Myron Miller
In previous editions, Robert I. Gregerman, MD, contributed to this chapter.
Pituitary Diseases
Both autopsy studies and the commonly used neuroimaging procedures of computed tomography (CT) and magnetic resonance imaging (MRI) have demonstrated that abnormalities in the region of the pituitary are relatively common findings. The majority of the abnormalities are a result of benign pituitary adenomas, with the remainder caused by pituitary cysts. Unsuspected pituitary adenomas found on CT or MRI are designated as incidentalomas (1). Autopsy data indicate that approximately 10% of men and women over the age of 30 years may have such pituitary tumors. A similar incidence has been found in patients who have had CT or MRI scans for nonpituitary-related indications. Pituitary adenomas are commonly classified on the basis of size as microadenomas (<10 mm in diameter) or macroadenomas (>10 mm in diameter).
Clinical Presentation
Clinically, disorders of the pituitary gland are manifest by mass effect with encroachment by a large tumor on adjacent structures, by a disturbance of function (hypersecretion or hyposecretion of trophic hormones), or by a combination of these processes (Table 81.1). The majority of pituitary tumors are benign adenomas that may be nonfunctional. Many of those adenomas that overproduce hormone are clinically inapparent microadenomas. Microadenomas rarely result in hormone hyposecretion. Macroadenomas, however, may either overproduce hormones or may compromise pituitary function and lead to hyposecretion of one or more of the pituitary hormones.
When a patient presents with evidence of decreased endocrine function, routine evaluation must include consideration of whether the process is primary (i.e., in the end organ) or is a result of pituitary disease (i.e., secondary glandular failure). For example, in most patients with hypothyroidism, thyroid-stimulating hormone (TSH) is elevated because of failure of normal inhibition of the negative feedback loop. However, if TSH is low or normal in the face of hypothyroidism, the possibility of pituitary origin of hypothyroidism must be considered. Similarly, in patients with hypogonadism, levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are almost always elevated when there is primary end-organ failure, but are low or normal in hypogonadism caused by pituitary disease.
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TABLE 81.1 Presentations of Pituitary Tumors |
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Mass Effect
When a pituitary tumor is large enough to produce increased pressure within the sella turcica, enlargement and erosion of the bony walls of that structure either produce no symptoms or may cause headache, typically described by the patient as severe and located behind the eyes. Tumor enlargement superiorly leads to encroachment on the adjacent optic chiasm and may produce temporal visual field defects. Pituitary tumors large enough to be anatomically apparent are often associated with failure of hormone secretion (hypopituitarism), a process that results in selective or multiple end-organ failure (hypoadrenalism, hypogonadism, and/or hypothyroidism).
A related problem is that of craniopharyngioma. This developmental abnormality may simulate a pituitary tumor. The lesion is usually outside the pituitary and presents as a suprasellar mass lesion readily evident on CT or MRI. Most cases are manifest during childhood.
Radiologic Evaluation of the Sella Turcica
The sella turcica as seen in plain films of the skull may appear deceptively normal when it harbors a pituitary adenoma or may appear abnormal when no tumor is present. MRI has almost totally replaced older techniques for evaluating the sella. MRI is most sensitive when the image is enhanced by gadolinium. CT is less expensive but is less sensitive than MRI in the detection of intrasellar microadenomas. In a few centers, petrosal venous sampling techniques for ACTH can lateralize many of the nonvisualizable adenomas that are the cause of Cushing disease, thus facilitating pituitary hemisectioning at surgery.
Empty Sella Syndrome
An enlarged sella does not always mean that a pituitary tumor is present. Evaluation commonly leads to demonstration of an empty sella turcica (i.e., one not completely filled by the pituitary gland). Empty sellas are often discovered when a head MRI or CT is obtained for reasons other than suspected hypopituitarism, usually headache, and usually are not associated with clinical endocrine disease. The cause of the empty sella syndrome is unknown, but open communication of cerebrospinal fluid through a defect in the diaphragma sellae or a ruptured cyst has been postulated. In most cases, a rim of nonvisualizable normal pituitary tissue remains, and pituitary function, which should be routinely evaluated (e.g., measurement of TSH, FSH, and LH), is normal; in some there is minimal hypopituitarism or a visual field defect for reasons that are not clear, but that could represent effects of a previous cyst. The diagnosis can be made definitively by MRI.
Pituitary Tumors and Disorders of Pituitary Hyperfunction
Chromophobe Adenomas
Chromophobe adenomas, the most common of the pituitary tumors, account for approximately 85% of cases; most occur between the ages of 30 and 60 years, and rarely are associated with parathyroid or pancreatic islet cell adenomas and, sometimes, with the Zollinger-Ellison syndrome (see Chapter 43). These associations constitute the syndrome of multiple endocrine adenomatosis type I.
Chromophobe adenomas are usually noninvasive but may infiltrate local structures and, on rare occasions, even behave as locally malignant lesions. Long thought to be functionless, many are now known to be prolactinomas (see Prolactinomas: Prolactin and Galactorrhea). A few produce growth hormone (GH); even fewer produce gonadotropins. The term chromophobe adenoma belongs to the era in which pituitary tumors were classified by their histologic staining characteristics (chromophobe, eosinophile, and basophile). A preferred, more precise contemporary classification is based on the secretory product of the tumor (e.g., somatotrope tumor, GH producing).
Pituitary function remains clinically normal until more than 75% of the normal pituitary has been destroyed by the adenoma. Hypogonadism is usually the earliest evidence of a hormone deficiency state (60% to 80% of cases), but hypothyroidism as an initial manifestation is almost as common. Adrenal insufficiency is usually the last problem to develop and is often inapparent except on laboratory testing. In approximately 10% of cases, diabetes insipidus develops.
The long-term course of nonfunctional microadenomas suggests that most will not undergo further increase in size
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or become hyperfunctional. Thus, after initial clinical and biochemical screening for hormone overproduction (prolactin, GH, adrenocorticotropic hormone [ACTH]), further followup can be done by obtaining an MRI yearly for 2 years and, if no change has occurred, subsequently lengthening the interval for further MRI (2).
Prolactinomas: Prolactin and Galactorrhea
In women, unilateral or bilateral galactorrhea may be the first clue to the presence of a prolactin-secreting adenoma (prolactinoma). In many cases, discharge from the breast is minimal and may be apparent only on physical examination when a few drops of milk may be expressible. Breast enlargement may occur in the male, but prolactin excess is an uncommon cause of gynecomastia (see Chapter 85). Galactorrhea in men, a rare event, is diagnostic of a prolactinoma. Prolactin secretion appears to inhibit the secretion of gonadotropins and hence may also be associated with evidence of hypogonadism, including impotence and amenorrhea (see Chapters 85 and 101).
Many cases of galactorrhea in women are not caused by tumoral hyperprolactinemia but rather by a functional disturbance of prolactin secretion, which, in turn, is either spontaneous or related to the use of certain drugs. The drugs most commonly incriminated in the production of galactorrhea are estrogens (including oral contraceptives), neuroleptics, tricyclic antidepressants, risperidone, haloperidol, and methadone. In either case, the hallmark of galactorrhea is an increase of the concentration of prolactin in serum. Rarely, galactorrhea occurs secondary to hypothyroidism.
The degree of prolactin elevation is strongly suggestive of the cause of the disorder. Levels of prolactin greater than 200 ng/mL are essentially diagnostic of a pituitary tumor, even in the absence of changes in the sella. Levels of prolactin greater than 250 ng/mL often indicate the presence of a macroadenoma while lesser degrees of elevation are more commonly associated with microadenoma. Elevated levels of prolactin less than 50 ng/mL are more likely to be caused by a functional disorder or a drug, but a pituitary tumor cannot be differentiated from other causes solely by quantification of the prolactin level. If suprasellar extension is present on CT or MRI, the patient should be referred for ophthalmologic examination of the visual fields.
Treatment
Most cases of galactorrhea, whether a result of macro or microadenoma or of another cause, can be treated successfully with the dopamine agonist bromocriptine (Parlodel), which often lowers the prolactin level, abolishes the galactorrhea, and restores normal menses. Bromocriptine not only reduces prolactin secretion, but in many cases caused by macroadenoma, causes the tumor to shrink so dramatically that even visual field defects can be reversed. A favorable response occurs in 80% of cases. The drug is now commonly given preoperatively, even when a large tumor is present, because surgical removal is facilitated. Long-term drug therapy may be an alternative to surgery (3). Treatment with bromocriptine can be undertaken by the nonspecialist if evaluation indicates that tumor is unlikely. The drug is available as 2.5-mg tablets and 5-mg capsules; the initial dosage is 1.25 to 2.50 mg/day. The dosage may be increased by 2.5 mg every 3 to 7 days until an optimal response is achieved—usually 5 to 7.5 mg/day. Adverse effects include nausea, headache, dizziness, and fatigue. If prolactin levels are very high, if radiographic evidence of tumor is present, or if the patient is intolerant of, or unresponsive to, bromocriptine, an endocrinologist should be consulted. An alternative dopamine agonist drug is cabergoline (Dostinex), which has the advantage over bromocriptine of a need for much less frequent dosing, in the range of 0.25 to 1 mg twice weekly (4). The adverse effects of the two drugs are similar.
Prolactin-secreting tumors in men tend to be diagnosed at a much later stage (i.e., as macroadenomas) than in women and to be associated with hypogonadism. Drug therapy is successful in approximately 80% of these cases (5).
Until recently the indications for surgical intervention (transsphenoidal; see Acromegaly) were mainly related to the size of the tumor. In the past, visual field impairment has been the major indication for urgent surgery, but extensive experience indicates that even patients with significant visual loss can be successfully treated with bromocriptine. With transsphenoidal surgery, microadenomas can often be removed successfully and normal pituitary function restored. With marked suprasellar extension, a transfrontal surgical approach may be needed. This is a much more formidable procedure. In many cases, a large tumor cannot be completely removed; postoperative radiation therapy prevents clinical recurrence in these instances.
Acromegaly
Pituitary tumors that produce an excess of GH result in the clinical state termed acromegaly. Approximately 75% of pituitary tumors causing acromegaly are macroadenomas, and approximately 25% are mixed tumors that secrete both GH and prolactin.
If GH excess occurs before cessation of growth, gigantism occurs. When GH excess begins in the adult, the most common clinical feature suggesting the presence of acromegaly is insidious alteration of facial appearance over many years. Old photographs may be useful in helping to identify such changes. Physical findings include enlargement (lengthening) of the mandible, sometimes with separation of the teeth; coarsening of facial features because
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of both overgrowth of frontal, malar, and nasal bones, and of soft tissue producing widening of the nose and protrusion of the lips; enlargement of the hands and feet, often noted by increasing glove and shoe size; and dermatologic changes that include skin thickening and sebaceous gland enlargement (hydradenitis) with accompanying increase in sweating. Patients may present with a nerve entrapment (carpal tunnel) syndrome. Osteoarthritis and diabetes mellitus are often seen in this disorder, but are too common to provide a clue to the presence of acromegaly. Tumors large enough to produce sellar enlargement may lead to headache and suprasellar extension may result in visual field defects.
The laboratory diagnosis is straightforward in overt cases but may be difficult in mild cases. GH varies rapidly during the day in the serum of acromegalic patients, so single measurements may not be helpful. The best test for screening is the determination of serum insulinlike growth factor 1 (IGF-1). The serum concentration of this product of GH action varies little and correlates well with the 24-hour integrated serum GH level, arguably the most definitive test. If GH is measured directly in screening, elevation of serum GH in the fasting basal state to values consistently greater than 10 ng/mL strongly suggests the diagnosis. However, stress, meals and physical activity may also elevate the GH levels. Elevated values must therefore be confirmed with a test of the ability of glucose to suppress the GH. During a standard glucose tolerance test (see Chapter 79), the GH—determined simultaneously with the glucose—should normally fall to a value of less than 1 ng/mL. Most acromegalics show no fall of GH, and a few exhibit a paradoxical rise during the test. Laboratory evidence of elevated IGF-1 or elevated and/or nonsuppressible GH warrants referral to an endocrinologist, as does the presence of equivocal clinical or laboratory findings in a patient with clinical features suggestive of acromegaly (6).
Treatment of Acromegaly
The decision regarding the most appropriate form of therapy should be made by an endocrinologist. Surgery is indicated when there is need for rapid reduction of tumor mass with symptoms of visual field loss or intractable headache. Transsphenoidal hypophysectomy is now standard for most cases and should, if acromegaly is caused by a microadenoma, include an attempt at selective removal of the microadenoma. The transsphenoidal operation involves minimal morbidity, a very low rate of complications, and essentially no mortality. Cure rates for microadenoma vary directly with the experience of the neurosurgeon, reaching approximately 70% in the most experienced hands, but being substantially lower when performed by neurosurgeons who do fewer cases. For macroadenomas, the cure rate even by the most experienced surgeons is only 20% to 50%.
Somatostatin analogues, potent inhibitors of GH secretion, are effective as long-term medical therapy and can be considered as initial therapy in most cases of both macroadenoma and microadenoma. The drugs require subcutaneous injection, but long-acting depot preparations (octreotide acetate [Sandostatin LAR]; lanreotide SR) are now available and can be given every 4 weeks (with usual doses of 20 to 30 mg for octreotide) (7). Tumor shrinkage of up to 40% of original volume is usually evident within 12 to 24 weeks of initiation of therapy and occurs in up to 75% of treated patients. The goals of treatment are to (a) reduce mean GH levels to <2.5 ng/mL and nadir GH after an oral glucose load to <1 ng/mL; (b) reduce IGF-1 to the age-adjusted normal range, a response achieved in approximately 70% of patients; (c) control symptoms of active acromegaly; and (d) reduce tumor mass. Treatment should be directed by an endocrinologist (6).
A second-line drug after somatostatin analogues is pegvisomant (Somavert), a GH receptor antagonist that inhibits the production of IGF-1. Although it normalizes IGF-1 levels in 97% of patients, it does not reduce tumor size and, in some patients, the tumor may actually increase in size. The role of pegvisomant in long-term management of acromegaly appears to be as an additional agent in patients whose GH and IGF-1 levels fail to normalize on a somatostatin analogue alone (8).
Irradiation of the pituitary, usually by external high-voltage techniques, had been standard treatment for years but is no longer considered to be primary therapy. Although it is effective, it may take several years to produce maximal suppression of hormone production and is often accompanied by development of hypopituitarism. The decision about what should be the most appropriate therapy in any individual patient should be determined by an endocrinologist.
Cushing Disease
When there is evidence of overproduction of glucocorticoids and testing suggests the presence of adrenal hyperplasia (see Adrenal Diseases), evaluation of the sella turcica is indicated. Most cases of Cushing disease with adrenal hyperplasia are caused by an ACTH-producing basophilic microadenoma of the pituitary that can be visualized preoperatively, in 80% of cases, with an optimal MRI examination (see Cushing Disease section). Transsphenoidal resection of the microadenoma can be curative.
Other Secretory Pituitary Tumors
Although quite rare, pituitary tumors that secrete thyrotropin (TSH) and produce hyperthyroidism do occur. Even rarer are cases of hypersecretion of TSH without demonstrable tumor. Patients with tumors have been successfully treated with a somatostatin analogue. Tumors
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that produce excessive amounts of gonadotropins are very rare.
Pituitary Failure (Hypopituitarism)
The most common causes of hypopituitarism are pituitary tumors and surgically induced hypopituitarism following either transsphenoidal or transfrontal resection of a pituitary tumor. Patients who have undergone these procedures will need to have residual pituitary function evaluated, generally at least 2 to 3 weeks after surgery, which is when any deficits will begin to become apparent. The pituitary may also be affected by severe head trauma, as well as by a wide variety of systemic illnesses, including granulomatous, infectious, vascular, and metastatic processes, but all are extremely uncommon causes of hypopituitarism.
Idiopathic Causes
Patients are occasionally encountered in whom pituitary failure occurs without evidence of pituitary tumor or of another demonstrable anatomic defect. Some are eventually found to have infiltrative processes (sarcoidosis, histiocytosis, lymphoma, benign lymphocytic infiltration [hypophysitis]). Hypopituitarism is diagnosed by the demonstration of end-organ failure with concurrent absence of the expected elevation of trophic hormone. Multiple trophic hormone deficiencies are usually present but isolated deficiencies of trophic hormones also rarely occur. Among these, the most likely to be encountered is hypogonadotropic hypogonadism in the male, sometimes associated with anosmia (Kallmann syndrome, see Chapter 85). In these patients, no anatomic basis is apparent.
Sheehan Syndrome (Postpartum Pituitary Failure)
Massive uterine hemorrhage occurring at delivery occasionally is accompanied by pituitary infarction and consequent panhypopituitarism. In this syndrome, failure of postpartum lactation and absence of menses are attended by development of debility and other evidence of end-organ failure. Because of improvements in obstetric care (prompt treatment of hemorrhage), such cases are now rare.
Pituitary Hemorrhage and Infarction
Rarely, hemorrhage into the pituitary gland (pituitary apoplexy), usually into an adenoma, leads to severe headache and/or signs of a rapidly expanding intracranial abnormality. Radiographic examination of the sella turcica is abnormal. Hormonal evaluation will demonstrate the presence of hypopituitarism. Another rare phenomenon is that of pituitary infarction occurring during the course of a febrile illness, presumably viral. Intense headache lasts for days and is usually, but not always, severe enough to require hospitalization. The acute febrile illness subsides with symptomatic therapy and without specific clinical or radiographic findings, only to be followed later by the development of hypopituitarism. Both men and women can be affected.
Hypopituitarism Secondary to Head Trauma
Head trauma has long been thought to account for only a tiny fraction of all cases of hypopituitarism, but recent reports indicate that head trauma, usually the result of a motor vehicle accident, can result in hormone deficiencies in as many as 80% of patients early in the period following head trauma. Laboratory findings are highly variable and range from panhypopituitarism to single hormone deficiencies. The most common findings are decreased gonadotropins and growth hormone and increased prolactin. Hormone deficits may resolve over time, but approximately 28% of individuals will be left with permanent deficiencies, most commonly GH, ACTH, and gonadotropins (9). Patients may not recall such an occurrence until helped to remember. Careful questioning of relatives often reveals a positive history that would otherwise remain obscure. The trauma may not have seemed severe; neither skull fracture nor loss of consciousness need occur, although most cases have had both. The typical case is a young male who is found on testing to have evidence of end-organ failure within a year of the traumatic episode, although many years may pass before a diagnosis is made. Pituitary imaging may show an empty sella, pituitary atrophy, and/or areas of hypodensity, cysts, or microcysts. Spontaneous recovery of pituitary function may occur as late as 10 or more years after the event.
Posterior pituitary dysfunction with diabetes insipidus has been found in approximately 22% of patients in the period immediately following traumatic brain injury. When it does occur in the immediate posttrauma period, it often resolves over the next several months with approximately one third of those affected having permanent diabetes insipidus on assessment 6 to 36 months after injury (10).
Disturbances of Pituitary Function Caused by Nonendocrine Disease
Much more common than decreased pituitary function resulting from intrinsic pituitary disease is altered gonadotropin secretion on a functional basis. Many illnesses can affect the functional integrity of the hypothalamic–pituitary–end-organ axis. This phenomenon is most obvious as a disturbance of menstruation in women and, less often, impotence in men (see Chapter 85). Many normal men, generally over the age of 80 years, experience a decline in LH secretion with consequent hypogonadism, a phenomenon sometimes referred to as “andropause.” This
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age-related alteration in hypothalamic/pituitary function of men differs from menopause, which is caused by end-organ failure of the ovary.
Any disease that results in malnutrition can lead to decreased gonadotropins and (secondary) amenorrhea in women or impotence in men. Alcoholism is an outstanding example. Liver disease does not need to be present in alcoholics to produce amenorrhea or impotence, but various liver diseases are themselves associated with loss of menses. The common factor seems to be malnutrition. In recent years, some individuals have undertaken caloric restriction in an attempt to extend their life span. Although such persons maintain that they are not malnourished but rather are undernourished, they share many of the symptomatic features described here.
The classic example of nonendocrine illness that simulates an endocrine disturbance is anorexia nervosa (see Chapter 11). In this psychiatric disturbance, which results in severe malnutrition with resultant weight loss, the most marked disturbance of endocrine function is cessation of menses resulting from a decrease of gonadotropins. Other trophic hormones are not affected. Thyroid function is usually normal. Axillary and pubic hair are retained, giving important clinical evidence for the preservation of adrenal function. Although cortisol secretion is low (urinary glucosteroid excretion is decreased), this results from slow metabolic disposal of cortisol rather than from a decreased ability to increase ACTH secretion appropriately; plasma cortisol is normal. GH concentration may be elevated, a consequence of starvation as a consequence of any cause. The diagnosis of anorexia nervosa should be based on the association of psychiatric abnormalities and obvious decrease in food intake. The tests described serve merely to support the diagnosis.
Women who engage in a high level of physical activity, such as long distance runners or gymnasts, may develop either primary or secondary amenorrhea as a result of hyposecretion of gonadotropins. A number of disorders and diseases may also result in secondary amenorrhea as a consequence of failure of gonadotropin secretion, including such diverse conditions as severe emotional disturbances, marked obesity, poorly controlled diabetes mellitus, and severe chronic infections.
Hormone Replacement Therapy for Hypopituitarism
Pituitary insufficiency, regardless of the cause, is treated with replacement of identified hormone deficiencies, that is, thyroid hormone (thyroxine, see Chapter 80), adrenal glucocorticoid (cortisol, see Glucocorticoid [Steroid] Replacement Therapy section), and gonadal hormone (testosterone [see Chapter 85] or an estrogen [see Chapter 106]). Except for GH, the pituitary trophic hormones themselves are not used routinely (see Growth Hormone Deficiency section). Occasionally, young women may be candidates for therapy with gonadotropins to produce ovulation and restore fertility. Such therapy may be effective but is available at only a few centers. Restoration of fertility in the male is also possible with the use of a combination of gonadotropins, but such therapy is not generally available. In men, normal libido and sexual performance consistent with age can be ensured with testosterone therapy.
Growth Hormone Deficiency
The name “growth hormone” has its historical roots in the period when it was found to be essential for normal growth and development in children. However, GH is a metabolic regulator, even in the adult. Except during aging (see below), GH deficiency in the adult is invariably caused by pituitary disease or pituitary surgery. Although most patients with pituitary disorders do reasonably well when end-organ hormones are replaced (adrenal, thyroid, gonadal), the role of GH replacement only was recognized relatively recently (11).
The clinical state of the adult human with isolated GH deficiency (i.e., patients receiving replacement therapy only with other end-organ hormones) is now considered to be a deficiency “syndrome” (12). The abnormalities attributed to GH deficiency are a reduction in lean body mass, bone mass, and muscle strength, an increase in body fat—especially abdominal fat—and alterations in mood (depression, emotional lability, anxiety) and energy level. Although these features are not specific for GH deficiency, treatment of GH-deficient adults improves psychological well-being, muscle strength, exercise tolerance, and bone mass. Objective evidence validating these changes is available from psychological testing and measurements of lean body mass (body composition studies showing increased muscle, decreased fat), bone mass, and exercise performance testing.
During normal aging, about one-half of the elderly develop a low GH state that is manifest primarily through loss of nocturnal GH secretion with an associated decrease in serum IGF-1. In the past few years, small numbers of such patients have been studied during GH replacement therapy, alone or in combination with sex steroids, in an effort to ameliorate some of the effects of aging, especially the loss of muscle mass (sarcopenia) and strength. Although improvement can be seen in measures of body composition and bone mass, the results of such studies do not suggest that GH will be a panacea for the adverse changes that accompany aging.
The diagnosis of GH deficiency in the adult is not simple. The gold standard is the insulin-tolerance test (ITT), that is, secretion of GH provoked by insulin-induced hypoglycemia. Various stimulatory tests have been proposed, using a variety of agents, alone and in combination. These
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tests are best left to a consulting endocrinologist, as is the advisability of using GH over the long-term as part of a replacement program. GH is available as a recombinant deoxyribonucleic acid (DNA) product and is administered by daily subcutaneous injection. The potential benefits may be considerable, as is the cost (13).
Adrenal Diseases
Adrenocortical Insufficiency (Addison Disease)
Primary adrenal insufficiency is a rare disorder with a prevalence of approximately 100 cases per 1 million people and an incidence of 5 cases per year per 1 million people. In ambulatory patients, the clinical presentation of adrenocortical insufficiency is related to a number of chronic complaints that are nonspecific in character. A high index of suspicion will result in far more tests than positive diagnoses, but detection of this rare problem is important to prevent morbidity culminating in acute hospitalization for full-blown disease (i.e., vascular collapse with addisonian crisis) or death.
Etiology and Association with Other Autoimmune Diseases
Adrenocortical insufficiency is now most commonly the result of autoimmune disease and is associated with the presence of antibodies to adrenal tissue. Most other cases are secondary to pituitary disease.
Many cases of autoimmune adrenocortical insufficiency are associated with autoimmune thyroiditis, although the two problems may develop years apart. The simultaneous occurrence of autoimmune thyroid and adrenal disease is termed Schmidt syndrome. Rarely, autoimmune adrenocortical insufficiency, autoimmune hypothyroidism, and autoimmune gonadal failure occur in the syndrome of polyglandular failure. There is also an association of autoimmune adrenocortical insufficiency with pernicious anemia and Sjögren syndrome, and probably with systemic lupus erythematosus. Tuberculosis, once a common cause, now only rarely produces adrenocortical insufficiency in the United States and other developed countries, probably because of a relatively decreased incidence of tuberculosis in the Western world and because of effective therapy. Other rare causes of adrenocortical insufficiency include histoplasmosis, paracoccidiomycosis (in Central and South Americans), and sarcoidosis. Human immunodeficiency virus infection and diseases associated with the acquired immunodeficiency syndrome (e.g., cytomegalovirus, histoplasmosis, mycobacterial infection; see Chapter 39) often cause asymptomatic adrenal dysfunction, but symptomatic adrenal insufficiency is uncommon. Although infectious causes of adrenal insufficiency are unlikely to be encountered in the United States, they should still be excluded, especially in the absence of evidence for coexistent autoimmune disease.
Clinical Presentation
Chronic symptoms include anorexia, weight loss, weakness, and decreased physical endurance. Nausea and vomiting may occur, and abdominal pain, sometimes resembling that of peptic ulcer disease, can be a presenting feature. Other symptoms include mental sluggishness, irritability, and symptoms of either postural hypotension or of hypoglycemia. In primary adrenal insufficiency, increasing pigmentation (white patients) or further darkening of skin (African American patients) may be noted. Loss of axillary and pubic hair—an important finding when present—may occur in women. Such hair loss is commonly overlooked on physical examination and is rarely volunteered as part of the history.
Physical examination often shows postural hypotension. Pigmentation is diffuse but is especially evident in the creases of the hands, the areolae, over pressure areas (knuckles, elbows), and in new scars. Pigmentation of buccal mucous membranes is a pathognomonic finding in white patients but is a normal finding in blacks. Lymphadenopathy is occasionally seen. When the adrenal insufficiency is secondary to pituitary disease, additional findings may relate to the manifestations of a pituitary tumor (headache, visual loss), to hypothyroidism (seeChapter 80), or to hypogonadism.
Laboratory Evaluation
Classically, hyponatremia associated with hyperkalemia and some degree of azotemia provides a clue to the diagnosis. These abnormalities are manifestations of severe disease and are often absent in the less-severe cases that are likely to be encountered in ambulatory practice. Various other nonspecific abnormalities occur occasionally, including anemia, lymphocytosis, and eosinophilia.
Laboratory diagnosis of adrenal insufficiency depends on determination of serum cortisol in the basal state and after adrenal stimulation by injection of the ACTH analogue cosyntropin (Cortrosyn) (14). Both the normal diurnal rhythm of cortisol and the high degree of variability of serum cortisol in normal people must be kept in mind. Serum cortisol can be measured initially at any time of the day, and a robust normal value (15 to 25 µg/dL) will exclude the diagnosis. However, afternoon determinations may be low simply because of the normal diurnal drop, and even the fasting morning cortisol is highly variable. Values lower than 5 µg/dL at any time are highly likely to be a result of adrenal insufficiency. Intermediate values
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(5 to 10 µg/dL) may be seen in less-severe cases and may overlap those of normal subjects. Thus, measurement of unstimulated serum cortisol, while useful in excluding the diagnosis, may fail to detect mild cases or may yield indeterminate values.
Further evaluation of low or borderline values of serum cortisol should always be made by administering cosyntropin and then measuring cortisol again. The ease with which such testing is performed—and the common failure of unstimulated serum cortisol values to give definitive information—provides a cogent argument for use of cosyntropin stimulation as the preferred screening procedure for adrenal insufficiency (14). Many variations of cosyntropin stimulation tests have been advocated. The bolus intravenous injection of 0.25 mg of cosyntropin has been used for years as a simple and reliable procedure in the diagnosis of adrenal insufficiency. The serum cortisol is measured at baseline and at 30 and 60 minutes after injection, and will normally rise by at least 7 µg/dL to at least 18 to 20 µg/dL. Patients with adrenocortical insufficiency show a subnormal response. A 1 µg cosyntropin dose has been demonstrated to yield slightly more accurate results and is used in many centers, but requires more frequent blood sampling to detect the peak cortisol response (15). Patients with an abnormal response to cosyntropin should be referred urgently to an endocrinologist for confirmation of the diagnosis and additional testing, including measurement of serum ACTH, in an attempt to distinguish primary from secondary adrenal insufficiency. An elevated ACTH level (>100 pg/mL) is seen in primary adrenal insufficiency.
Other Tests
Tests of adrenal function based on 24-hour urinary steroid excretion (free cortisol) are less useful in screening for adrenal insufficiency. These tests offer no advantage over serum cortisol measurements and will yield artificially low values if urine collection is incomplete. The adrenal response to cosyntropin is slow in secondary adrenal insufficiency and requires stimulation for up to 3 days. In the past, 2- to 3-day infusions were used to discriminate between primary and secondary adrenal insufficiency. However, the presence of low serum ACTH in the setting of low serum cortisol is a more definitive indicator of secondary adrenal insufficiency. The finding of other pituitary hormone deficits, such as follicle-stimulating hormone, LH, and GH, further points to secondary adrenal disease (16).
Although the adrenal mineralocorticoid aldosterone may be low in adrenal insufficiency, the hormone is secreted by the zona glomerulosa rather than the more central portion of the adrenal cortex, and may be relatively unaffected by processes that destroy much of the glucocorticoid-producing zone of the gland. Consequently, measurements of plasma and urinary aldosterone have no place in routine diagnosis of adrenocortical insufficiency. Routine radiographic studies should include a chest radiograph and, if appropriate (e.g., suspicion of adrenal hemorrhage or metastases), CT or MRI of the adrenals.
Functional Adrenal Insufficiency
In recent years, it has been recognized that some patients with critical illness may develop clinical and laboratory features suggestive of adrenal insufficiency, including subnormal serum cortisol response to adrenal stimulation with cosyntropin (17). However, if the individual recovers, the manifestations of adrenal insufficiency will resolve and subsequent assessment of adrenal function will be normal. This condition of transient apparent adrenal insufficiency has been named functional adrenal insufficiency and in the acute setting may be difficult to distinguish from authentic adrenal insufficiency. It can be recognized by the finding in a critically ill person of a serum cortisol less than 15 µg/dL that does not rise by at least 9 µg/dL following stimulation with ACTH (17). These findings warrant prompt treatment with parenteral hydrocortisone at a dose of 50 mg every 6 hours. Complicating making a diagnosis of adrenal insufficiency is the observation that low serum cortisol measured in the presence of severe physiologic stress may be the consequence of altered cortisol binding protein as measurement of serum free cortisol may be normal (18). Functional adrenal insufficiency is unlikely to be diagnosed in an ambulatory setting, but if it is, it warrants immediate hospitalization.
Treatment of Established Adrenal Insufficiency
The addisonian patient should be helped to realize the importance of taking hormone therapy regularly, of self-care (dose adjustment) during situations of stress, and of the necessity of life-long replacement therapy.
Glucocorticoid (Steroid) Replacement Therapy
Replacement dosage for cortisol was established empirically decades ago. Secretion rates determined by stable isotope dilution suggest that 24-hour cortisol secretion is in the range of 8 to 15 mg per day (14), although older studies using radioactive labels gave somewhat higher values. Large or obese persons need more, but too much individual variation exists to make dose-to-weight calculations meaningful. Most patients can be treated with 15 to 25 mg of cortisol or its equivalent daily (20 mg of cortisol is equivalent to 25 mg of cortisone plus 5 mg of prednisone plus 0.5 mg of dexamethasone). The simplest scheme is 10 mg of cortisol (hydrocortisone) given twice daily. Some authorities prefer to simulate the normal diurnal rhythm of cortisol secretion, although no evidence indicates that this scheme is of any special benefit. In this approach, 10 to 15 mg of cortisol is taken on rising and 5 to 10 mg in the evening. Some
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clinicians still prescribe as much as 30 mg of cortisol (hydrocortisone) per day, an amount that exceeds physiologic replacement for most persons and should be avoided.
Equivalent doses of prednisone or another glucocorticoid (Table 81.2) may be used but have no advantage. Indeed, their use might dictate a requirement for additional mineralocorticoid therapy because glucocorticoids such as prednisone and dexamethasone have much less mineralocorticoid activity than does cortisol (or cortisone).
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TABLE 81.2 Commonly Used Glucocorticoidsa |
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Overtreatment with glucocorticoids should be avoided. Frequently increasing the dosage for treatment of nonspecific complaints is a common practice but should be avoided because iatrogenic subclinical Cushing syndrome (or, at a minimum, hypertension) is a real hazard to the long-term well-being of patients with Addison disease. The initial response to replacement therapy varies: weakness and lassitude ordinarily abate within hours to days, but other symptoms may diminish somewhat more slowly.
The requirement for glucocorticoids (cortisol) is increased during stress. In the ambulatory patient, minor stress (common “cold” without fever; simple dental extraction under local anesthesia) can be handled by a properly instructed and motivated patient. On such occasions, a modest increase in dosage is often needed, for example, an additional 5 or 10 mg of cortisol. Telephone contact with the caregiver is also useful—or even essential—on many such occasions, especially in the early months of therapy before the patient's ability to deal with these episodes has been demonstrated. The most common stress for the ambulatory patient is an infection, often a febrile viral illness. Ordinarily, a febrile response to approximately 101°F (38°C) that is unaccompanied by vomiting or diarrhea can be handled simply by increasing the cortisol dose to 50 to 75 mg per day in divided doses. A more-severe illness episode may require 100 mg for a few days. The occurrence of vomiting or significant diarrhea requires contact with a physician and may demand the use of parenteral glucocorticoids.
The need for hospitalization during stress must be determined by the caregiver and depends on the circumstances. It is obviously prudent to be cautious, but in this long-term chronic illness, frequent and precipitous hospitalizations
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should be avoided. Many minor events can be handled by judicious increase of steroid dosage. Perioperative management is described inChapter 93.
Although not all patients with fully developed adrenal insufficiency require mineralocorticoid therapy in addition to cortisol replacement, such therapy is usually started when the diagnosis is first made. The initial dose is 0.1 mg of fludrocortisone daily (Florinef, 0.1 mg tablets). Aldosterone is not available for therapy of Addison disease. Only rarely will patients require more than 0.1 mg of fludrocortisone. In the early days of replacement therapy, dosages as high as 0.2 mg/day were used, but hypertension and edema were common. A maintenance dosage of 0.05 mg is average, and some individuals require as little as 0.05 mg every other day. Adequacy of therapy can be judged by determinations of serum sodium and potassium levels and clinical observations, including normalization of blood pressure without postural hypotension. During stress, when the dosage of cortisol is increased beyond 50 to 75 mg/day, fludrocortisone therapy becomes unnecessary because the mineralocorticoid activity of cortisol is sufficient to maintain salt balance when taken in greater than basal physiologic amounts.
The patient and members of the patient's household should be educated about the symptoms of addisonian crisis and how to respond in emergencies. In addition, the patient should carry an identification document or wear an inscribed bracelet that identifies the addisonian state and contains instructions for therapy. Appropriate information, in addition to name, address, and telephone number, should read approximately as follows:
I am a patient with adrenal insufficiency (Addison disease). If I am seriously injured, found unconscious, or am vomiting, I should be given an injection of dexamethasone as emergency treatment for addisonian crisis. A filled syringe is with my belongings. Notify my health care giver (name, telephone number) or other medical authority immediately.
Syringes containing dexamethasone phosphate (4 mg in 1 mL of water) are available for patients and can be carried conveniently.
All patients with Addison disease should consume a liberal quantity of sodium (100 to 150 mEq [6 to 9 g NaCl] per day), regardless of whether mineralocorticoids are used. In the event of intercurrent diarrhea or profuse sweating, additional salt above the normal intake should be consumed. Electrolytes should be checked periodically (every 3 to 4 months during the critical first year of therapy). Mineralocorticoid therapy should be cautiously reduced if edema, hypertension, or hypokalemia is noted, and salt or mineralocorticoid should be increased if postural hypotension, hyponatremia, or hyperkalemia appears. Overtreatment with glucocorticoids should be carefully avoided. Over the long-term, it should be borne in mind that if the Addison disease is idiopathic (i.e., autoimmune), related diseases and their own manifestations may appear at any time (hypothyroidism, hypoparathyroidism, hypogonadism).
Adrenocortical Hyperfunction: Cushing Syndrome
The adrenal glands produce several steroid products: glucocorticoids (chiefly cortisol), mineralocorticoids (chiefly aldosterone), and adrenal androgens. Clinical disorders may affect predominantly the secretion of one or other of these hormones. Table 81.3 lists these disorders of adrenal hyperfunction. Most are rather uncommon or rare, but some essentially functional disorders are commonly encountered. The approach presented here is predominantly oriented to the recognition—or exclusion—and initial evaluation of these diseases in ambulatory patients. Once the practitioner is reasonably certain that a problem exists, detailed evaluation often requires consultation with an endocrinologist and sometimes hospitalization for special procedures. However, many relatively simple tests to assess adrenal function can be performed on an ambulatory basis. The specific steps of this diagnostic workup vary widely even among specialists and are in constant evolution as new hormone assays and tests emerge.
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TABLE 81.3 Categories of Adrenocortical Hyperfunction |
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Etiologies of Cushing Syndrome (Glucocorticoid Excess of Any Cause)
In this syndrome, a supraphysiologic amount of glucocorticoid (cortisol) is secreted along with varying amounts of adrenal androgens (19). Most cases are a result of hypersecretion of ACTH from the pituitary with resultant varying degrees of adrenal hyperplasia. The term Cushing disease refers to this particular variety of Cushing syndrome. In recent years it has become apparent that almost all of these cases (perhaps 90%) are caused by pituitary microadenomas that produce excessive amounts of ACTH (see Pituitary Diseases). A smaller number of cases of Cushing syndrome are caused by adrenal adenomas or, rarely, carcinomas. Cushing syndrome may also occasionally be caused by ectopic production of ACTH by carcinoid tumors and a variety of malignant tumors, the most common of which is small cell carcinoma of the lung. When a tumor causes Cushing syndrome, the malignancy is usually obvious, although small neoplasms may be inapparent by conventional CT and MRI when the evidence of glucocorticoid excess first appears (see Adrenal Carcinoma section).
Cushing Disease (Adrenocorticotropic Hormone-Dependent Adrenal Hyperfunction)
ACTH-dependent hypercortisolism is caused by either Cushing disease or ectopic ACTH production. MRI of the pituitary is relatively insensitive, identifying only 50% of ACTH-producing pituitary microadenomas. The significant incidence of pituitary “incidentalomas” (seePituitary Diseases section) further lowers the accuracy of MRI in establishing the pituitary as the source of ACTH hypersecretion. Other tests, such as low- and high-dose dexamethasone tests, peripherally administered corticotropin-releasing hormone (CRH), and metyrapone stimulation tests have all been used to identify the 5% to 10% of cases of ACTH-dependent Cushing syndrome that are caused by ectopic ACTH production. If radionuclide scintigraphy or positron emission tomography (PET) fails to identify an ectopic cause of ACTH production (see Ectopic Adrenocorticotropic Hormone Syndrome section), cavernous sinus sampling by retrograde catheterization or inferior petrosal sinus venous sampling with CRH stimulation is likely to make the distinction but, of course, cannot be of help in localizing the ectopic lesion. Such invasive sampling is performed in only a few centers (20). Once a diagnosis of hypercortisolism is made or strongly suspected, referral to an endocrinologist for further workup is essential.
Clinical Presentation of Cushing Syndrome
The severity of the signs and symptoms in Cushing syndrome depends on the magnitude of the steroid excess, the rapidity with which it develops, and the degree to which androgen production is increased. The signs and symptoms of glucocorticoid excess are familiar to all clinicians who have seen the entire picture of this disease emerge as the result of long-term treatment of patients with pharmacologic amounts of prednisone and similar drugs. Glucocorticoid excess produces increased deposition of subcutaneous fat in the face (moon facies) and in the upper body (buffalo hump, supraclavicular fat pads, and truncal obesity). Skin changes include facial erythema, telangiectasia over the face, atrophy and thinning of the skin with easy or spontaneous bruising, ecchymoses, and development of purplish abdominal striae. Hyperpigmentation is sometimes seen. Muscle weakness results from so-called steroid myopathy (often associated with elevated serum creatine kinase) and is especially prominent in the shoulder and pelvic girdle areas. The extremities become thin as muscle wasting occurs. Bone mineral loss occurs, producing osteoporosis with its resultant back pain. Compression fractures of the vertebrae are common and often spontaneous, and hip or wrist fractures may occur after minimal trauma. Hypertension and diabetes mellitus are common. Hypokalemia may occur. Probably less well recognized are the psychiatric disturbances that result from chronic glucocorticoid excess. Lability of mood, depression, mania, and frank psychoses may all be precipitated by glucocorticoid excess.
Androgenic effects occur from both the intrinsic properties of the glucocorticoids and the associated production of adrenal androgens. With glucocorticoid excess alone, only mild signs are usually evident: hirsutism (facial, extremities, truncal) and acne. More profound androgenic effects that include virilization suggest adrenal tumor, especially adrenal carcinoma. These include frontal baldness in women, oligomenorrhea, increase in muscle mass, and enlargement of the clitoris. Androgenic effects cannot, of course, be appreciated in men.
Ectopic Adrenocorticotropic Hormone Syndrome
Small cell lung cancer, bronchial and other carcinoids, gastrinomas, nonsecreting islet cell tumors, insulinomas, glucagonomas, somatostatinomas, and even metastatic medullary carcinomas of the thyroid all are known to produce this syndrome. 111In-pentetreotide or octreotide scintigraphy and PET are localization techniques that are being used currently, but even with these methods, the localization can be unsuccessful. These cases are challenges for even the most skillful endocrinologists and nuclear medicine experts (21).
Cushing Syndrome Caused by Bilateral Adrenocortical Nodular Hyperplasia
ACTH-independent Cushing syndrome is an uncommon cause of hypercortisolism. Occasionally, a single adrenal adenoma is the cause. More often the adrenals contain
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multiple functioning macronodules. In rare cases, the abnormal adrenal tissue is hyperresponsive to gastrointestinal inhibitory peptide or to other hormones or cytokines (e.g., vasopressin, LH, interleukin 1β), apparently because of aberrant expression of increased numbers of receptors for these messengers. When gastrointestinal inhibitory peptide receptors are involved, the increased output of cortisol by the adenomatous tissue is increased even further by eating, which normally triggers gastrointestinal inhibitory peptide release. The term food-dependent Cushing syndrome has been given to such cases (22).
Cushing Syndrome versus Pseudo-Cushing States
Patients with Obesity, Hirsutism, Hypertension, and/or Type 2 Diabetes Mellitus
In women, obesity is often associated with hirsutism, hypertension, and type 2 diabetes mellitus. When weight gain is rapid, striae may appear, and a truncal supraclavicular fat pad and a buffalo hump can be seen. These findings often raise the possibility of Cushing syndrome and provoke laboratory screening for this disorder. Few such patients are found to have Cushing syndrome. In recent years conditions that resemble Cushing syndrome have come to be called pseudo-Cushing states (see Other Pseudo Cushing States section).
Fifty percent of obese people do have increased cortisol production, which is a phenomenon of unknown mechanism resulting from the obese state. In these people the 24-hour urinary excretion of steroid metabolites is increased, reflecting increased cortisol production, and may fall into the range of that seen in Cushing syndrome. Expression of the urinary steroid metabolite excretion as per gram of creatinine in the 24-hour urine sample will usually result in a corrected steroid value which falls in the normal range. In contrast to Cushing syndrome, such obese people have serum cortisol concentrations that are normal rather than elevated (23). The 24-hour urine free cortisol is usually normal also and has now replaced measurement of other urinary steroids as the preferred screening test for Cushing syndrome. Furthermore, the suppressibility of the pituitary–adrenal axis in obesity is also normal (see Diagnosis). The obesity-related increase of urinary steroid metabolite excretion is one of several reasons why such measurements should be avoided for screening purposes.
Psychiatric Illness
Psychiatric symptoms are common in Cushing syndrome. However, it has also been appreciated that major depressive illness may be associated with excessive production of glucocorticoids and lack of suppressibility with dexamethasone (see Suppression Tests Based on Serum Cortisol section). These patients do not appear clinically to have full-blown Cushing syndrome, but some clinical features often suggest the diagnosis and may lead to laboratory investigation. Differentiation from true Cushing syndrome by laboratory tests may be difficult at first, but the differential diagnosis eventually becomes clear because remission of the psychiatric disturbance results in disappearance of the abnormal laboratory findings.
Other Pseudo-Cushing States
In addition to obesity and psychiatric disease, pseudo-Cushing states are seen in some patients with alcoholism, the alcohol-withdrawal syndrome, and the polycystic ovary syndrome.
Diagnosis
Tests of both adrenal and pituitary function are useful. Static measurements of serum cortisol and ACTH or urine cortisol (free cortisol) and the adrenal androgens may be combined. Dynamic testing after stimulation or inhibition of the pituitary–adrenal axis may also be helpful. The goal of the primary caregiver should be to use relatively simple and reliable screening tests to evaluate suspected cases in ambulatory patients and to refer equivocal cases to an endocrinologist for more extensive evaluations.
Screening Tests for Suspected Cushing Syndrome
Cushing syndrome is relatively uncommon and its manifestations are quite nonspecific. Many patients with common nonendocrine disorders show similar or identical clinical findings to those seen in patients with Cushing syndrome. Typical cases of Cushing syndrome have clearly abnormal laboratory findings, but patients with evolving (early) Cushing syndrome or mild disease may have laboratory results that overlap with those of the pseudo-Cushing states. There is no gold standard for the diagnosis of mild-to-moderate Cushing syndrome. Currently used screening tests will be able to discriminate readily between patients with Cushing syndrome and those with pseudo-Cushing syndrome 80% of the time, although several observations (clinical and laboratory) are often required. A useful initial screening test is a 24-hour urine collection for measurement of free cortisol and creatinine. A cortisol value greater than three times the upper limit of normal is highly suggestive of the presence of Cushing syndrome, whereas elevated levels less than three times upper normal may be seen in mild Cushing syndrome and in pseudo-Cushing states.
Suppression Tests Based on Serum Cortisol
Steroid production in patients with mild Cushing syndrome may not be greatly increased and there may be considerable overlap with normal values. Accordingly, determination of serum cortisol or urinary steroid excretion may not be helpful.
An overnight dexamethasone test has long been advocated as a screening test. A single oral dose of 1 mg is given
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between 11 p.m. and midnight, and the serum cortisol is measured at 8 to 9 a.m. the following morning. The sensitivity of the test depends on the diagnostic cut point for the suppressed cortisol level chosen. Most normal individuals will suppress the morning serum cortisol to less than 2 µg/dL. At 100% specificity, a plasma cortisol value above 7.5 µg/dL distinguishes Cushing syndrome from pseudo-Cushing syndrome with a sensitivity of 96% (18). If the test is abnormal, a more complicated, but more reliable, suppression test is performed in which dexamethasone is given orally at a dosage of 0.5 mg every 6 hours for 2 days. Serum cortisol, urinary free cortisol, or both can be monitored during this test. A plasma cortisol value at the end of the suppression period of less than 1.8 µg/dL separates Cushing patients from normal with 98% accuracy (24). Urinary free cortisol during the second 24-hour urine collection should not exceed 10 µg (25).
Serum Cortisol and Its Diurnal Variation
The normal diurnal rhythm of serum cortisol tends to be obliterated in Cushing syndrome. In normal individuals, the 4 p.m. cortisol is, on average, 50% of that obtained in the early morning. Although widely advocated for diagnosis, determination of this rhythm by measurement of morning and evening (usually midnight) cortisol is an unreliable screening procedure in distinguishing Cushing and pseudo-Cushing syndrome (25). The values overlap too much with normal ones to be useful or reliable discriminators for clinically questionable cases.
Other Tests
All of the following have had their advocates: the standard low-dose (48 hours, 2 mg/day) dexamethasone suppression test measuring urine 17-hydroxycorticosteroid; high-dose dexamethasone tests measuring urinary free cortisol; and the CRH test with dexamethasone pretreatment (25). A promising study was reported of the use of 1-deamino-8-D-arginine vasopressin (or desmopressin). Desmopressin stimulates the release of ACTH (and cortisol) in patients with Cushing syndrome. The test seems to discriminate quite well between normal subjects, patients with pseudo-Cushing syndrome, and patients with Cushing syndrome (26). Performance of these tests is best done by an endocrinologist.
Interpreting Tests and Additional Diagnostic Maneuvers
If Cushing syndrome is clearly established or if the tests are equivocal and the clinical features strongly suggestive, referral to an endocrinologist is appropriate. In expert hands, a variety of maneuvers can usually establish or exclude the diagnosis and differentiate among the causes of Cushing syndrome, but familiarity with the specialized test procedures is essential. Often a degree of laboratory precision is required that is not always achieved by ordinary commercial laboratories. Useful tests in such consultations, in addition to those described, include multiple samplings of plasma cortisol throughout the day and night (integrated blood levels), determinations of urinary excretion of steroids on multiple occasions, variations of the dexamethasone suppression test with the use of different doses of the steroid, and plasma ACTH measurements.
Procedures such as CT or MRI of the sella turcica and of the adrenal areas are not indicated until strong laboratory evidence is at hand to indicate that steroid production is abnormal. While not useful in screening, they are important in determining the locus and cause of steroid excess once evidence for the presence of Cushing syndrome has been obtained.
Treatment of Cushing Disease and Cushing Syndrome
It is now appreciated that most cases of Cushing disease can be treated by transsphenoidal surgical removal of a pituitary microadenoma, and this has become the preferred therapy with up to 90% cure rate when carried out by an experienced neurosurgeon (27). A lower cure rate occurs in patients with macroadenoma. However, a significant number (estimates range from 5% to 25%) of patients treated in this manner experience recurrence within a short time despite apparently successful removal of the tumor.
Although bilateral adrenalectomy was accepted for years as the most effective therapy for Cushing disease, this treatment has been abandoned except for rare indications. Induction of permanent adrenal insufficiency and the risk of development of an enlarging pituitary adenoma accompanied by hyperpigmentation (Nelson syndrome) are drawbacks of adrenalectomy for this condition.
Medical therapy with an inhibitor of adrenal steroid synthesis is effective for surgical failures and in patients who are not surgical candidates, either alone or in combination with pituitary irradiation (28). Drugs available are ketoconazole 600 to 1,600 mg/day, mitotane (o,p′-DDD) 2 to 10 mg/day, metyrapone 500 mg every 6 hours, and aminoglutethimide 250 to 500 mg every 6 hours. Patients treated with these drugs require physiologic replacement doses of a glucocorticoid to avoid drug-induced adrenal insufficiency. The selection of the most appropriate therapeutic approach for the individual patient should be made by an endocrinologist.
Unilateral laparoscopic adrenalectomy is the treatment of choice for Cushing syndrome caused by an adrenal adenoma, and bilateral adrenalectomy is the treatment of Cushing syndrome caused by bilateral adrenal macronodular hyperplasia.
Those patients found to have ectopic ACTH-secreting tumors as the cause of Cushing syndrome should have surgical resection of the tumors when possible. If surgery cannot be performed or has failed to cure ACTH
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overproduction, the steroidogenesis inhibitors described above can be used to reduce high levels of cortisol. The somatostatin analogues octreotide and lanreotide have been successful in suppressing ACTH secretion from carcinoid tumors in as many as 33% of cases in which it has been attempted. A recent report indicates that the combination of the dopamine agonist cabergoline with a somatostatin analogue leads to prompt and sustained normalization of urinary free cortisol levels (29).
Adrenal Carcinoma
A small number of patients with Cushing syndrome will be found to have adrenal carcinoma as the cause. These patients usually have marked elevations of both adrenal glucocorticoids and androgens. An adrenal mass will commonly be found on CT, MRI, or ultrasonography of the abdomen. Occasionally, the presence of an adrenal mass will be the initial finding leading to the diagnosis of adrenal carcinoma. Classical physical features of Cushing syndrome may be mild or lacking, and the dominant initial laboratory finding may be hypokalemia. Surgical resection is often not possible because of extent of tumor growth. In this circumstance, treatment is by administration of inhibitors of adrenal steroid biosynthesis as above (28).
Adrenal Androgen Excess
If evidence of Cushing syndrome coexists with signs of androgen excess, the 24-hour excretion of adrenal androgens should be measured. When an adrenal tumor is the cause of the syndrome, measurement of urinary androgens may be the most abnormal test. Some adrenal tumors (benign adenomas or carcinomas) produce enormous amounts of androgens. In suspected cases of adrenal tumor, such as an abnormal CT or MRI of the adrenal gland, measurement of androgens is specifically indicated. Serum testosterone may be elevated in women, but not in men (see Adrenal Mass Lesions).
Hirsutism
Hirsutism without virilism (androgen-dependent hirsutism) is common (see Chapter 101). The combination of hirsutism plus virilism, which is rare, is invariably associated with elevated urinary androgens. When such a patient is encountered, referral to an endocrinologist is the most appropriate course. In adults, most cases prove to be caused by adrenal tumors. Other causes, such as congenital adrenal hyperplasia (female pseudohermaphroditism, isosexual precocity in men, hypertension, and salt loss), become apparent in childhood. Only a few cases (caused by 21-hydroxylase deficiency) have been seen in adults.
Other Adrenal Diseases
Mineralocorticoid Excess
The classic condition resulting from mineralocorticoid excess is primary aldosteronism because of a benign adrenocortical adenoma (Conn syndrome). Clinical features include hypertension and the manifestations of hypokalemia. A larger number of patients, however, are normokalemic and are identified by screening of patients with hypertension. Screening is accomplished by simultaneous measurement of plasma aldosterone and renin and then expressing the results as an aldosterone-to-renin ratio. A value greater than 30 warrants further investigation. A significant number of cases are caused by bilateral adrenocortical nodular hyperplasia. The evaluation of this condition is described in Chapter 50.
Mineralocorticoid Deficiency
Aldosterone deficiency is part of classic adrenal insufficiency (Addison disease) but may also occur as a selective functional deficiency state in the syndrome of hyporeninemic hypoaldosteronism. The identifying feature is hyperkalemia.
Pheochromocytoma
Pheochromocytoma is a rare catecholamine (epinephrine, norepinephrine)-producing tumor that is usually considered in relationship to the evaluation of hypertension. Evaluation for this tumor is described in Chapter 67.
Adrenal Mass Lesions, Incidentally Identified (Adrenal Incidentalomas)
An adrenal incidentaloma is defined as a mass lesion greater than 1 cm in diameter found during CT or MRI of the abdomen performed for reasons other than suspected adrenal disease. Such masses are found in 2% to 15% of individuals at autopsy and in approximately 2% of all abdominal CT scans. The majority are benign, clinically silent adenomas. When such a lesion is discovered, consideration should be given to the possible presence of Cushing syndrome, of adrenal carcinoma, of mineralocorticoid or catecholamine excess producing intermittent or sustained hypertension (aldosteronism, pheochromocytoma), of hirsutism and virilization, and of feminization. A detailed history and physical examination focusing on signs and symptoms of adrenal hyperfunction or malignancy is the initial step in evaluation. Subclinical Cushing syndrome has been found in 5% to 8%, pheochromocytoma in 5%, and primary aldosteronism in 1% of patients with adrenal incidentaloma. Biochemical testing should be initiated as appropriate based on clues from the history and physical examination.
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A major concern is whether the mass represents a carcinoma. Three considerations are relevant in attempting to make this distinction: biochemical activity, size and appearance of the lesion on CT or MRI, and the very low incidence of adrenal carcinoma. Most carcinomas produce high levels of biochemically measurable products, including glucocorticoids and adrenal androgens. Rarely, only testosterone or aldosterone levels are increased. Benign adenomas may also produce excess quantities of steroids. Nevertheless, tumors producing biochemical products generally should be removed.
If no biochemical abnormality is demonstrable, the size and appearance of the lesion on CT give some indication of whether it is benign or malignant. When discovered, most benign adenomas are small (<6 cm diameter), round and homogeneous, and have a low attenuation value with no enhancement following intravenous contrast. Most carcinomas are large (>6 cm diameter) and the presence of necrosis, hemorrhage, or calcifications on CT or MRI suggest adrenal carcinoma. With tumors larger than 6 cm, approximately three operations would be necessary to remove one carcinoma, and more than 4,000 operations would be needed to remove a single carcinoma if one considers all lesions of diameter greater than 1 cm.
When there is suspicion of malignancy based on the above criteria, adrenal iodocholesterol scanning may be of value in differentiating benign from malignant adenomas as those that take up iodocholesterol are usually benign, whereas those that do not are usually malignant.
Occasionally, the adrenal mass is cystic. Large cystic masses can be aspirated by needle puncture; clear fluid indicates a benign lesion, but bloody fluid is indeterminate and cytology is not helpful. Similarly, needle aspiration biopsy is usually not useful in distinguishing benign from malignant cystic lesions.
In followup of biochemically silent adrenal masses, imaging by CT or MRI at 3, 12, and 18 to 24 months and then yearly are indicated, along with biochemical reassessment at yearly intervals. Lesions that are stable at 18 to 24 months and less than 4 cm in diameter can be considered benign and should not be removed (29). A few cases develop a new contralateral mass; a few others will enlarge and should be surgically removed (30). Subtle hypercortisolism in several standard tests of the hypothalamic–pituitary–adrenal axis may develop in approximately 4% of patients at 1 year and 6% of patients at 5 years of followup. These lesions have come to be termed “subclinical Cushing syndrome” and probably should be removed, as many will progress to overt Cushing syndrome (31).
Pharmacologic Uses of Steroids
Most steroid (glucocorticoid) use is related to treatment of diseases other than adrenal insufficiency. In normal persons, basal cortisol production is approximately 25 mg per 24 hours and under maximal stress can reach approximately 200 mg per 24 hours. Doses of administered glucocorticoid that exceed these values are best termed supraphysiologic or, simply, pharmacologic. The anti-inflammatory and immunosuppressive properties of these drugs constitute an invaluable part of the modern therapeutic armamentarium, but such uses, when prolonged, are invariably associated with side effects. Short-term use, generally for less than 3 weeks, is usually not associated with adverse effects. All available glucocorticoids share these properties to an equal degree, although potency (effectiveness per milligram) varies widely (Table 81.2). Despite this fact, certain glucocorticoid compounds are associated with the treatment of particular conditions (e.g., dexamethasone for treatment of cerebral edema, methylprednisolone for hepatic disease). Often there is no pharmacologic basis to support such exclusive practices. On the other hand, differences between available preparations do exist that include different rates of absorption, metabolic disposal, and solubility and inherent mineralocorticoid activity. Exploitation of such properties is seen in dermatologic use. Triamcinolone and fluocinolone acetonides appear to be much more effective than hydrocortisone for topical use, a phenomenon apparently related to properties of absorption.
Adverse Effects
Table 81.4 lists untoward effects of glucocorticoids. These problems are related to dose and, equally important, to duration of therapy. No contraindication exists to a single dose of glucocorticoid, regardless of the size of that dose. Thus, treatment of an allergic reaction with one or a few doses carries no risk. Long-term therapy, however, should be instituted only after consideration of the risks and benefits.
Adverse effects of steroids are related not only to duration of therapy but also to the dosage used. Obviously, the minimally effective dosage should be used. Nonetheless, some people seem especially vulnerable to unwanted side effects. Poorly nourished, debilitated, and elderly patients are more prone to the muscle-wasting effects of steroids (steroid myopathy). Postmenopausal women (already prone to develop osteoporosis) are especially vulnerable to the demineralization that accompanies steroid use. Bisphosphonate inhibitors of bone resorption (e.g., alendronate) should be considered for such patients (see Chapters 84 and 103). Genetically predisposed individuals or patients in the early phase of the metabolic syndrome may develop overt diabetes mellitus when given glucocorticoids. Peptic ulcer disease may be reactivated, and complications such as bleeding or perforation may be precipitated. Prophylactic use of antiulcer therapy should be considered in patients with a history of peptic ulcer
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disease. Dormant tuberculosis, clinically inapparent except for a positive tuberculin test, may reactivate. The role of isoniazid prophylaxis in this situation is described in Chapter 34. A gamut of psychiatric problems may be seen in patients who receive corticosteroids—emotional lability, depression, euphoria—which may necessitate adjustment of the dosage.
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TABLE 81.4 Untoward Effects of Chronic Glucocorticoid Therapy |
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Topical Therapy
When steroids can be used locally, such use is preferred, especially when long-term treatment is involved. Although absorption may be complete from a local site, the amount of steroid required is often far less when use is local. This avoids, to some extent, systemic effects, side effects, and pituitary–adrenal suppression. In addition to dermatologic use of topical steroids, treatments of some ophthalmologic conditions, allergic rhinitis, asthma, and localized joint disease are examples of this principle.
Intermittent Therapy
Usually, severe disease requires initiation of steroid therapy given as multiple daily doses. When the disease intensity has waned (e.g., 1 to 2 weeks), conversion to alternate-day therapy can be made. Intermittent therapy of this type should always be considered when long-term use is contemplated. Such therapy is to be preferred because pituitary–adrenal suppression is less likely, and the adverse effects of glucocorticoids are minimized. When initiating intermittent therapy, the daily dose is given as a single morning dose. After this dose has been shown to be tolerated for several days, the single daily dose may be doubled and given as a single dose every other day. Thereafter, the dose given every other day can be reduced slowly, as clinically indicated. The patient may be symptomatic on the off day, particularly when alternate-day therapy is first started. To handle this situation, small doses of glucocorticoid may be given on this day. Nonsteroidal anti-inflammatory agents may also be helpful in ameliorating symptoms during transition.
Use of Adrenocorticotropic Hormone
The clinical indications for the use of ACTH rather than a glucocorticoid are practically nonexistent. The practice continues, however, because ACTH was available for clinical use even before cortisone was. It is clear that in sufficient amounts (100 units), long-acting preparations (gel or zinc suspensions) given once daily are capable of stimulating adrenal secretion of up to 300 mg of cortisol daily. However, disadvantages are multiple: the route is parenteral, the magnitude of response is unpredictable, the
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mineralocorticoid effects (salt and fluid retention, potassium wasting) are considerable, and the response in patients previously treated with glucocorticoids is slow and unpredictable. The only advantage is that adrenal responsiveness is maintained during therapy. Combined ACTH–glucocorticoid therapy has been advocated for this reason, as has the occasional injection of ACTH to prevent adrenal atrophy. However, the advantage of such an approach over that of intermittent glucocorticoid therapy is unclear. When ACTH is used alone at high dosages for a prolonged period, pituitary suppression occurs even though adrenal suppression does not. Another disadvantage of ACTH therapy is failure to produce more than the equivalent of 300 mg of cortisol (75 mg of prednisone) despite maximal stimulation of the adrenals. Such a dosage, although considerable, may be insufficient to produce the desired clinical effect.
Withdrawal from Acute or Chronic Glucocorticoid Therapy
Treatment with glucocorticoids (e.g., cortisone, hydrocortisone, prednisone) produces suppression of the hypothalamus–pituitary–adrenal axis; the output of ACTH falls, and there is subsequent adrenal atrophy and an inability to respond to stress with increased cortisol output. The time required for initial suppression is highly variable (see Recovery from Hypothalamus–VPituitary–VAdrenal Suppression). Patients receiving daily pharmacologic doses of glucocorticoids (5 mg or more of prednisone or its equivalent daily) for more than 1 week should be presumed to have a suppressed response to stress (32). If stressed by surgery, trauma, or severe infection, these patients should be treated with replacement glucocorticoids as if they had Addison disease. On the other hand, glucocorticoids may be discontinued abruptly after 2 to 4 weeks of pharmacologic steroid therapy provided that the patient is not under stress, because baseline—as opposed to stress-related—adrenal function is almost always adequate. Patients who have been treated with alternate-day steroid therapy are not at risk because pituitary–adrenal function seems well preserved in these individuals.
When it becomes desirable to terminate glucocorticoid therapy, the question arises of how to accomplish this goal while avoiding adrenal insufficiency. In the presence of active underlying disease, for which the glucocorticoids may have been given in the first place, a dilemma quickly becomes apparent. The nonspecific symptoms of adrenal insufficiency may be similar or identical to those of the disease that was under treatment. In addition, the occurrence of the “steroid withdrawal syndrome” (see Steroid Withdrawal Syndrome: Distinction from Acute Adrenal Insufficiency) may further compound the issue.
Withdrawal Schedule
No single scheme can solve this difficult clinical problem, although many have been proposed. However, a few general points can be made. First, even after prolonged therapy, in the absence of active underlying systemic disease, symptoms of true adrenal insufficiency will not occur until the daily dose of glucocorticoid drops below physiologic replacement (20 mg of cortisol, 5 mg of prednisone, or equivalent; seeTable 81.2). Symptoms similar to those of adrenal insufficiency may occur as the daily dose is being reduced (see Steroid Withdrawal Syndrome: Distinction from Acute Adrenal Insufficiency), although most patients will not be symptomatic if they take a single 20- to 30-mg daily dose of cortisol (or 5 to 7.5 mg of prednisone). Continuation of 20 mg of cortisol daily for 2 months should ensure some degree of recovery of pituitary–adrenal function. Further withdrawal begins to re-establish the normal pituitary–adrenal relationship. Additional reductions of 5 mg of cortisol can be made every 2 to 3 weeks over the next 2 months or, alternatively, an every-other-day program can be tried over the same period; the glucocorticoid can then usually be stopped without producing symptoms. A laboratory assessment of the functional status of the patient's adrenals at this point is described below (see Recovery from Hypothalamus–Pituitary–Adrenal Suppression: Limitations of Testing with Adrenocorticotropin Hormone).
Steroid Withdrawal Syndrome: Distinction from Acute Adrenal Insufficiency
Abrupt withdrawal of pharmacologic doses of glucocorticoids, even after months of therapy, does not always produce chemical evidence of adrenal insufficiency. Nonetheless, the patient may experience many of the symptoms of adrenal insufficiency (e.g., lethargy, malaise, anorexia, nausea, vomiting, myalgias, fever, and, in severe cases, desquamation of skin in a manner resembling exfoliative dermatitis). Less-than-abrupt withdrawal may result in similar, but not as severe, symptoms. Such patients may be found to have normal or elevated levels of cortisol. This phenomenon is not simply adrenal insufficiency but rather is a pharmacologic withdrawal syndrome. Symptoms subside promptly with reinstitution of glucocorticoid therapy.
Recovery from Hypothalamic– Pituitary–Adrenal Suppression: Limitations of Testing with Adrenocorticotropin Hormone
Recovery of the hypothalamus–pituitary–adrenal axis after 1 week of “steroid burst therapy” (e.g., 40 mg of
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prednisone for 3 days, followed by a 4-day taper) appears complete within 1 additional week (32), but the rate of recovery is unpredictable after withdrawal from longer courses of therapy. After long-term glucocorticoid therapy (pharmacologic doses for a year or more), recovery of normal pituitary–adrenal responsiveness does not occur for at least several months, even if the patient receives no exogenous steroid therapy during that time. In the first month after withdrawal, both pituitary and adrenal function remain depressed (low plasma ACTH and low plasma cortisol). Over the following 4 months, pituitary function recovers first (plasma ACTH is elevated), but adrenal function remains subnormal (plasma cortisol is lower than normal). Eventually, adrenal function recovers (plasma cortisol levels normalize) and elevated plasma ACTH returns to normal. The entire process may require up to 9 months. During this interval the patient may fare well, provided there is no stress, but replacement therapy with glucocorticoids may become necessary at any time. Accordingly, no patient should be considered to have normal pituitary–adrenal function unless at least 1 year has elapsed after complete withdrawal of chronic glucocorticoid therapy. Occasional patients seem never to recover normal responsiveness. Ideally, therefore, all patients with a history of long-term steroid therapy, if they are to be tested for normality of the axis, should be tested 1 year after withdrawal. It is not clear, however, whether any practical test is available.
Assessment of a glucocorticoid-treated patient's adrenal function under baseline conditions is easy. Both plasma cortisol measurements and urinary excretion of steroid metabolites give a reasonable estimate of baseline function. However, predicting the response to stress is more difficult. Because hypothalamic–pituitary function usually recovers first, followed by adrenal function, a normal response to exogenous ACTH would seem to indicate recovery of the entire axis but in fact does not do so with a reasonable degree of reliability. An accurate assessment of the integrity of the axis can be made by induction of hypoglycemia with insulin (ITT). Hypoglycemia triggers ACTH release and the cortisol secretory response of the adrenal. A normal ITT essentially ensures that if the patient is subjected to stressful circumstances, replacement therapy with steroids will be unnecessary. However, the ITT must be done with careful monitoring and is considered to be dangerous and therefore inappropriate in patients with a history of seizures or who are at risk for or have known cardiac disease. It should be performed only under the direct supervision of an endocrinologist who is experienced in the procedure. An ITT is indicated only in the small number of previously glucocorticoid-treated patients who have experienced symptoms suggestive of adrenal insufficiency when under stress.
Administration of CRH rather than ACTH has been advocated as an alternative to the insulin-induced hypoglycemia test. The end point is the plasma cortisol response. This procedure is easier and is completely safe. However, the correlation between the CRH and ITT is only fair, and the magnitude of the response is only a 1.5-fold mean increase in plasma cortisol, requiring a laboratory with optimal accuracy. Ideally, a CRH stimulation test should be done only by an endocrinologist.
As a practical matter, empirical short-term corticosteroid administration (“coverage”) during stress is probably the simplest, safest, and cheapest way to manage patients in whom the status of the adrenal–pituitary axis is uncertain.
Disorders of Water Metabolism
Disorders of water metabolism can be divided into two major categories: those associated with impaired ability to conserve water (polyuric disorders) and those associated with impaired ability to excrete water (hyponatremic disorders).
Polyuric Disorders
The combination of excess thirst, increased intake of water, and increased output of urine is a common clinical presentation of a number of conditions (Table 81.5). In most of these, the symptoms are related to some event that results in excessive loss of fluid via the kidney.
Causes
The classical polyuric disorder of water metabolism in ambulatory patients is diabetes insipidus, a deficiency of antidiuretic hormone (ADH) (arginine vasopressin). This condition may be idiopathic, in which case it is unassociated with other evidence of pituitary–hypothalamic disease. More commonly, it is caused by head trauma; neurosurgical procedures in the region of the pituitary; malignancy metastatic to the pituitary; pituitary adenoma or other disease in the hypothalamic–pituitary stalk-pituitary area (craniopharyngioma, aneurysm); hypoxic encephalopathy; a variety of infiltrative diseases (sarcoidosis, tuberculosis); or central nervous system infections.
Less commonly, diabetes insipidus results from nephrogenic diabetes insipidus, an inherited renal tubular resistance to ADH, and usually presents in childhood. Acquired forms of ADH-resistant polyuria are more common in later life and may be less severe than the congenital forms. The most common is the ADH-resistant disorder that results from use of lithium for bipolar affective illness. Other causes of acquired ADH resistance are hypokalemia,
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hypercalcemia, acute tubular necrosis, chronic pyelonephritis, renal amyloidosis, multiple myeloma and Sjögren syndrome.
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TABLE 81.5 Causes of Polyuria |
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A common cause of polyuria is hyperglycemia from poorly controlled diabetes mellitus, which results in a large solute load (glucose) being presented to the renal tubules with an obligatory loss of water (osmotic diuresis). Other causes of osmotic diuresis are increased urinary sodium excretion (diuretic-induced or excessive dietary sodium intake) and mannitol administration.
The ingestion of large quantities of beer, sometimes referred to as beer potomania, can produce polyuria with associated hyponatremia that may be severe enough to produce central nervous system (CNS) symptoms ranging from confusion to stupor to seizures. Patients who present with this disorder are usually binge beer drinkers with poor dietary intake.
Patients with severe psychiatric disorders, especially those with chronic schizophrenia, are at risk of excessive fluid intake that can result in polyuria and dilutional hyponatremia, which may be severe and symptomatic (33). In a study involving a large group of psychiatric inpatients, defects in urinary dilution, osmoregulation of water intake and secretion of ADH were identified. Drugs may play a role in many of the episodes of hyponatremia in these patients as well (34).
A less common cause of polyuria is primary polydipsia, which leads to prolonged, increased fluid intake. The disorder may arise without other evident CNS dysfunction or in response to disease, particularly that affecting the hypothalamic and other regions of the brain associated with control of thirst perception. It is usually accompanied by chronic hyponatremia; symptoms may be few but on occasion can be severe.
Occasionally, people begin excessive water intake in the mistaken impression that drinking large quantities of water is healthful. Regardless of the cause, once such behavior is started, a compulsive pattern tends to persist and is reinforced by a pathophysiologic mechanism. A large urine output, if it persists for a long time, produces a reversible impairment of urine-concentrating ability due to washout of renal medullary solutes. Thus, the behavior pattern, although basically of psychogenic origin, may become self-perpetuating. Attempts to have the patient restrict water intake when urinary concentrating ability is impaired under these conditions lead to continued water loss, and the resulting hyperosmolality leads to intense thirst. Weaning from excessive water intake may be difficult.
Approach to the Patient with Polydipsia and Polyuria
The history should be corroborated by family or friends if possible. Important historical points are rapidity of onset of symptoms, a preference for use of iced water, and nocturnal drinking habits. Sudden onset and preference for iced water are classic features of diabetes insipidus. Numerous spontaneous awakenings at night to drink and urinate also strongly suggest this diagnosis, whereas absence of such events is in favor of functional disease. A careful psychiatric and pharmacologic history is important.
Initial laboratory workup should be straightforward. A morning fasting serum glucose, sodium, and osmolality determination should be made along with serum potassium, calcium, urea nitrogen, and creatinine determinations. Normal serum calcium and potassium concentrations exclude several metabolic problems, whereas abnormalities of calcium, potassium, or renal function make it clear that the problem is caused by altered renal water-conserving ability. If considerable glucosuria and hyperglycemia are present, the cause of the patient's problem is evident and should respond to correction of hyperglycemia.
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The patient should collect all urine over one or two 24-hour periods to be examined for volume, osmolality, total urine glucose excretion, and total sodium and creatinine excretion, the latter serving as a marker for completeness of the collection. Measurement of urine specific gravity is inaccurate and obsolete and should be replaced by measurement of urine osmolality. Normal 24-hour urine volume ranges from 1,000 to 2,500 mL. Urine osmolality is decidedly low when the value is well below that of serum (<300 mOsm/kg); the urine is maximally dilute at 50 to 70 mOsm/kg.
The presence of a normal serum sodium or osmolality indicates only that the process is not severe enough to have overwhelmed the ability to excrete water or the homeostatic (thirst) mechanism. Elevated serum osmolality strongly suggests diabetes insipidus while reduced osmolality suggests psychogenic water drinking. In both diabetes insipidus and psychogenic water drinking, urine volume usually exceeds 4 L per day. Values less than 5 to 6 L per day do not distinguish between these possibilities, but do indicate less-than-complete diabetes insipidus, in which urine volumes often approach 10 to 12 L per day, as they may also in cases of severe psychogenic water drinking. If the serum sodium and osmolality are low and the urine volume is large with low osmolality, a diagnosis of psychogenic water drinking is essentially established. If diabetes insipidus is suspected, the next step is to determine the response of urine osmolality to administered antidiuretic hormone (aqueous vasopressin 5 units subcutaneously or 10 µg desmopressin intranasally). Failure of urine osmolality to rise 1 hour after hormone administration indicates the presence of nephrogenic diabetes insipidus.
If there is a large urine volume of low osmolality and normal serum electrolyte concentrations, additional testing is necessary to establish a diagnosis. Referral to an endocrinologist or a nephrologist is appropriate. Hospitalization for testing under metabolic conditions is usually preferred in these cases.
Treatment
The treatment of psychogenic water drinking involves psychiatric counseling. These patients are difficult to manage, especially if they become severely hyponatremic. Weaning such patients from water may also be a slow process, not only because of the profound nature of their psychiatric disturbance but because of their acquired inability to concentrate urine, a process that is only slowly reversible.
The treatment of diabetes insipidus involves use of ADH in some form. For ambulatory patients, ADH is available as the synthetic analogue desmopressin or DDAVP (1-deamino-8-D-arginine vasopressin) and can be administered as a nasal spray, oral tablets, or parenterally. Treatment with nasal spray is begun with 0.05 to 0.1 mL (5 to 10 µg) every 12 to 24 hours with individual titration thereafter. A single dose usually acts for 12 hours or longer. Nasal absorption may be impaired by rhinitis or respiratory tract infections, during which treatment with injectable or oral desmopressin (100 to 400 mg/day) may be necessary. Serum sodium must be monitored closely on initiation of therapy to avoid the development of significant hyponatremia as a consequence of excessive water retention. Patients with partial diabetes insipidus have been managed in the past with chlorpropamide (Diabinese, 250 to 500 mg/day), a drug that potentiates endogenous ADH. However, hypoglycemia is a significant hazard and current preference is for use of desmopressin. Nephrogenic diabetes insipidus, both idiopathic and secondary to lithium, is partially responsive to sodium restriction and thiazide diuretics to induce chronic intravascular volume depletion and consequent increased renal water reabsorption.
Hyponatremic Disorders
Prevalence and Incidence
Hyponatremia is the most common electrolyte disorder, especially among elderly persons. In one study, 7% of healthy subjects older than age 65 years and living at home had a serum sodium of 137 mEq/L or lower. Similarly, hyponatremia was observed in 11% of outpatients from a geriatric medicine clinic (35). Hyponatremia is even more common among hospitalized than nonhospitalized patients, among whom the prevalence increases with age (36). Elderly residents of long-term care institutions appear to be especially susceptible to hyponatremia. In a survey of nursing home residents 60 years of age and older, 18% had a serum sodium less than 136 mEq/L. In a longitudinal analysis of this population, 53% had one or more episodes of hyponatremia during a 12-month period. Persons with CNS and spinal cord disease were at highest risk, and water-load testing indicated that most patients with hyponatremia had features consistent with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) (37).
Causes of Hyponatremia
Medical Diseases
Many diseases can cause SIADH in any population, but the elderly are at highest risk (38). Almost all CNS disorders can lead to dysfunction of the hypothalamic system involved in the normal regulation of arginine vasopressin (AVP) secretion, leading to increased secretion of the hormone and, consequently, to water retention and hyponatremia. Such CNS disorders include vascular injury (thrombosis, embolism, hemorrhage); trauma accompanied by subdural hematoma; vasculitis; tumor; and infection. Cancer can cause SIADH as a result of autonomous release of AVP from malignant tissue, where the hormone is synthesized, stored, and discharged in the absence
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of known stimuli. The cancer most commonly associated with SIADH is small cell carcinoma of the lung. As many as 68% of patients who have this cancer demonstrate impaired water excretion and elevated blood AVP concentration. Other cancers associated with SIADH include pancreatic carcinoma, thymoma, pharyngeal carcinoma, and lymphoma. Inflammatory lung diseases, such as bronchiectasis, pneumonia, lung abscess, and tuberculosis, can also cause SIADH, perhaps as a result of AVP production by diseased pulmonary tissue.
Many other diseases are associated with an increased risk of hyponatremia, including chronic obstructive pulmonary disease, hypertension, diabetes, heart failure, cirrhosis, nephrotic syndrome, renal failure, and hypothyroidism (39). Approximately 50% of patients hospitalized for acquired immune deficiency syndrome (AIDS) also have hyponatremia. Of these, more than half have symptoms consistent with SIADH (40).
SIADH should be differentiated from another form of hyponatremia mediated by the CNS. Renal sodium excretion from the excessive release of natriuretic factor in the brain can lead to cerebral salt wasting (CSW) (41). CSW and SIADH are both syndromes of hypo-osmotic serum and increased urine sodium. Patients with CSW, however, have a low effective intravascular blood volume as a consequence of marked natriuresis and secondary osmotic diuresis. In contrast, patients with SIADH are usually euvolemic or have mildly increased extracellular fluid volume. CSW can be diagnosed by the clinical and laboratory findings that define diminished extracellular fluid volume, including orthostatic hypotension, tachycardia, and elevated hematocrit, serum urea nitrogen (SUN), and creatinine levels.
Surgery
Although men and women of any age are at risk of hyponatremia after undergoing operative procedures, premenopausal women who undergo surgery, often for elective gynecologic problems, are especially susceptible to severe hyponatremia in the postoperative period. Hyponatremia can appear within 9 days after surgery, but its progress can be rapid enough to produce severe symptoms within a period of hours. Early symptoms include headache, nausea, vomiting, weakness, lethargy, confusion, and slurred speech. Abrupt respiratory arrest may occur and is associated with the development of cerebral edema and hypoxic encephalopathy. Unless the syndrome is recognized and treated promptly, permanent brain damage or death is likely to occur (42).
Drugs
Numerous drugs can cause hyponatremia by increasing the release of AVP from the neurohypophyseal system, by enhancing AVP action on the kidney, or by acting directly on the kidney (43). In particular, many drugs increase the risk of SIADH.
Hyponatremia with the characteristics of SIADH is recognized as an adverse effect of tricyclic antidepressants and of several older antipsychotic agents, such as fluphenazine, thiothixene, and phenothiazine. The selective serotonin reuptake inhibitor (SSRI) antidepressants can also induce SIADH, which occurs in 3.5 to 6.3 per 1,000 patients annually who take these drugs (44). Although fluoxetine is the SSRI most commonly associated with hyponatremia, other SSRIs, including paroxetine, sertraline, and fluvoxamine, are also known to produce the disorder. Patients at highest risk for SSRI-induced hyponatremia are those older than age 65 years, in whom the disorder typically occurs within 2 weeks after the initiation of therapy. In a recent prospective study of depressed elderly patients given paroxetine, approximately 12% had hyponatremia (with a serum sodium as low as 124 mEq/L) within 9 days, on average, after starting SSRI therapy. In all of these patients, the hyponatremia had features consistent with SIADH (45).
Angiotensin-converting enzyme (ACE) inhibitors are also associated with dilutional hyponatremia (46). In most such cases, the hyponatremia has been severe and accompanied by symptoms ranging from confusion to seizures and coma. Although initial reports indicated that the risk was greatest when ACE inhibitors were used in combination with thiazide diuretics, it now appears that the ACE inhibitors alone can precipitate hyponatremia. Hyponatremia induced by ACE inhibitors appears to be dilutional, is accompanied by features of SIADH, and may be mediated by the potentiation of plasma renin activity. This activity subsequently increases angiotensin levels in the brain, which, in turn, stimulate both the release of AVP from the hypothalamus and the thirst response. Discontinuing the ACE inhibitor therapy leads to a resolution of the hyponatremia.
Diuretics, especially thiazides, can decrease renal diluting capacity. In the elderly, generally men over the age of 65 years, this effect becomes especially important when it is superimposed on the already diminished diluting capacity of the aged kidney and thus increases the risk of hyponatremia by impairing the kidney's ability to excrete excess water promptly. In a review of 129 patients with diuretic-induced hyponatremia (serum sodium <115 mEq/L), thiazides were the cause of the disorder in 83% of patients, chlorthalidone in 10%, and furosemide or spirolactone in 7% (47). Loop diuretics appear to have a greater natriuretic effect in older than in younger persons. Hyponatremia can occur when diuretic-induced sodium and water loss is replaced by hypotonic fluid, resulting in a combined depletional and dilutional hyponatremia. Thiazide diuretic-induced sodium loss is often accompanied by the loss of total body potassium, which consequently decreases intracellular solute content and cell volume. This combination
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can activate hypothalamic volume receptors and thus trigger AVP secretion, water retention, and SIADH, a reaction that occurs almost exclusively in the elderly and can be reversed by correcting the underlying potassium depletion.
Other drugs associated with the development of hyponatremia in the elderly include the sulfonylurea chlorpropamide; the anticonvulsant carbamazepine; the antineoplastic agents vincristine, vinblastine, and cyclophosphamide; calcium channel blockers; nonsteroidal anti-inflammatory drugs; desmopressin acetate; and nicotine. Analgesics, particularly the opioid narcotics, may be responsible for the occurrence of hyponatremia in elderly patients who have undergone surgery.
Of particular concern in the emergency department is the occurrence of acute, severe hyponatremia in young persons who have taken the hallucinogenic drug “ecstasy” (N-methyl-3,4-methylenedioxyamphetamine, or MDMA). These patients, who may present with seizures and respiratory arrest caused by cerebral edema, may be resistant to therapy.
Idiopathic Hyponatremia of Aging
Advanced age itself may be a risk factor for hyponatremia. SIADH has been observed in elderly persons, usually older than age 80 years, in whom no identifiable cause for hyponatremia is evident. This finding suggests there is an idiopathic form of SIADH that may occur in response to the physiologic changes that occur in the regulation of water balance during aging. African American patients appear to be at lower risk than whites or Hispanics (35).
Diagnosis
Hyponatremia is often underdiagnosed and undertreated because patients may have only subtle symptoms or remain asymptomatic until the serum sodium drops below 125 mEq/L. The diagnosis of hyponatremia, which can be dilutional, depletional, or of mixed origin, rests on a thorough history of concurrent illness and medication use, physical examination, and an assessment of volume status and readily available laboratory measures (Table 81.6).
Dilutional versus Depletional Hyponatremia
The characteristic features of dilutional hyponatremia, as caused by SIADH, for example, are a low serum sodium and serum hypo-osmolality accompanied by clinical euvolemia without edema. Other features include a failure of the urine to be appropriately dilute, excretion of sodium in the urine at a concentration of greater than 20 mEq/L, and the absence of other disorders that cause hyponatremia, including hypothyroidism, adrenal insufficiency, congestive heart failure, cirrhosis, and renal disease (48).
Depletional hyponatremia typically occurs after a prolonged period of inadequate sodium intake or is caused by increased sodium loss from the gastrointestinal tract or urine. Extracellular fluid volume depletion is often evident as well, and the physical findings and laboratory values usually indicate hypovolemia.
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TABLE 81.6 Diagnosis of Dilutional versus Depletional Hyponatremia |
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Laboratory evaluation plays a critical role in diagnosing hyponatremia. It is important to determine whether the effective serum osmolality reflects true hypo-osmotic hyponatremia, normotonic pseudohyponatremia (caused by hyperproteinemia or hypertriglyceridemia), or elevated tonicity caused by the presence of other osmoles, as may occur in hyperglycemic patients or those undergoing mannitol infusion.
Once serum hypo-osmolality is confirmed, the ability of the kidneys to concentrate urine should be evaluated. Hyponatremia that occurs when the urine is dilute (<100 mOsm/kg) indicates AVP secretion is appropriately suppressed and suggests primary polydipsia as the likely cause of hyponatremia (33,34). Reset osmostat syndrome may underlie hyponatremia that occurs with normal or dilute urine and is caused by a lowered threshold at which osmoreceptors trigger AVP release. This syndrome occurs in patients who have normal adrenal, renal, and thyroid function without cardiac or hepatic disease and whose urine is diluted normally in response to oral water loading (excretion of >80% in 4 hours). Patients who have concentrated urine (>100 mOsm/kg) may have hypovolemic, euvolemic, or hypervolemic hyponatremia. Differentiating hypovolemic from euvolemic hyponatremia by clinical examination alone can be challenging. Decreased effective intravascular blood volume indicates hypovolemia. The serum uric acid concentration may provide insight, as it tends to be elevated in patients with low effective intravascular blood volume and is reduced in volume-expanded
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states such as SIADH. In most cases, both the urine sodium and volume status will provide clues. An abnormally low urine sodium (<20 mEq/L) in patients with hypovolemia is common and often accompanied by extrarenal volume depletion caused by diarrhea, vomiting, and integumentary losses. In contrast, urine sodium >20 mEq/L in patients with hypovolemia may suggest sodium loss caused by nephropathy, adrenal insufficiency, or CSW. In patients with hypervolemia accompanied by edema, the urinary sodium level will be diminished in the presence of congestive heart failure (CHF), cirrhosis, or nephrotic syndrome, but elevated in the presence of renal failure.
Euvolemic or mildly hypovolemic hyponatremia is often accompanied by hypotonic serum and concentrated urine. Urine sodium of 40 mEq/L or greater in such cases usually indicates SIADH. Hypothyroidism and adrenal insufficiency must be ruled out to confirm the diagnosis of SIADH.
Treatment
The treatment of hyponatremia should not be initiated solely on the evidence of abnormally low serum sodium. The role of management is not only to correct the sodium level, but also to identify and correct the underlying cause of hyponatremia and to restore body-water homeostasis when possible to avoid potentially harmful sequelae. Usually, the most important factors that determine the rapidity of treatment are the absence or presence of symptoms and their severity, whether the disorder is acute or chronic, and, if the hyponatremia is acute, the rapidity of onset of the condition or symptoms.
Asymptomatic Patients
Some patients with hyponatremia may be incorrectly considered asymptomatic if their signs or symptoms are subtle or attributed to another condition. Patients whose hyponatremia is chronic, subacute, or of unknown duration may have few or no overt clinical symptoms. Patients likely to be asymptomatic or mildly symptomatic are those with sodium loss caused by diuretics, digestive losses, or nephrotic syndrome. The treatment of chronic asymptomatic hyponatremia should be conservative, with the initial efforts focused on identifying the cause.
Conservative therapy for asymptomatic euvolemic hyponatremia starts with fluid restriction. The gradual correction of hyponatremia will counteract the stimulus for AVP release and, eventually, sodium balance will be restored. The ability of a patient to produce dilute urine should govern the degree of fluid restriction, but limiting water intake to less than free water loss will increase sodium regardless of the underlying cause of hyponatremia. Fluid restriction should be sufficient to affect serum sodium in euvolemic hyponatremia, whereas in hypervolemic hyponatremia, both salt and fluid intake restrictions may be necessary. Normal saline (0.9%) can be administered to correct extracellular fluid volume deficit in hypovolemic hyponatremia. If thyroid or adrenal insufficiencies are detected, appropriate treatment should be sufficient to correct the hyponatremia. If thiazide diuretics are responsible for hyponatremia, they should be discontinued or replaced with a nonthiazide diuretic. When SIADH is identified as the cause of hyponatremia, treatment of the underlying process causing hormonal imbalance of AVP is the appropriate approach.
The presence of risk factors for neurologic complications should always be considered. The rate of serum sodium correction for asymptomatic and mildly symptomatic hyponatremia should not exceed 0.5 mEq/L per hour on the first day and should not be increased to more than 12 mEq/L in the first 24 hours. After that time, and until symptoms resolve, the rate of correction should be increased no more than 0.25 mEq/L per hour.
Symptomatic Patients
Untreated severe hyponatremia can produce cerebral edema and increased intracranial pressure, both of which lead to neuropathologic sequelae or death. Accordingly, symptomatic or severe hyponatremia justifies prompt treatment. The major risk of correcting sodium too rapidly is the development of central pontine myelinolysis (CPM). Thus, the goal of therapy is to achieve a rate of correction sufficient to resolve the symptoms and to reduce cerebral edema, but not so rapid as to risk CPM. Patients with severe or symptomatic hyponatremia should be hospitalized promptly and correction of the hyponatremia carried out under the guidance of a physician who is experienced with the management of the disorder.
Acute symptomatic hyponatremia is most often associated with polydipsia or postsurgical conditions. The rapid correction of serum sodium levels in cases in which the duration of hyponatremia is known to be short is rarely necessary unless symptoms are severe; however, rapid correction is unlikely, in theory, to increase the risk of neurologic demyelination. When symptoms are present, a prompt initial increase in sodium level is necessary and can be achieved with the intravenous administration of 3.0% NaCl. Such treatment should be carried out in a setting in which serum sodium can be monitored closely, initially at 1- to 2-hour intervals. Most patients are best managed in a hospital intensive care unit.
Chronic hyponatremia may still be symptomatic, even if present for only several days, and there may be a superimposed acute episode. If the duration of hyponatremia is unknown or longer than 48 hours, the clinician must proceed with care because the brain's compensatory mechanisms mandate slow correction. The treatment of chronic hyponatremia accompanied by severe symptoms is similar to that of acute symptomatic hyponatremia, but in this case extreme caution is necessary and is best carried out in an intensive care unit with close laboratory monitoring.
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AVP-Receptor Antagonists and Aquaresis
Because hyponatremia associated with water retention is a result of excess AVP, the most rational approach to therapy for this disorder is to either decrease secretion of the AVP hormone or block its effects on the kidney.
The tetracycline antibiotic demeclocycline has been used in doses of 600 to 1,200 mg daily to produce a state of renal AVP resistance through its ability to block AVP-induced activation of the renal adenyl cyclase–cyclic adenosine monophosphate (cAMP) system (49). This drug-induced state of partial nephrogenic diabetes insipidus produces a modest increase in urine volume with a decrease in urine osmolality to near isotonicity and a corresponding rise in serum sodium. Each patient's response to this agent is variable, however, and several days of therapy are necessary before a response does occur. In addition, the treatment may be complicated by renal and hepatotoxicity.
In the treatment of hyponatremia, aquaresis, the excretion of water without electrolyte loss, is preferable to diuresis (50). In recent years, several nonpeptide molecules capable of inhibiting AVP at the level of its tissue receptors have been developed and designated as aquaretics. These compounds are capable of directly inhibiting AVP V1 vascular and/or V2 renal receptors located on the distal tubules. By counteracting the effect of AVP V2 receptors and thus inducing free water excretion, AVP V2-receptor antagonists can treat hyponatremia directly. Aquaretic agents that target the AVP V2 receptor or V1a and V2 receptors have shown promising clinical results, and early trials have demonstrated their ability to normalize sodium levels safely in patients who have euvolemic or hypervolemic hyponatremia with SIADH and CHF (51, 52, 53).
Demeclocycline and aquaretics should be considered in patients with chronic hyponatremia when the underlying cause cannot be corrected and when the patient is experiencing symptoms attributable to hyponatremia. The aquaretic agents may play a role in the acute management of symptomatic hyponatremia as their onset of action is within minutes of administration and the dose can be tailored to produce the desired level of water excretion. These agents will be available for clinical use in the near future.
Hypoglycemia
Because many of the symptoms of hypoglycemia are nonspecific, it is suspected more often than it is present. Chemical hypoglycemia, defined as a serum glucose concentration of less than 40 mg/dL, may not be symptomatic, although levels less than 30 mg/dL are nearly always associated with symptoms. Hypoglycemia produces symptoms by two mechanisms: by triggering the release of epinephrine, one of several homeostatic responses that tend to normalize a low blood sugar, and by depriving the nervous system of glucose, its essential energy source.
Adrenergic versus Neuroglycopenic Symptoms
Many of the symptoms of hypoglycemia relate to stimulation of the release of epinephrine by low blood glucose. These symptoms are termedadrenergic or sympathetic. Usually, these symptoms are of rapid onset, and more than one is ordinarily present. Typically, they last only 15 to 30 minutes and include sweating, tremor (shakiness), a sensation of hunger, and anxiety. Irritability and palpitations are often mentioned but are rarely spontaneous or prominent complaints.
Symptoms related to glucose deprivation of the central and, to a lesser extent, peripheral nervous systems are termed neuroglycopenic, and when severe, mimic those of central nervous system hypoxia. Minimal symptoms are headache, mental dullness, and sudden fatigue. Confusion and visual disturbances (blurring, dimming of vision) are associated with moderate to severe hypoglycemia, whereas unconsciousness and seizures are indications of very severe hypoglycemia.
Causes
The numerous causes of hypoglycemia (Table 81.7) can be divided into two large categories: those mediated by insulin and those caused by impaired glucose production. By far the most common cause is an excess effect of insulin or of sulfonylureas in the treatment of diabetes mellitus, especially in patients who are aggressively managed in an attempt to maintain their blood sugar levels in the normal or near-normal range (see Chapter 79) (54). Of the other conditions that produce hypoglycemia associated with insulin overproduction, the rarest is an insulinoma. So-called postprandial hypoglycemia (within 2 to 4 hours of eating) has been considerably overdiagnosed (55). The attribution of postprandial hypoglycemia to gastrectomy or early diabetes mellitus is not well established and symptomatic hypoglycemia in these conditions is uncommon. Idiopathic postprandial hypoglycemia also appears to be quite rare (55,56). Rarely, some drugs can produce hypoglycemia (Table 81.7). Selected, specific diseases that cause hypoglycemia are discussed below.
Nonhypoglycemia
The frequency with which self-diagnosis of hypoglycemia occurs depends on the patient population (57). The condition has been termednonhypoglycemia and extends the concept of “nondisease,” as it originates from misattribution by the clinician, such as misinterpretation of laboratory values, or misattribution of the patient. Identification of such individuals is important, as is their re-education.
The recognition of nonhypoglycemia requires a careful history that fails to demonstrate the legitimate symptoms of hypoglycemia as well as a clear demonstration that glucose metabolism is normal (see below). Exclusion of
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other organic disease is important (Table 81.7). Distinction from the rare idiopathic postprandial syndrome must be made. Finally, psychiatric disease must be considered, based on positive findings rather than merely on an exclusion of organic illness.
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TABLE 81.7 Causes of Hypoglycemia in Ambulatory Adults |
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If the evaluation fails to establish the presence of bona fide hypoglycemia, the issue of the therapy of nonhypoglycemia remains. This difficult problem includes at least three steps that have been termed disattribution, explanation and ventilation, and reattribution (57). Disattribution involves confrontation of the patient with the results of the test procedure. For some patients the mechanics or ritual of the procedure itself is impressive and therefore helpful. If the patient clings to the diagnosis of hypoglycemia despite strong evidence to the contrary, an attempt should be made to explore the reason for the patient's need to do so. During this process, an effort should be made to have the patient fully explain his or her notions about hypoglycemia and verbalize what might happen if those notions are challenged. Finally, an alternate explanation must be provided for the symptoms, that is, reattribution, along with a treatment plan or a willingness to assist the patient in accepting an uncertain and ambiguous situation. Unless grossly apparent psychosocial problems become evident during this process, psychiatric referral may not be necessary. (Chapters 19 and 20 describe in detail interviewing and psychotherapeutic techniques for working with patients such as these.)
Diagnosis
In some patients, the history suggests to the clinician that the patient is experiencing periodic hypoglycemia. Other patients will themselves suggest to their caregiver that hypoglycemia accounts for the symptoms. Verification of the presence of hypoglycemia can be attempted by instructing the patient in the use of a glucometer.
Defining Hypoglycemic Symptoms
Because laboratory confirmation may be difficult in some cases, an extraordinarily careful history is essential. Two issues guide the process. First, what exactly are the symptoms? Second, do the symptoms occur postprandially or in the fasting state?
An accurate history is essential to identify the time at which hypoglycemia occurs. In general, symptoms of true hypoglycemia do not occur within hours of eating a meal unless insulin or sulfonylurea has been prescribed in excess. There are exceptions to this statement, however, both in rare patients with an insuloma and in patients who have a disorder that causes true postprandial hypoglycemia, such as infrequently can occur in persons who have had a gastrectomy.
Inquiry concerning the patient's dietary habits may be revealing. Some patients restrict carbohydrate intake intermittently. When this is done and a large carbohydrate meal follows, hypoglycemia may be precipitated. Moderate to high levels of caffeine intake can cause the development of hypoglycemic symptoms in individuals whose plasma glucose levels are in the low normal range, as can occur in the late postprandial period after ingestion of a large carbohydrate load (58). The amount of alcohol consumed should be noted because ethanol ingestion may precipitate hypoglycemia, even in the nonfasting patient (see Alcohol Abuse section). Often, the patient may recall milder symptomatic episodes experienced over a long period because the intensity of postprandial hypoglycemia tends to wax and wane over the years. A family history of diabetes mellitus should be sought as rarely postprandial hypoglycemia may be an early manifestation of type 2 diabetes mellitus. Although symptoms and signs of anxiety or depression may be present, they have no diagnostic usefulness.
General physical examination can be expected to be negative. Even if early diabetes mellitus is found by glucose tolerance testing to be the cause of the hypoglycemia, complications of diabetes that can be found on physical examination (retinopathy, neuropathy) will not be present.
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Laboratory Evaluation
As discussed above, an attempt can be made to determine the presence or absence of hypoglycemia by instructing the patient in the use of a glucometer. If the results are normal or equivocal and the diagnosis is still suspected, determination of serum glucose concentration needs to be done in a controlled setting. Blood sugar should be low at the time symptoms are experienced, and the symptoms should abate when the patient is fed carbohydrate. The glucose tolerance test has been largely abandoned as a diagnostic procedure for postprandial hypoglycemia because of its unreliability in establishing the diagnosis. If it is done, it should be modified to include more frequent sampling (30-minute intervals) and a longer period (5 hours). The patient should be observed during the entire test. Again, correlation of blood sugar values with symptoms is essential.
In patients with a history suggestive of fasting hypoglycemia, evaluation is based on measurement of serum glucose and insulin during a period of closely monitored fasting, which must be done in a hospital setting. An overnight (12-hour) fast followed by determination of serum glucose and insulin is the simplest screening procedure. If hypoglycemia cannot be documented in this time period, the duration of fasting is extended until blood glucose drops to less than 40 mg/dL or the fast has lasted for 72 hours. Frequent blood sampling for glucose level is necessary and blood for simultaneous measurement of glucose, insulin, and C-peptide is drawn at the end of the fasting period. Ninety-five percent of patients with fasting hypoglycemia will be detected by 48 hours (59).
A sex difference in response to fasting is well established. Normal men may fast for up to 72 hours and will not show fasting plasma glucose below 50 mg/dL. In contrast, women often exhibit a progressive fall in the concentration of plasma glucose during prolonged fasting. At 72 hours, many premenopausal women have a concentration of glucose less than 50 mg/dL, with some having a concentration as low as 25 mg/dL. However, these women remain asymptomatic and insulin levels are appropriately suppressed.
Selected Specific Entities Causing Hypoglycemia
Insulinoma
This pancreatic tumor occurs with equal frequency in men and women and at any age. Symptoms of headache on arising, confusion before breakfast, or nocturnal or early morning seizures may be present for years before the diagnosis is suspected. Hyperinsulinism may produce abnormal hunger, weight gain, and obesity (although insulinoma is a very rare cause of obesity). Neuropsychiatric symptoms may lead to neurologic or psychiatric evaluations or to hospitalizations. In some of these cases, permanent neurologic deficits have been seen and are presumably related to long duration of symptomatic hypoglycemia before diagnosis.
Diagnosis
In addition to the demonstration of hypoglycemia, the simultaneous determination of plasma insulin activity remains the most definitive diagnostic test (60). During fasting in normal people, both glucose and insulin levels decline and the ratio of immunoreactive insulin (IRI) to glucose is maintained at less than 0.3 (milliunits of IRI/mg of glucose/dL). In many patients with insulinoma, an abnormally high IRI-to-glucose ratio is apparent after a sufficient period of fasting. These determinations should be made repeatedly because fasting hypoglycemia and an abnormal IRI-to-glucose ratio often occur only intermittently, even in patients with subsequently proven insulinomas. In addition, a single abnormal ratio never establishes the diagnosis. Insulin-to-glucose ratios may be misinterpreted if the glucose concentration is not at hypoglycemic levels. The clinician should be cautious in accepting the accuracy of IRI values obtained from commercial laboratories. Proinsulin levels are elevated in 85% of patients with insulinoma and can be a useful adjunct, especially in those whose insulin levels are low (60).
A variety of other useful procedures should, if deemed necessary, be conducted by an endocrinologist. If fasting for 48 hours fails to provoke hypoglycemia (see above), the fast can be continued to 72 hours or the patient can be exercised as vigorously as tolerable. Up to 2 hours of exercise should be completed with sampling of plasma glucose every 15 to 20 minutes before concluding that hypoglycemia has not developed. An exercise bicycle, jogging, or vigorous calisthenics may be used. Exercise raises glucose levels in normal people but lowers plasma concentration further in patients with insulinoma. Provocative tests of insulin secretion (tolbutamide, leucine, glucagon) can be used with appropriate caution. Suppression of endogenous insulin C-peptide is another useful procedure in difficult cases, but it requires induction of hypoglycemia by infusion of insulin under controlled conditions, a procedure that must be performed by an endocrinologist in a hospital.
The localization procedure of choice is ultrasonography of the pancreas; CT and MRI are less sensitive. Celiac axis arteriography may be useful for localizing lesions smaller than 2 to 3 cm (i.e., those that can be expected to be seen with sonography) (61). These procedures should be performed only after demonstration of abnormal secretion of insulin.
Treatment
The definitive treatment of an insulinoma is surgical, with a cure rate greater than 80%.
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Noninsulinoma Pancreatogenous Hypoglycemia Syndrome
An unusually severe form of exclusively postprandial hypoglycemia has been seen in a small number of mostly male adults and in patients who have had gastric bypass surgery for severe obesity (62,63). Their 72-hour fasts were negative for insulinoma and all imaging and angiographic studies of the pancreas failed to identify a pancreatic tumor. Partial pancreatectomy disclosed diffuse islet cell hypertrophy and hyperfunction and was curative in most patients (62,63).
Noninsulinoma Tumoral Hypoglycemia
A number of tumors are associated with severe fasting hypoglycemia, producing a clinical picture identical to insulinoma. However, hyperinsulinemia is absent. Most common are large mesenchymal tumors that can be either benign or malignant. Other neoplasms are sarcomas, hepatocellular tumors, and carcinoidlike tumors. The tumors are usually easily detectable by radiologic or ultrasonograph study because of their large size. Treatment is by surgical resection with followup radiotherapy for residual tumor mass.
Insulin and Sulfonylurea Self-Administration (Factitious Hypoglycemia)
Occasional nondiabetic patients, usually family members of diabetics or people with medically related occupations, engage in surreptitious insulin administration. Examination may reveal needle marks. Other clues can be provided by the presence of antibodies to insulin, which are present only in persons given insulin or by the measurement of insulin C-peptide. In people who are secreting insulin, C-peptide is also produced concomitantly, but C-peptide is not present in commercial insulin and will be present in very low concentrations or will be absent in the serum of patients whose hypoglycemia is induced by exogenous insulin.
Oral hypoglycemic drugs (sulfonylureas; see Chapter 79), like insulin, may occasionally be abused and cause fasting hypoglycemia. In the experience of one group, these agents produce the greatest difficulty in the diagnosis of factitious hypoglycemia (59). Urinary sulfonylurea measurement can be helpful in identifying this problem.
Alcohol Abuse
Alcohol abuse probably produces hypoglycemia more commonly than any other single cause. As stated above, ingestion of ethanol can produce postprandial hypoglycemia in normal well-nourished people who engage in social drinking. However, fasting hypoglycemia related to ethanol ingestion occurs in chronic alcohol abusers and especially in those who are malnourished. The situation most likely to provoke hypoglycemia is cessation of food intake and continued ingestion of ethanol over the ensuing 10 to 20 hours. Under these circumstances, ethanol intoxication (i.e., drunkenness) may mistakenly be thought to be responsible for the symptoms.
Liver Disease, Chronic Congestive Heart Failure, and Renal Disease
Diffuse acquired liver disease can result in impaired hepatic gluconeogenesis. Although hypoglycemia can be seen in severe acute hepatitis or as a result of chronic passive congestion in long-standing congestive heart failure, liver disease does not usually produce hypoglycemia until late in the course. Patients with severe cirrhosis may occasionally have fasting hypoglycemia, but the development of hypoglycemia in such a patient should suggest the presence of a hepatoma. In patients with well-differentiated hepatoma, hypoglycemia may be an early symptom. Diabetic patients with renal insufficiency may become hypoglycemic because of a reduced clearance of insulin (see Chapter 79).
Endocrine Disease
Glucocorticoids and GH are important regulators of glucose metabolism and gluconeogenesis. Thus, either pituitary insufficiency or adrenal insufficiency (primary or secondary to hypopituitarism) can result in hypoglycemia as a presenting manifestation. The diagnosis of these disorders is described elsewhere in this chapter.
Autoimmune Hypoglycemia
There are rare conditions in which autoantibodies develop to insulin receptors. Patients have no history of insulin use. They often have acanthosis nigricans and a variety of clinical features of autoimmune disease. The hypoglycemia is often severe and refractory. These conditions are unlikely to be encountered in a nonspecialty setting.
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
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