359. Brown EM, Pollak M, Hebert SC. Sensing of extracellular Ca2+
by parathyroid and kidney cells: cloning and characterization
of an extracellular Ca(2+)-sensing receptor. Am J Kidney Dis
1995;25:506–513.
360. Brown EM, Pollak M, Seidman CE, et al. Calcium-ion-sensing
cell-surface receptors. N Engl J Med 1995;333:234–240.
361. Brown EM, Gamba G, Riccardi D, et al. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from
bovine parathyroid. Nature 1993;366:575–580.
362. Bogin E, Massry SG, Harary I. Effect of parathyroid hormone
on rat heart cells. J Clin Invest 1981;67:1215–1227.
363. Katoh Y, Klein KL, Kaplan RA, et al. Parathyroid hormone has
a positive inotropic action in the rat. Endocrinology 1981;
109:2252–2254.
364. Schluter KD, Weber M, Piper HM. Parathyroid hormone induces
protein kinase C but not adenylate cyclase in adult cardiomyocytes and regulates cyclic AMP levels via protein kinase C-
11/24/2006 10:58:09 AM
en docr in e disor ders a n d the he a rt
dependent phosphodiesterase activity. Biochem J 1995;310(pt
2):439–444.
365. Schluter KD, Piper HM. Cardiovascular actions of parathyroid
hormone and parathyroid hormone-related peptide. Cardiovasc
Res 1998;37:34–41.
366. Mok LL, Nickols GA, Thompson JC, et al. Parathyroid hormone
as a smooth muscle relaxant. Endocr Rev 1989;10:420–436.
367. Budayr AA, Nissenson RA, Klein RF, et al. Increased serum
levels of a parathyroid hormone-like protein in malignancyassociated hypercalcemia. Ann Intern Med 1989;111:807–812.
368. Henderson JE, Shustik C, Kremer R, et al. Circulating concentrations of parathyroid hormone-like peptide in malignancy and
in hyperparathyroidism. J Bone Miner Res 1990;5:105–113.
369. Beall DP, Scofield RH. Milk-alkali syndrome associated with
calcium carbonate consumption. Report of 7 patients with
parathyroid hormone levels and an estimate of prevalence
among patients hospitalized with hypercalcemia. Medicine
(Baltimore) 1995;74:89–96.
370. Pollak MR, Brown EM, Chou YH, et al. Mutations in the
human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.
Cell 1993;75:1297–1303.
371. Neufeld M, Maclaren NK, Blizzard RM. Two types of autoimmune Addison’s disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore)
1981;60:355–362.
372. Hanley DA, Davison KS. Vitamin d insufficiency in North
America. J Nutr 2005;135:332–337.
373. Levis S, Gomez A, Jimenez C, et al. Vitamin D deficiency and
seasonal variation in an adult south Florida population. J Clin
Endocrinol Metab 2005;90:1557–1562.
374. Mosekilde L. Vitamin D and the elderly. Clin Endocrinol (Oxf)
2005;62:265–281.
375. Daniels J, Goodman AD. Hypertension and hyperparathyroidism. Inverse relation of serum phosphate level and blood pressure. Am J Med 1983;75:17–23.
376. Diamond TW, Botha JR, Wing J, et al. Parathyroid hypertension. A reversible disorder. Arch Intern Med 1986;146:1709–
1712.
377. Lafferty FW, Hubay CA. Primary hyperparathyroidism. A
review of the long-term surgical and nonsurgical morbidities
as a basis for a rational approach to treatment. Arch Intern Med
1989;149:789–796.
378. Roberts WC, Waller BF. Effect of chronic hypercalcemia on the
heart. An analysis of 18 necropsy patients. Am J Med 1981;71:
371–384.
379. Slavich GA, Antonucci F, Sponza E. Primary hyperparathyroidism and angina pectoris. Int J Cardiol 1988;19:266–267.
380. Thandroyen FT, Morris AC, Hagler HK, et al. Intracellular
calcium transients and arrhythmia in isolated heart cells. Circ
Res 1991;69:810–819.
381. Hedback G, Tisell LE, Bengtsson BA, et al. Premature death in
patients operated on for primary hyperparathyroidism. World J
Surg 1990;14:829–835; discussion 836.
382. Hedback G, Oden A. Increased risk of death from primary
hyperparathyroidism—an update. Eur J Clin Invest 1998;28:
271–276.
383. Palmer M, Adami HO, Bergstrom R, et al. Mortality after
surgery for primary hyperparathyroidism: a follow-up of 441
patients operated on from 1956 to 1979. Surgery 1987;102:1–7.
384. Ogard CG, Engholm G, Almdal TP, et al. Increased mortality
in patients hospitalized with primary hyperparathyroidism
during the period 1977–1993 in Denmark. World J Surg 2004;
28:108–111.
385. Garcia de la Torre N, Wass JA, Turner HE. Parathyroid adenomas and cardiovascular risk. Endocr Relat Cancer 2003;10:
309–322.
CAR108.indd 2325
2325
386. Andersson P, Rydberg E, Willenheimer R. Primary hyperparathyroidism and heart disease—a review. Eur Heart J 2004;25:
1776–1787.
387. Lafferty FW. Primary hyperparathyroidism. Changing
clinical spectrum, prevalence of hypertension, and discriminant analysis of laboratory tests. Arch Intern Med 1981;141:
1761–1766.
388. Kovacs L, Goth MI, Szabolcs I, et al. The effect of surgical
treatment on secondary hyperaldosteronism and relative hyperinsulinemia in primary hyperparathyroidism. Eur J Endocrinol
1998;138:543–547.
389. Rayner HC, Hasking DJ. Hyperparathyroidism associated with
severe hypercalcaemia and myocardial calcification despite
minimal bone disease. Br Med J (Clin Res Ed) 1986;293:
1277–1278.
390. Stefenelli T, Wikman-Coffelt J, Wu ST, et al. Calciumdependent fluorescence transients during ventricular fibrillation. Am Heart J 1990;120:590–597.
391. Nuzzo V, Tauchmanova L, Fonderico F, et al. Increased intimamedia thickness of the carotid artery wall, normal blood pressure profile and normal left ventricular mass in subjects with
primary hyperparathyroidism. Eur J Endocrinol 2002;147:453–
459.
392. Kosch M, Hausberg M, Kisters K, et al. [Alterations of arterial
vessel wall properties in hyperparathyroidism]. Med Klin
(Munich) 2000;95:267–272.
393. Kosch M, Hausberg M, Vormbrock K, et al. Studies on flowmediated vasodilation and intima-media thickness of the brachial artery in patients with primary hyperparathyroidism.
Am J Hypertens 2000;13:759–764.
394. Kosch M, Hausberg M, Vormbrock K, et al. Impaired flowmediated vasodilation of the brachial artery in patients with
primary hyperparathyroidism improves after parathyroidectomy. Cardiovasc Res 2000;47:813–818.
395. Kosch M, Hausberg M, Barenbrock M, et al. Arterial distensibility and pulse wave velocity in patients with primary hyperparathyroidism before and after parathyroidectomy. Clin
Nephrol 2001;55:303–308.
396. Stefenelli T, Mayr H, Bergler-Klein J, et al. Primary hyperparathyroidism: incidence of cardiac abnormalities and partial
reversibility after successful parathyroidectomy. Am J Med
1993;95:197–202.
397. Stefenelli T, Abela C, Frank H, et al. Cardiac abnormalities in
patients with primary hyperparathyroidism: implications for
follow-up. J Clin Endocrinol Metab 1997;82:106–112.
398. Piovesan A, Molineri N, Casasso F, et al. Left ventricular
hypertrophy in primary hyperparathyroidism. Effects of successful parathyroidectomy. Clin Endocrinol (Oxf) 1999;50:
321–328.
399. Almqvist EG, Bondeson AG, Bondeson L, et al. Cardiac dysfunction in mild primary hyperparathyroidism assessed by
radionuclide angiography and echocardiography before and
after parathyroidectomy. Surgery 2002;132:1126–1132; discussion 1132.
400. Nappi S, Saha H, Virtanen V, et al. Left ventricular structure
and function in primary hyperparathyroidism before and after
parathyroidectomy. Cardiology 2000;93:229–233.
401. Procopio M, Magro G, Cesario F, et al. The oral glucose tolerance test reveals a high frequency of both impaired glucose
tolerance and undiagnosed type 2 diabetes mellitus in primary
hyperparathyroidism. Diabet Med 2002;19:958–961.
402. Hagstrom E, Lundgren E, Lithell H, et al. Normalized dyslipidaemia after parathyroidectomy in mild primary hyperparathyroidism: population-based study over five years. Clin
Endocrinol (Oxf) 2002;56:253–260.
403. Riggs JE. Neurologic manifestations of electrolyte disturbances. Neurol Clin 2002;20:227–239, vii.
11/24/2006 10:58:09 AM
2326
chapter
404. Diercks DB, Shumaik GM, Harrigan RA, et al. Electrocardiographic manifestations: electrolyte abnormalities. J Emerg Med
2004;27:153–160.
405. Huddle KR. Cardiac dysfunction in primary hypoparathyroidism. A report of 3 cases. S Afr Med J 1988;73:242–244.
406. Giles TD, Iteld BJ, Rives KL. The cardiomyopathy of hypoparathyroidism. Another reversible form of heart muscle disease.
Chest 1981;79:225–229.
407. Rimailho A, Bouchard P, Schaison G, et al. Improvement of
hypocalcemic cardiomyopathy by correction of serum calcium
level. Am Heart J 1985;109:611–613.
408. Levine SN, Rheams CN. Hypocalcemic heart failure. Am J
Med 1985;78:1033–1035.
409. Hurley K, Baggs D. Hypocalcemic cardiac failure in the emergency department. J Emerg Med 2005;28:155–159.
410. Avsar A, Dogan A, Tavli T. A rare cause of reversible dilated
cardiomyopathy: hypocalcemia. Echocardiography 2004;21:
609–612.
411. Csanady M, Forster T, Julesz J. Reversible impairment of myocardial function in hypoparathyroidism causing hypocalcaemia. Br Heart J 1990;63:58–60.
412. Holick MF. Vitamin D. A millennium perspective. J Cell
Biochem 2003;88:296–307.
413. Krause R, Buhring M, Hopfenmuller W, et al. Ultraviolet B and
blood pressure. Lancet 1998;352:709–710.
414. Rostand SG. Ultraviolet light may contribute to geographic and
racial blood pressure differences. Hypertension 1997;30:150–
156.
415. Zittermann A, Schleithoff SS, Tenderich G, et al. Low vitamin
D status: a contributing factor in the pathogenesis of congestive
heart failure? J Am Coll Cardiol 2003;41:105–112.
416. Olgun H, Ceviz N, Ozkan B. A case of dilated cardiomyopathy
due to nutritional vitamin D deficiency rickets. Turk J Pediatr
2003;45:152–154.
417. Cantorna MT, Hayes CE, DeLuca HF. 1,25–Dihydroxyvitamin
D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. Proc Natl Acad Sci U S A
1996;93:7861–7864.
418. Luscombe CJ, Fryer AA, French ME, et al. Exposure to
ultraviolet radiation: association with susceptibility and age
at presentation with prostate cancer. Lancet 2001;358:641–
642.
419. Grant WB. An ecologic study of dietary and solar ultraviolet-B
links to breast carcinoma mortality rates. Cancer 2002;94:
272–281.
420. Chen TC, Holick MF. Vitamin D and prostate cancer prevention and treatment. Trends Endocrinol Metab 2003;14:423–
430.
421. Hypponen E, Laara E, Reunanen A, et al. Intake of vitamin D
and risk of type 1 diabetes: a birth-cohort study. Lancet 2001;
358:1500–1503.
422. Martin KJ, Akhtar I, Gonzalez EA. Parathyroid hormone: new
assays, new receptors. Semin Nephrol 2004;24:3–9.
423. Goodman WG, Juppner H, Salusky IB, et al. Parathyroid
hormone (PTH), PTH-derived peptides, and new PTH assays in
renal osteodystrophy. Kidney Int 2003;63:1–11.
424. Heath H 3rd Familial benign (hypocalciuric) hypercalcemia. A
troublesome mimic of mild primary hyperparathyroidism.
Endocrinol Metab Clin North Am 1989;18:723–740.
425. Marx SJ, Attie MF, Levine MA, et al. The hypocalciuric or
benign variant of familial hypercalcemia: clinical and biochemical features in fi fteen kindreds. Medicine (Baltimore)
1981;60:397–412.
426. Holick MF. Sunlight and vitamin D. Both good for cardiovascular health. J Gen Intern Med 2002;17:733–735.
427. Malabanan A, Veronikis IE, Holick MF. Redefi ning vitamin D
insufficiency. Lancet 1998;351:805–806.
CAR108.indd 2326
10 8
428. Holick MF. Vitamin D importance in the prevention of cancers,
type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr
2004;79:362–371.
429. Bilezikian JP, Silverberg SJ. Clinical spectrum of primary
hyperparathyroidism. Rev Endocr Metab Disord 2000;1:237–
245.
430. Bilezikian JP, Potts JT Jr, Fuleihan Gel H, et al. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin Endocrinol
Metab 2002;87:5353–5361.
431. Silverberg SJ, Bone HG 3rd, Marriott TB, et al. Short-term inhibition of parathyroid hormone secretion by a calcium-receptor
agonist in patients with primary hyperparathyroidism. N Engl
J Med 1997;337:1506–1510.
432. Shoback DM, Bilezikian JP, Turner SA, et al. The calcimimetic
cinacalcet normalizes serum calcium in subjects with primary
hyperparathyroidism. J Clin Endocrinol Metab 2003;88:5644–
5649.
433. Ogata H, Ritz E, Odoni G, et al. Beneficial effects of calcimimetics on progression of renal failure and cardiovascular risk
factors. J Am Soc Nephrol 2003;14:959–967.
434. Bilezikian JP, Brandi ML, Rubin M, et al. Primary hyperparathyroidism: new concepts in clinical, densitometric and biochemical features. J Intern Med 2005;257:6–17.
435. Block GA, Martin KJ, de Francisco AL, et al. Cinacalcet for
secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 2004;350:1516–1525.
436. Peacock M, Bilezikian JP, Klassen PS, et al. Cinacalcet hydrochloride maintains long-term normocalcemia in patients with
primary hyperparathyroidism. J Clin Endocrinol Metab 2005;
90:135–141.
437. Attie MF. Treatment of hypercalcemia. Endocrinol Metab Clin
North Am 1989;18:807–828.
438. Bilezikian JP. Management of acute hypercalcemia. N Engl J
Med 1992;326:1196–1203.
439. Binstock ML, Mundy GR. Effect of calcitonin and glucocorticoids in combination on the hypercalcemia of malignancy.
Ann Intern Med 1980;93:269–272.
440. Mundy GR, Wilkinson R, Heath DA. Comparative study of
available medical therapy for hypercalcemia of malignancy.
Am J Med 1983;74:421–432.
441. Stewart AF. Clinical practice. Hypercalcemia associated with
cancer. N Engl J Med 2005;352:373–379.
442. Adams JS. Vitamin D metabolite-mediated hypercalcemia.
Endocrinol Metab Clin North Am 1989;18:765–778.
443. Sutton RA. Diuretics and calcium metabolism. Am J Kidney
Dis 1985;5:4–9.
444. Stier CT Jr, Itskovitz HD. Renal calcium metabolism and
diuretics. Annu Rev Pharmacol Toxicol 1986;26:101–116.
445. Heaney RP, Dowell MS, Hale CA, et al. Calcium absorption
varies within the reference range for serum 25–hydroxyvitamin D. J Am Coll Nutr 2003;22:142–146.
446. Evans RM. The steroid and thyroid hormone receptor superfamily. Science 1988;240:889–895.
447. Lazar MA. Steroid and thyroid hormone receptors. Endocrinol
Metab Clin North Am 1991;20:681–695.
448. Fazio S, Palmieri EA, Lombardi G, et al. Effects of thyroid
hormone on the cardiovascular system. Recent Prog Horm Res
2004;59:31–50.
449. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular
system. N Engl J Med 2001;344:501–509.
450. Ojamaa K, Klemperer JD, Klein I. Acute effects of thyroid
hormone on vascular smooth muscle. Thyroid 1996;6:505–512.
451. Toft AD, Boon NA. Thyroid disease and the heart. Heart
2000;84:455–460.
452. Dillmann WH. Biochemical basis of thyroid hormone action in
the heart. Am J Med 1990;88:626–630.
11/24/2006 10:58:10 AM
en docr in e disor ders a n d the he a rt
453. Carr AN, Kranias EG. Thyroid hormone regulation of calcium
cycling proteins. Thyroid 2002;12:453–457.
454. Litten RZ 3rd, Martin BJ, Low RB, et al. Altered myosin
isozyme patterns from pressure-overloaded and thyrotoxic
hypertrophied rabbit hearts. Circ Res 1982;50:856–864.
455. Holubarsch C, Goulette RP, Litten RZ, et al. The economy of
isometric force development, myosin isoenzyme pattern and
myofibrillar ATPase activity in normal and hypothyroid rat
myocardium. Circ Res 1985;56:78–86.
456. Kim D, Smith TW, Marsh JD. Effect of thyroid hormone on
slow calcium channel function in cultured chick ventricular
cells. J Clin Invest 1987;80:88–94.
457. MacKinnon R, Gwathmey JK, Allen PD, et al. Modulation by
the thyroid state of intracellular calcium and contractility in
ferret ventricular muscle. Circ Res 1988;63:1080–1089.
458. Poggesi C, Everts M, Polla B, et al. Influence of thyroid state
on mechanical restitution of rat myocardium. Circ Res 1987;
60:142–151.
459. Klein I, Hong C. Effects of thyroid hormone on cardiac size and
myosin content of the heterotopically transplanted rat heart.
J Clin Invest 1986;77:1694–1698.
460. Korecky B, Zak R, Schwartz K, et al. Role of thyroid hormone
in regulation of isomyosin composition, contractility, and size
of heterotopically isotransplanted rat heart. Circ Res 1987;
60:824–830.
461. Ross DS. Serum thyroid-stimulating hormone measurement
for assessment of thyroid function and disease. Endocrinol
Metab Clin North Am 2001;30:245–264, vii.
462. Harjai KJ, Licata AA. Effects of amiodarone on thyroid function. Ann Intern Med 1997;126:63–73.
463. Martino E, Safran M, Aghini-Lombardi F, et al. Environmental
iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med 1984;101:28–34.
464. Trip MD, Wiersinga W, Plomp TA. Incidence, predictability,
and pathogenesis of amiodarone-induced thyrotoxicosis and
hypothyroidism. Am J Med 1991;91:507–511.
465. Burger A, Dinichert D, Nicod P, et al. Effect of amiodarone on
serum triiodothyronine, reverse triiodothyronine, thyroxin,
and thyrotropin. A drug influencing peripheral metabolism of
thyroid hormones. J Clin Invest 1976;58:255–259.
466. Roti E, Minelli R, Gardini E, et al. Thyrotoxicosis followed by
hypothyroidism in patients treated with amiodarone. A possible consequence of a destructive process in the thyroid. Arch
Intern Med 1993;153:886–892.
467. Canaris GJ, Steiner JF, Ridgway EC. Do traditional symptoms
of hypothyroidism correlate with biochemical disease? J Gen
Intern Med 1997;12:544–550.
468. Fredlund BO, Olsson SB. Long QT interval and ventricular
tachycardia of “torsade de pointe” type in hypothyroidism.
Acta Med Scand 1983;213:231–235.
469. Slovis C, Jenkins R. ABC of clinical electrocardiography:
Conditions not primarily affecting the heart. BMJ 2002;324:
1320–1323.
470. Polikar R, Burger AG, Scherrer U, et al. The thyroid and the
heart. Circulation 1993;87:1435–1441.
471. Ladenson PW. Recognition and management of cardiovascular
disease related to thyroid dysfunction. Am J Med 1990;88:
638–641.
472. Fommei E, Iervasi G. The role of thyroid hormone in blood
pressure homeostasis: evidence from short-term hypothyroidism in humans. J Clin Endocrinol Metab 2002;87:1996–
2000.
473. Fletcher AK, Weetman AP. Hypertension and hypothyroidism.
J Hum Hypertens 1998;12:79–82.
474. Streeten DH, Anderson GH Jr, Howland T, et al. Effects of
thyroid function on blood pressure. Recognition of hypothyroid
hypertension. Hypertension 1988;11:78–83.
CAR108.indd 2327
2327
475. Bengel FM, Nekolla SG, Ibrahim T, et al. Effect of thyroid hormones on cardiac function, geometry, and oxidative metabolism assessed noninvasively by positron emission tomography
and magnetic resonance imaging. J Clin Endocrinol Metab
2000;85:1822–1827.
476. Graettinger JS, Muenster JJ, Checchia CS, et al. A correlation
of clinical and hemodynamic studies in patients with hypothyroidism. J Clin Invest 1958;37:502–510.
477. Wieshammer S, Keck FS, Waitzinger J, et al. Left ventricular
function at rest and during exercise in acute hypothyroidism.
Br Heart J 1988;60:204–211.
478. Vora J, O’Malley BP, Petersen S, et al. Reversible abnormalities
of myocardial relaxation in hypothyroidism. J Clin Endocrinol
Metab 1985;61:269–272.
479. Levey GS, Skelton CL, Epstein SE. Decreased myocardial
adenyl cyclase activity in hypothyroidism. J Clin Invest 1969;
48:2244–2250.
480. Zimmerman J, Yahalom J, Bar-On H. Clinical spectrum of
pericardial effusion as the presenting feature of hypothyroidism. Am Heart J 1983;106:770–771.
481. Steinberg AD. Myxedema and coronary artery disease—a comparative autopsy study. Ann Intern Med 1968;68:338–344.
482. Biondi B, Palmieri EA, Lombardi G, et al. Effects of subclinical
thyroid dysfunction on the heart. Ann Intern Med 2002;137:
904–914.
483. Brenta G, Mutti LA, Schnitman M, et al. Assessment of left
ventricular diastolic function by radionuclide ventriculography
at rest and exercise in subclinical hypothyroidism, and its
response to L-thyroxine therapy. Am J Cardiol 2003;91:1327–
1330.
484. Vitale G, Galderisi M, Lupoli GA, et al. Left ventricular myocardial impairment in subclinical hypothyroidism assessed by
a new ultrasound tool: pulsed tissue Doppler. J Clin Endocrinol
Metab 2002;87:4350–4355.
485. Di Bello V, Monzani F, Giorgi D, et al. Ultrasonic myocardial
textural analysis in subclinical hypothyroidism. J Am Soc
Echocardiogr 2000;13:832–840.
486. Biondi B, Fazio S, Palmieri EA, et al. Left ventricular diastolic
dysfunction in patients with subclinical hypothyroidism. J
Clin Endocrinol Metab 1999;84:2064–2067.
487. Kahaly GJ. Cardiovascular and atherogenic aspects of subclinical hypothyroidism. Thyroid 2000;10:665–679.
488. Hak AE, Pols HA, Visser TJ, et al. Subclinical hypothyroidism
is an independent risk factor for atherosclerosis and myocardial
infarction in elderly women: the Rotterdam Study. Ann Intern
Med 2000;132:270–278.
489. Duntas LH. Thyroid disease and lipids. Thyroid 2002;12:
287–293.
490. Duntas LH, Mantzou E, Koutras DA. Circulating levels of oxidized low-density lipoprotein in overt and mild hypothyroidism. Thyroid 2002;12:1003–1007.
491. Canaris GJ, Manowitz NR, Mayor G, et al. The Colorado
thyroid disease prevalence study. Arch Intern Med 2000;160:
526–534.
492. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid
disease: scientific review and guidelines for diagnosis and management. JAMA 2004;291:228–238.
493. Morris MS, Bostom AG, Jacques PF, et al. Hyperhomocysteinemia and hypercholesterolemia associated with hypothyroidism in the third US National Health and Nutrition Examination
Survey. Atherosclerosis 2001;155:195–200.
494. Fish LH, Mariash CN. Hyperprolactinemia, infertility, and
hypothyroidism. A case report and literature review. Arch
Intern Med 1988;148:709–711.
495. Beyer IW, Karmali R, Demeester-Mirkine N, et al. Serum creatine kinase levels in overt and subclinical hypothyroidism.
Thyroid 1998;8:1029–1031.
11/24/2006 10:58:10 AM
2328
chapter
496. Robuschi G, Safran M, Braverman LE, et al. Hypothyroidism
in the elderly. Endocr Rev 1987;8:142–153.
497. Keating FR Jr, Parkin TW, Selby JB, et al. Treatment of heart
disease associated with myxedema. Prog Cardiovasc Dis 1961;
3:364–381.
498. Fish LH, Schwartz HL, Cavanaugh J, et al. Replacement dose,
metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary
feedback in humans. N Engl J Med 1987;316:764–770.
499. Hennessey JV, Evaul JE, Tseng YC, et al. L-thyroxine dosage: a
reevaluation of therapy with contemporary preparations. Ann
Intern Med 1986;105:11–15.
500. Gharib H, Tuttle RM, Baskin HJ, et al. Subclinical thyroid
dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American
Thyroid Association, and the Endocrine Society. J Clin Endocrinol Metab 2005;90:581–585; discussion 586–587.
501. Col NF, Surks MI, Daniels GH. Subclinical thyroid disease:
clinical applications. JAMA 2004;291:239–243.
502. Roberts CG, Ladenson PW. Hypothyroidism. Lancet 2004;363:
793–803.
503. Ladenson PW, Levin AA, Ridgway EC, et al. Complications of
surgery in hypothyroid patients. Am J Med 1984;77:261–266.
504. Drucker DJ, Burrow GN. Cardiovascular surgery in the hypothyroid patient. Arch Intern Med 1985;145:1585–1587.
505. Wehmann RE, Gregerman RI, Burns WH, et al. Suppression of
thyrotropin in the low-thyroxine state of severe nonthyroidal
illness. N Engl J Med 1985;312:546–552.
506. Hamblin PS, Dyer SA, Mohr VS, et al. Relationship between
thyrotropin and thyroxine changes during recovery from severe
hypothyroxinemia of critical illness. J Clin Endocrinol Metab
1986;62:717–722.
507. Brent GA, Hershman JM. Thyroxine therapy in patients with
severe nonthyroidal illnesses and low serum thyroxine concentration. J Clin Endocrinol Metab 1986;63:1–8.
508. Chopra IJ, Hershman JM, Pardridge WM, et al. Thyroid function in nonthyroidal illnesses. Ann Intern Med 1983;98:946–
957.
509. Wartofsky L, Burman KD. Alterations in thyroid function in
patients with systemic illness: the “euthyroid sick syndrome”.
Endocr Rev 1982;3:164–217.
510. Tibaldi JM, Surks MI. Effects of nonthyroidal illness on thyroid
function. Med Clin North Am 1985;69:899–911.
511. Kaptein EM, Weiner JM, Robinson WJ, et al. Relationship of
altered thyroid hormone indices to survival in nonthyroidal
illnesses. Clin Endocrinol (Oxf) 1982;16:565–574.
512. Surks MI, Hupart KH, Pan C, et al. Normal free thyroxine in
critical nonthyroidal illnesses measured by ultrafiltration of
undiluted serum and equilibrium dialysis. J Clin Endocrinol
Metab 1988;67:1031–1039.
513. Becker RA, Vaughan GM, Ziegler MG, et al. Hypermetabolic
low triiodothyronine syndrome of burn injury. Crit Care Med
1982;10:870–875.
514. Franklyn JA, Gammage MD, Ramsden DB, et al. Thyroid status
in patients after acute myocardial infarction. Clin Sci (Lond)
1984;67:585–590.
515. Hamilton MA, Stevenson LW, Luu M, et al. Altered thyroid
hormone metabolism in advanced heart failure. J Am Coll
Cardiol 1990;16:91–95.
516. Holland FW, 2nd, Brown PS Jr, Weintraub BD, et al. Cardiopulmonary bypass and thyroid function: a “euthyroid sick syndrome”. Ann Thorac Surg 1991;52:46–50.
517. Klemperer JD, Klein I, Gomez M, et al. Thyroid hormone treatment after coronary-artery bypass surgery. N Engl J Med
1995;333:1522–1527.
518. Bettendorf M, Schmidt KG, Tiefenbacher U, et al. Transient
secondary hypothyroidism in children after cardiac surgery.
Pediatr Res 1997;41:375–379.
CAR108.indd 2328
10 8
519. Klein I, Ojamaa K. Thyroid hormone treatment of congestive
heart failure. Am J Cardiol 1998;81:490–491.
520. Klemperer JD. Thyroid hormone and cardiac surgery. Thyroid
2002;12:517–521.
521. Vargas MT, Briones-Urbina R, Gladman D, et al. Antithyroid
microsomal autoantibodies and HLA-DR5 are associated with
postpartum thyroid dysfunction: evidence supporting an autoimmune pathogenesis. J Clin Endocrinol Metab 1988;67:327–
333.
522. Becks GP, Burrow GN. Thyroid disease and pregnancy. Med
Clin North Am 1991;75:121–150.
523. Lazarus JH, Othman S. Thyroid disease in relation to pregnancy. Clin Endocrinol (Oxf) 1991;34:91–98.
524. DeGroot WJ, Leonard JJ. Hyperthyroidism as a high cardiac
output state. Am Heart J 1970;79:265–275.
525. Sandler G, Wilson GM. The nature and prognosis of heart
disease in thyrotoxicosis. A review of 150 patients treated with
131 I. Q J Med 1959;28:347–369.
526. Ikram H. The nature and prognosis of thyrotoxic heart disease.
Q J Med 1985;54:19–28.
527. Forfar JC, Muir AL, Sawers SA, et al. Abnormal left ventricular
function in hyperthyroidism: evidence for a possible reversible
cardiomyopathy. N Engl J Med 1982;307:1165–1170.
528. Kahaly GJ, Kampmann C, Mohr-Kahaly S. Cardiovascular
hemodynamics and exercise tolerance in thyroid disease.
Thyroid 2002;12:473–481.
529. Biondi B, Fazio S, Cuocolo A, et al. Impaired cardiac reserve
and exercise capacity in patients receiving long-term thyrotropin suppressive therapy with levothyroxine. J Clin Endocrinol
Metab 1996;81:4224–4228.
530. Dillmann WH. Cellular action of thyroid hormone on the
heart. Thyroid 2002;12:447–452.
531. Osman F, Franklyn JA, Daykin J, et al. Heart rate variability
and turbulence in hyperthyroidism before, during, and after
treatment. Am J Cardiol 2004;94:465–469.
532. Ojamaa K, Klein I, Sabet A, et al. Changes in adenylyl cyclase
isoforms as a mechanism for thyroid hormone modulation of
cardiac beta-adrenergic receptor responsiveness. Metabolism
2000;49:275–279.
533. Hoit BD, Khoury SF, Shao Y, et al. Effects of thyroid hormone
on cardiac beta-adrenergic responsiveness in conscious baboons.
Circulation 1997;96:592–598.
534. Liggett SB, Shah SD, Cryer PE. Increased fat and skeletal
muscle beta-adrenergic receptors but unaltered metabolic
and hemodynamic sensitivity to epinephrine in vivo in experimental human thyrotoxicosis. J Clin Invest 1989;83:803–
809.
535. Klein I, Ojamaa K. Thyrotoxicosis and the heart. Endocrinol
Metab Clin North Am 1998;27:51–62.
536. Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin
concentrations as a risk factor for atrial fibrillation in older
persons. N Engl J Med 1994;331:1249–1252.
537. Gilligan DM, Ellenbogen KA, Epstein AE. The management of
atrial fibrillation. Am J Med 1996;101:413–421.
538. Woeber KA. Thyrotoxicosis and the heart. N Engl J Med
1992;327:94–98.
539. Shimizu T, Koide S, Noh JY, et al. Hyperthyroidism and
the management of atrial fibrillation. Thyroid 2002;12:489–
493.
540. Petersen P. Thromboembolic complications in atrial fibrillation. Stroke 1990;21:4–13.
541. Petersen P, Hansen JM. Stroke in thyrotoxicosis with atrial
fibrillation. Stroke 1988;19:15–18.
542. Glikson M, Freimark D, Leor R, et al. Unstable anginal syndrome and pulmonary oedema due to thyrotoxicosis. Postgrad
Med J 1991;67:81–83.
543. Toft AD. Clinical practice. Subclinical hyperthyroidism. N
Engl J Med 2001;345:512–516.
11/24/2006 10:58:10 AM
en docr in e disor ders a n d the he a rt
544. Auer J, Scheibner P, Mische T, et al. Subclinical hyperthyroidism as a risk factor for atrial fibrillation. Am Heart J 2001;
142:838–842.
545. Cooper DS. Antithyroid drugs. N Engl J Med 2005;352:905–917.
546. Forfar JC, Feek CM, Miller HC, et al. Atrial fibrillation and
isolated suppression of the pituitary-thyroid axis: response to
specific antithyroid therapy. Int J Cardiol 1981;1:43–48.
547. Grund FM, Niewoehner CB. Hyperthyroxinemia in patients
receiving thyroid replacement therapy. Arch Intern Med 1989;
149:921–924.
548. Fazio S, Biondi B, Carella C, et al. Diastolic dysfunction in
patients on thyroid-stimulating hormone suppressive therapy
with levothyroxine: beneficial effect of beta-blockade. J Clin
Endocrinol Metab 1995;80:2222–2226.
549. Bartalena L, Brogioni S, Grasso L, et al. Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results of a
prospective study. J Clin Endocrinol Metab 1996;81:2930–2933.
550. Bartalena L, Grasso L, Brogioni S, et al. Serum interleukin-6 in
amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab
1994;78:423–427.
551. Isley WL, Dahl S, Gibbs H. Use of esmolol in managing a thyrotoxic patient needing emergency surgery. Am J Med 1990;
89:122–123.
552. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715
carcinoid tumors. Cancer 2003;97:934–959.
553. Hemminki K, Li X. Incidence trends and risk factors of carcinoid tumors: a nationwide epidemiologic study from Sweden.
Cancer 2001;92:2204–2210.
554. Berge T, Linell F. Carcinoid tumours. Frequency in a defi ned
population during a 12–year period. Acta Pathol Microbiol
Scand [A] 1976;84:322–330.
555. Akerstrom G, Hellman P, Hessman O, et al. Management of
midgut carcinoids. J Surg Oncol 2005;89:161–169.
556. Pearse AG. The cytochemistry and ultrastructure of polypeptide hormone-producing cells of the APUD series and the
embryologic, physiologic and pathologic implications of the
concept. J Histochem Cytochem 1969;17:303–313.
557. Moller JE, Connolly HM, Rubin J, et al. Factors associated with
progression of carcinoid heart disease. N Engl J Med 2003;
348:1005–1015.
558. Zuetenhorst JM, Taal BG. Metastatic carcinoid tumors: a clinical review. Oncologist 2005;10:123–131.
559. Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med 1999;
340:858–868.
560. Moertel CG. Karnofsky memorial lecture. An odyssey in the
land of small tumors. J Clin Oncol 1987;5:1502–1522.
561. Zuetenhorst JM, Korse CM, Bonfrer JM, et al. Daily cyclic
changes in the urinary excretion of 5-hydroxyindoleacetic
acid in patients with carcinoid tumors. Clin Chem 2004;50:
1634–1639.
562. Oberg K, Theodorsson-Norheim E, Norheim I. Motilin in
plasma and tumor tissues from patients with the carcinoid
syndrome. Possible involvement in the increased frequency of
bowel movements. Scand J Gastroenterol 1987;22:1041–1048.
563. Fox DJ, Khattar RS. Carcinoid heart disease: presentation, diagnosis, and management. Heart 2004;90:1224–1228.
564. Lundin L, Norheim I, Landelius J, et al. Carcinoid heart disease:
relationship of circulating vasoactive substances to ultrasounddetectable cardiac abnormalities. Circulation 1988;77:264–269.
565. Robiolio PA, Rigolin VH, Wilson JS, et al. Carcinoid heart
disease. Correlation of high serotonin levels with valvular
abnormalities detected by cardiac catheterization and echocardiography. Circulation 1995;92:790–795.
566. Ferrans VJ, Roberts WC. The carcinoid endocardial plaque; an
ultrastructural study. Hum Pathol 1976;7:387–409.
567. Modlin IM, Shapiro MD, Kidd M. Carcinoid tumors and fibrosis: an association with no explanation. Am J Gastroenterol
2004;99:2466–2478.
CAR108.indd 2329
2329
568. Zuetenhorst JM, Bonfrer JM, Korse CM, et al. Carcinoid heart
disease: the role of urinary 5-hydroxyindoleacetic acid excretion and plasma levels of atrial natriuretic peptide, transforming growth factor-beta and fibroblast growth factor. Cancer
2003;97:1609–1615.
569. Jick H, Vasilakis C, Weinrauch LA, et al. A population-based
study of appetite-suppressant drugs and the risk of cardiacvalve regurgitation. N Engl J Med 1998;339:719–724.
570. Weissman NJ, Tighe JF Jr, Gottdiener JS, et al. An assessment
of heart-valve abnormalities in obese patients taking dexfenfluramine, sustained-release dexfenfluramine, or placebo. Sustained-Release Dexfenfluramine Study Group. N Engl J Med
1998;339:725–732.
571. Khan MA, Herzog CA, St Peter JV, et al. The prevalence of
cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs. N Engl J Med 1998;339:713–718.
572. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart
disease associated with fenfluramine-phentermine. N Engl J
Med 1997;337:581–588.
573. Pellikka PA, Tajik AJ, Khandheria BK, et al. Carcinoid heart
disease. Clinical and echocardiographic spectrum in 74
patients. Circulation 1993;87:1188–1196.
574. Schweizer W, Gloor F, Von B, et al. Carcinoid heart disease with
left-sided lesions. Circulation 1964;29:253–257.
575. Strickman NE, Rossi PA, Massumkhani GA, et al. Carcinoid
heart disease: a clinical pathologic, and therapeutic update.
Curr Probl Cardiol 1982;6:1–42.
576. Chaowalit N, Connolly HM, Schaff HV, et al. Carcinoid heart
disease associated with primary ovarian carcinoid tumor. Am
J Cardiol 2004;93:1314–1315.
577. Pandya UH, Pellikka PA, Enriquez-Sarano M, et al.
Metastatic carcinoid tumor to the heart: echocardiographicpathologic study of 11 patients. J Am Coll Cardiol 2002;40:1328–
1332.
578. Bajetta E, Ferrari L, Martinetti A, et al. Chromogranin A,
neuron specific enolase, carcinoembryonic antigen, and
hydroxyindole acetic acid evaluation in patients with neuroendocrine tumors. Cancer 1999;86:858–865.
579. Kema IP, Schellings AM, Meiborg G, et al. Influence of a serotonin- and dopamine-rich diet on platelet serotonin content
and urinary excretion of biogenic amines and their metabolites. Clin Chem 1992;38:1730–1736.
580. Meijer WG, Kema IP, Volmer M, et al. Discriminating capacity
of indole markers in the diagnosis of carcinoid tumors. Clin
Chem 2000;46:1588–1596.
581. Kema IP, Willemse PH, De Vries EG. Carcinoid tumors. N Engl
J Med 1999;341:453–454; author reply 454–455.
582. Taal BG, Hoefnagel CA, Valdes Olmos RA, et al. Combined
diagnostic imaging with 131I-metaiodobenzylguanidine and
111In-pentetreotide in carcinoid tumours. Eur J Cancer 1996;
32A:1924–1932.
583. Janson ET, Westlin JE, Eriksson B, et al. [111In-DTPA-DPhe1]octreotide scintigraphy in patients with carcinoid
tumours: the predictive value for somatostatin analogue treatment. Eur J Endocrinol 1994;131:577–581.
584. Hoegerle S, Altehoefer C, Ghanem N, et al. Whole-body 18F
dopa PET for detection of gastrointestinal carcinoid tumors.
Radiology 2001;220:373–380.
585. Oberg K, Eriksson B, Janson ET. The clinical use of interferons
in the management of neuroendocrine gastroenteropancreatic
tumors. Ann N Y Acad Sci 1994;733:471–478.
586. Connolly HM. Carcinoid heart disease: medical and surgical
considerations. Cancer Control 2001;8:454–460.
587. Zuetenhorst JM, Korse CM, Bonfrer JM, et al. Role of
natriuretic peptides in the diagnosis and treatment of
patients with carcinoid heart disease. Br J Cancer 2004;90:
2073–2079.
11/24/2006 10:58:10 AM
2330
chapter
588. Lamberts SW, van der Lely AJ, de Herder WW, et al. Octreotide.
N Engl J Med 1996;334:246–254.
589. Wymenga AN, Eriksson B, Salmela PI, et al. Efficacy and safety
of prolonged-release lanreotide in patients with gastrointestinal neuroendocrine tumors and hormone-related symptoms.
J Clin Oncol 1999;17:1111.
590. Kvols LK, Martin JK, Marsh HM, et al. Rapid reversal of carcinoid crisis with a somatostatin analogue. N Engl J Med 1985;
313:1229–1230.
CAR108.indd 2330
10 8
591. Anderson AS, Krauss D, Lang R. Cardiovascular complications of malignant carcinoid disease. Am Heart J 1997;134:693–
702.
592. Connolly HM, Schaff HV, Mullany CJ, et al. Surgical management of left-sided carcinoid heart disease. Circulation 2001;104:
I36–40.
593. Connolly HM, Nishimura RA, Smith HC, et al. Outcome of
cardiac surgery for carcinoid heart disease. J Am Coll Cardiol
1995;25:410–416.
11/24/2006 10:58:10 AM