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The hypothalamus and pituitary are implicated in the pathophysiology of a variety of complex diseases. These include anxiety disorders, in which abnormalities of the hypothalamic-pituitary-growth hormone axis appear to be a specific pathologic marker; alcoholism, in which neuropeptide Y has been implicated in mouse models of this condition; and obesity, in which a host of hypothalamic neuropeptides are affected and, in turn, affect parameters of fuel homeostasis. In most of these disorders, it remains unclear whether hypothalamic and endocrine dysregulation are important causative factors in pathogenesis or epiphenomena mirroring central nervous dysfunction.
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Changes in body weight can occur through alteration of several variables, including (1) amount and type of food ingested, (2) central control of satiety, (3) hormonal control of assimilation or storage, and (4) physical activity or metabolic rate.
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Clinical Presentation & Etiology
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Obesity can be defined as excess body weight sufficient to increase overall morbidity and mortality. Although extreme obesity is associated with dramatically increased mortality, the risks of mild to moderate obesity are less clear. An index of “fatness” is the body mass index (BMI), which equals the weight (in kilograms) divided by height (in meters squared). The normal range is 18.5–25 kg/m2, and clinically significant obesity is a BMI > 30 kg/m2. More than 20% of the U.S. population is obese by this criterion. Individuals with a BMI of 150% of normal have an overall twofold risk of premature death, whereas those who are 200% of normal BMI have a 10-fold risk. Table 19–5 lists some important causes of morbidity and mortality associated with obesity, and Figure 19–10 shows possible pathophysiologic mechanisms involved in their production.
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Recognition that obesity plays a role in the pathophysiology of disease comes from epidemiologic studies identifying obesity as a risk factor without providing insight into the mechanism of the risk.
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Although growing, only a very small number of cases of monogenetic disorders result in obesity in humans. Those syndromes highlight the importance of the aforementioned hypothalamic regulatory systems of body weight control. Several mutations in leptin or the leptin receptor, both resulting in the lack of sufficient leptin effect on the hypothalamus, have been described as a cause of both human and murine obesity. Most strikingly, leptin replacement therapy in cases of leptin deficiency leads to complete normalization of body weight. Other mutations have been described in the hypothalamic POMC system. Mutations in the MC4-R as well as mutations in the POMC gene or in POMC-processing proteases, both resulting in reduced MSH levels, lead to severe childhood obesity. Consistent with data describing the involvement of the POMC system in hypothalamic body weight regulation, all mutations within this system result in decreased signaling through the MC4-R and, therefore, increased food intake.
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Aside from the monogenic disorders mentioned previously, obesity appears to be the result of multiple mechanisms and many studies have established an imbalance in the neuroendocrine hypothalamic and brain-gut systems. Thus, obesity may be either a cause or a consequence of disease, depending on the disorder. For example, type 2 diabetes mellitus is sometimes first manifested clinically by sudden weight gain, and this disorder can be difficult to control without weight loss, reflecting the insulin-resistant character of the obese state. Moreover, if the weight can be lost, the diabetes may once again become latent, controlled by diet and exercise alone. In such cases, obesity seems clearly to be an etiologic factor in the development of diabetes mellitus. Yet insulin injections, which may be necessary to control the symptoms of diabetes in such a patient, further exacerbate the weight gain that precipitated the disorder in the first place. Such “chicken-or-egg” relationships make the pathophysiology of obesity particularly difficult to dissect. Nevertheless, important progress has been made toward developing a coherent framework in which to view obesity as both cause and consequence of disease. Some of these observations are noted next.
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The number of fat cells in the body is probably established during infancy. One hypothesis is that obesity appearing during adulthood results from enlargement of individual fat cells (hypertrophy) rather than an increased number of fat cells (hyperplasia). Obesity from fat cell hypertrophy appears to be much more easily controlled than obesity from fat cell hyperplasia. Perhaps feedback signals in response to the degree of fat cell hypertrophy are important to the hypothalamic “lipostat.”
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It now appears that where fat is deposited is more important than how much is deposited. Thus, so-called visceral or central obesity (omental fat in the distribution of blood flow draining into the portal vein) seems far more important as a risk factor for obesity-related morbidity and mortality than so-called subcutaneous (gynecoid, lower body) or peripheral fat. It appears that visceral fat is more sensitive to catecholamines and less sensitive to insulin, making it a marker of insulin resistance. Consistent with these findings is the observation that obese individuals who engage in vigorous physical activity and whose obesity is largely due to high caloric intake (eg, sumo wrestlers) have subcutaneous rather than visceral fat and do not demonstrate substantial increased insulin resistance. In contrast, the obesity associated with a sedentary lifestyle is believed to be largely visceral obesity and is associated with a greater degree of insulin resistance in patients both with and without a diagnosis of diabetes mellitus. A parameter reflecting the different kinds of fat distribution is the waist-to-hip ratio, which has been shown to correlate with morbidity.
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As mentioned, mutated leptin genes are also associated with obesity in some humans. However, in the vast majority of obese humans, excessive rather than deficient leptin levels are observed. Thus, it appears that the most common form of human obesity involves leptin resistance in the face of high endogenous leptin levels rather than defective leptin secretion as observed in ob/ob mice. An animal model for this condition is the obese db/db mouse, in which there is a defective leptin receptor. A variety of mechanisms, including diminished signaling through the leptin receptor and diminished transport across the blood-brain barrier, could account for leptin resistance in different individuals.
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Psychologic factors also make an important contribution to the development of obesity. For example, obese individuals appear to regulate their desire for food by greater reliance on external cues (eg, time of day, appeal of the food) rather than endogenous signals (eg, feeling hungry).
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Last, there is great interest in the development of drugs that alter these pathways (eg, neuropeptide Y and endocannabinoid antagonists) in ways that would promote weight loss as a treatment for obesity. On the contrary, endocannabinoid agonists are used to promote appetite and weight gain in the setting of severe wasting syndrome.
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Checkpoint
Define obesity.
What diseases are associated with obesity?
Outline several pathophysiologic mechanisms by which obesity contributes to disease.
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An adenoma is a benign tumor of epithelial cell origin. Pituitary adenomas are of particular significance because (1) the pituitary is in an enclosed space with very limited capacity to accommodate an expanding mass and (2) pituitary adenomas may arise from cells that secrete hormones, giving rise to hormone overproduction syndromes.
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Clinical Presentation
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Pituitary adenomas are extremely common and are observed in about one in six autopsies. The majority of pituitary adenomas are clinically inapparent, either because they are nonfunctional or because hormone production does not reach the critical threshold to elicit clinical symptoms. If pituitary adenomas come to medical attention, symptoms and signs are related either to an expanding intracranial mass (headaches, diabetes insipidus, vision changes) or to manifestations of excess or deficiency of one or more pituitary hormones. Hormone deficiency results from destruction of the normal pituitary by the expanding adenoma. Hormone excess occurs when the adenoma secretes a particular hormone. Microadenomas (<10 mm in diameter) are more likely to present with complaints related to hormone excess than to local mass effects because they are small. Conversely, whether or not they secrete hormones, macroadenomas (>10 mm in diameter) can impinge on the optic chiasm above the sella turcica or the cavernous sinuses laterally.
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Any cell type in the pituitary gland can undergo hyperplasia or give rise to a tumor. Whether the patient with a pituitary tumor presents with a mass effect or symptoms referable to pituitary hormones depends on the size, growth rate, and secretory characteristics of the tumor. Which, if any, hormones the tumor secretes is generally a reflection of the cell type from which the tumor originated. Gigantism and acromegaly are due to oversecretion of growth hormone. Cushing disease is a syndrome of glucocorticoid excess resulting from oversecretion of ACTH. Galactorrhea occurs in patients with prolactin-secreting tumors. Tumors secreting TSH, LH, and FSH are extremely rare and (in accordance with their physiological function) can cause secondary hyperthyroidism, precocious puberty, or ovarian hyperstimulation.
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Most pituitary adenomas are clonal in origin: A single cell with altered growth control and feedback regulation gives rise to the adenoma. Evidence for the involvement of genetic mutations in the cause of pituitary adenomas comes from the occurrence of familial pituitary tumor syndromes. At least four different syndromes caused by defined genetic mutations are known to raise significantly the incidence of pituitary tumor formation: multiple endocrine neoplasia type 1 (MEN-1), Carney complex (CNC), McCune-Albright syndrome, and AIP (aryl hydrocarbon receptor–interacting protein)-related predisposition to pituitary adenoma. Mutation of the MENIN tumor suppressor gene is the underlying cause of the multiple endocrine neoplasia syndrome type 1 (MEN-1). As is typical for tumor suppressor genes, loss of heterozygosity results in tumor formation. Pituitary tumors as well as tumors of the pancreas and hyperplasia of the parathyroid glands are typical manifestations in MEN-1 patients. Pituitary hyperplasia and microadenomas are also part of CNC. A subgroup of these patients harbor a mutation in the gene encoding for a protein A kinase subunit, resulting in an altered response to growth regulatory factors. In McCune-Albright syndrome, the GNAS1 gene, which encodes a G-protein stimulatory subunit, is mutated and renders the protein product constitutively active. Thus, cyclic adenosine monophosphate levels are chronically elevated in these cells, resulting in constitutive hormone gene activation and cell hyperplasia. Patients with AIP mutations are mainly predisposed to the development of growth hormone–secreting tumors.
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Aside from these rare syndromes, the pathogenesis of pituitary adenomas is believed to be a multistep process analogous to the well-described consecutive mutations necessary for the induction of colon carcinomas. Several known or proposed factors have been shown to be part of transformation of pituitary cells (eg, GNAS1, PTTG). Other factors promoting pituitary tumor formation include chromosomal instability, presumably because of an unknown gene mutation, that results in further gene mutations and aneuploidy, altered hypothalamic signaling, and other endocrine and paracrine factors (eg, estrogens, growth factors).
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Clinical Manifestations
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Clinical manifestations related to mass effects are summarized in Figure 19–11. Bitemporal hemianopia is the classic visual field defect in a patient with an expanding pituitary mass (see Figure 19–11, panel C). It occurs because the crossing fibers of the optic tract, which lie directly above the pituitary gland and innervate the part of the retina responsible for temporal vision, are compressed by the tumor. However, in practice, a wide variety of visual field defects is seen, reflecting the unpredictable nature of the direction and extent of tumor growth as well as anatomic variability. The clinical manifestations of hormone excess are discussed under specific syndromes next.
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Regardless of whether a pituitary tumor is producing hormones or not, infarction of or hemorrhage into the expanding mass can destroy the normal pituitary gland. This leaves the patient without one or more of the pituitary hormones. The resulting clinical manifestations are considered later in the discussion of panhypopituitarism.
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Hyperprolactinemia is the most common anterior pituitary disorder and has many causes (Table 19–6). Pathologic hyperprolactinemia, caused by prolactin-secreting adenomas (prolactinomas) or other clinical states that result in elevated prolactin levels such as primary hypothyroidism or dopamine-receptor blocking drug therapy, must be distinguished from the physiologic hyperprolactinemia of pregnancy and lactation. Roughly 40% of pituitary adenomas found in autopsies are prolactinomas. Most of the patients had no symptoms from microadenomas and died of unrelated causes.
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Patients with prolactin-secreting macroadenomas generally present with mass effect symptoms, whereas those with microadenomas may develop symptoms related to hormonal effects, from either the direct actions of prolactin (galactorrhea in 30–80% of women and up to 33% of men) or prolactin’s inhibitory effects on the hypothalamic-pituitary-gonadal axis. The resulting reproductive dysfunction presents variably: amenorrhea, irregular menses, or menses with infertility in women and decreased libido and partial or complete impotence or infertility in men.
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Decreased bone density is another common consequence of hyperprolactinemia resulting from hypogonadism and perhaps also poorly understood direct effects of prolactin on bone.
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Growth Hormone–Secreting Adenoma
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GH-secreting tumors give rise to the syndromes of gigantism or acromegaly depending on whether they develop before or after closure of the epiphyses. Clinical findings in gigantism and acromegaly are summarized in Table 19–7 and reflect a combination of the insulin-like effects of the hormone, promoting visceromegaly, and the counterregulatory effects, promoting glucose intolerance.
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ACTH-Secreting Pituitary Adenoma (Cushing Syndrome)
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Secretion of excess cortisol as a result of overproduction of ACTH by a pituitary adenoma is the most common cause of spontaneous Cushing syndrome (Chapter 21). ACTH-secreting pituitary adenomas are eight times more common in women than in men and must be distinguished from the effects caused by CRH or ACTH arising from outside the hypothalamus and pituitary gland, respectively, and from hypercortisolism due to adrenal adenomas and carcinomas.
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The symptoms and signs of ACTH-secreting pituitary adenomas are a consequence of both local mass effects, similar to those discussed previously for other types of pituitary tumors, and effects from overproduction of cortisol by the adrenal gland, as discussed in Chapter 21. Nelson syndrome is the rapid progression of an ACTH-secreting pituitary adenoma, which is often observed after bilateral adrenalectomy to control the symptoms of cortisol excess. With the advent of vigorous glucocorticoid substitution regimens, transsphenoidal pituitary surgery, and radiation therapy, the incidence of this complication has greatly diminished.
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Checkpoint
What is a pituitary adenoma?
What brings patients with pituitary adenomas to medical attention?
What are the most common forms of pituitary adenoma?
How does a pituitary adenoma develop?
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Panhypopituitarism is the syndrome resulting from complete loss of all of the hormones secreted by the pituitary gland. Hypopituitarism refers to the loss of one or more pituitary hormones. Causes of hypopituitarism are listed in Table 19–8.
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Clinical Presentation
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The complex of symptoms in hypopituitarism varies depending on the extent and duration of disease. Regardless of the underlying cause, in non-congenital forms of hypopituitarism, GH deficiency occurs as the earliest hormonal deviance, followed by ACTH and gonadotropin (LH and FSH) deficiencies, and finally, TSH deficiency. In some cases, panhypopituitarism is of sudden onset (eg, caused by pituitary infarction or trauma). These patients may rapidly develop two potentially life-threatening situations as a consequence of loss of ACTH and vasopressin. First, since the patient is unable to mount a stress response because of a lack of ACTH-stimulated glucocorticoid secretion, even relatively mild stress may be lethal. Second, a patient unable to maintain water intake will be unable to compensate for the massive diuresis associated with vasopressin deficiency (diabetes insipidus). Thus, the patient will quickly become comatose as a result of profound water loss and the complications of dehydration and hyperosmolarity.
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In other cases, pituitary insufficiency develops more insidiously (eg, from progressive destruction of the pituitary gland by a nonsecreting tumor or subsequent to pituitary radiation therapy). In many of these slowly developing cases of panhypopituitarism, the patient comes to medical attention with complaints related to reproductive functions (amenorrhea in women; infertility or erectile dysfunction in men) caused by LH and FSH deficiency. Other patients have nonspecific complaints (eg, lethargy or altered bowel habits), perhaps related to the gradual development of hypothyroidism (from TSH deficiency). Panhypopituitarism may be unmasked only when the patient does poorly during some other unrelated medical emergency because of an inability to mount a protective stress response because of an ACTH and consequent glucocorticoid deficiency.
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Panhypopituitarism of sudden onset is usually due to traumatic disruption of the pituitary stalk, infarction and hemorrhage into a pituitary tumor, or ischemic destruction of the pituitary after systemic hypotension (eg, Sheehan syndrome or postpartum hypopituitarism after massive blood loss in childbirth). A number of rare genetic causes have also been reported (Table 19–8, Figure 19–4). Gradually acquired hypopituitarism is most often due to extension of pituitary tumors or occurs as a complication of radiation therapy for brain tumors.
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The biochemical hallmark of hypopituitarism is low levels of pituitary hormones in the face of low end-organ products of one or more components of the neuroendocrine axes involving the pituitary. By contrast, primary end-organ failure results in compensatory high levels of the relevant pituitary hormones.
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Another biochemical difference between primary end-organ failure and end-organ failure secondary to hypopituitarism is that not all end-organ functions are equally controlled by the pituitary. In the case of the adrenal cortex, for example, although mineralocorticoid secretion can be stimulated by ACTH, it is not dependent on it.
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Both of the biochemical distinctions between primary end-organ failure and pituitary failure have important clinical implications. For example, hyperpigmentation occurs in primary adrenal insufficiency because several POMC-derived peptides (MSHs, ACTH) stimulate skin pigmentation via binding to the melanocortin-1 receptor (MC1-R). Because levels of POMC-derived peptides are not elevated in pituitary and hypothalamic insufficiency, hyperpigmentation does not occur. Similarly, the symptoms of adrenal insufficiency secondary to pituitary disease may be more subtle than in the case of primary adrenal failure, because a significant fraction of mineralocorticoid production is preserved even in the absence of ACTH (Chapter 21).
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In the case of trauma and pituitary stalk transection, it is notable that hypopituitarism may improve over time as local edema diminishes and some degree of integrity of the pituitary stalk with its connection to the hypothalamus is reestablished. Sometimes, however, these symptoms and signs may worsen over time as the few residual intact cells or connections are lost.
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Notably, injuries disconnecting the pituitary from the hypothalamus result in deficiencies of most of the anterior pituitary hormones except prolactin. Indeed, prolactin secretion is usually preserved or elevated because it is the only pituitary hormone regulated by tonic hypothalamic inhibition.
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Clinical Manifestations
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The symptoms and signs of hypopituitarism depend on the extent and duration of specific pituitary hormone deficiencies and the patient’s overall clinical status. Thus, a relative deficiency of vasopressin can be compensated for by increasing water intake; adrenal insufficiency may not be manifest until the patient needs to mount a stress response. Hypothyroidism may become manifest gradually over months because of the relatively long half-life and large reservoir of thyroid hormone normally available in the gland.
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The clinical manifestations of hypopituitarism are those of the end-organ deficiency syndromes. Most important are adrenal insufficiency, hypothyroidism, and diabetes insipidus. Less crucial but often the most sensitive clues to the presence of pituitary disease are amenorrhea in women and infertility or impotence in men.
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Checkpoint
What are the most common causes of panhypopituitarism?
How do patients with panhypopituitarism come to medical attention?
How would you determine what replacement therapy is required for a patient with panhypopituitarism?
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Diabetes insipidus is a syndrome of polyuria resulting from the inability to concentrate urine and, therefore, to conserve water as a result of lack of vasopressin action.
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Clinical Presentation
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The initial clinical presentation of diabetes insipidus is polyuria that persists in circumstances that would normally lead to diminished urine output (eg, dehydration), accompanied by thirst. Adults may complain of frequent urination at night (nocturia), and children may present with bed-wetting (enuresis). No further symptoms develop if the patient is able to maintain a water intake commensurate with water loss. The volume of urine produced in the total absence of vasopressin may reach 10–20 L/d. Thus, should the patient’s ability to maintain this degree of fluid intake be compromised (eg, damage to hypothalamic thirst regulating centers), dehydration can develop and may rapidly progress to coma.
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Diabetes insipidus can be due to (1) diseases of the CNS (central diabetes insipidus), affecting the synthesis or secretion of vasopressin; (2) diseases of the kidney (nephrogenic diabetes insipidus), with loss of the kidney’s ability to respond to circulating vasopressin by retaining water; or (3) pregnancy, with probable increased metabolic clearance of vasopressin. In both central and nephrogenic diabetes insipidus, urine is hypotonic. The most common central causes are accidental head trauma, intracranial tumor (eg, craniopharyngioma), and the postintracranial surgery state. Less common causes are listed in Table 19–9. Nephrogenic diabetes insipidus may be familial or caused by renal damage from a variety of drugs. Diabetes insipidus–like syndromes may result from mineralocorticoid excess, pregnancy, and other causes. True nephrogenic diabetes insipidus must be distinguished from an osmotic (and hence vasopressin-resistant) diuresis. Likewise, washout of the medullary interstitial osmotic gradient, which is necessary for the concentration of urine, may occur with prolonged diuresis resulting from any cause and may be confused with true diabetes insipidus. In both cases (osmotic diuresis and medullary washout), the urine is hypertonic or isotonic rather than hypotonic. Finally, extreme primary polydipsia (drinking excessive amounts of water, often because of a psychiatric disorder) results in an appropriately large volume of dilute urine and a low plasma vasopressin level, thus mimicking true central diabetes insipidus.
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Central Diabetes Insipidus
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Central diabetes insipidus can be either permanent or transient, reflecting the natural history of the underlying disorder (Table 19–9). Only about 15% of the vasopressin-secreting cells of the hypothalamus need to be intact to maintain fluid balance under normal conditions. Simple destruction of the posterior pituitary does not cause sufficient neuronal loss to result in permanent diabetes insipidus. Rather, destruction of the hypothalamus or at least some of the supraoptic-hypophysial tract must also occur.
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A more common finding is transient disease resulting from acute injury with neuronal shock and edema (eg, post-infarction or post-trauma), leading to cessation of vasopressin secretion with subsequent resumption of sufficient vasopressin secretion to resolve symptoms, because of either neuronal recovery or resolution of edema with reestablishment of hypothalamic-pituitary neurovascular integrity.
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Nephrogenic Diabetes Insipidus
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Familial nephrogenic diabetes insipidus is the result of a generalized defect in either the V2 class of vasopressin receptors or the aquaporin-2 water channel of the renal collecting ducts.
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Drug-induced nephrogenic diabetes insipidus appears to result from sensitivity of the vasopressin receptor to lithium, fluoride, and other salts. This occurs in 12–30% of patients treated with these drugs. It is generally reversible on termination of exposure to the offending drug (Table 19–9).
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Diabetes Insipidus–Like Syndromes
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There are several diabetes insipidus–like syndromes. As an example, diabetes insipidus is a rare complication of pregnancy. It appears to be due to excessive vasopressinase in plasma. This enzyme, which selectively degrades vasopressin, is presumably released from the placenta. A hallmark of this entity is that it is reversed by administration of the vasopressin analog desmopressin acetate, which is resistant to degradation by the enzyme.
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Clinical Manifestations
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Diabetes insipidus must be distinguished from other causes of polyuria and hypernatremia (Table 19–10). The hallmark of diabetes insipidus is dilute urine, even in the face of hypernatremia. Dipstick testing of the urine for glucose distinguishes diabetes mellitus. Conditions in which osmotic diuresis is responsible for polyuria can be distinguished from diabetes insipidus by their normal or elevated urine osmolality. Primary polydipsia is distinguished by the presence of hyponatremia, whereas in diabetes insipidus the serum sodium should be normal or elevated. In primary polydipsia, uncontrolled excess water ingestion drives the polyuria, whereas in diabetes insipidus, hypertonicity stimulates thirst.
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Distinguishing central from nephrogenic diabetes insipidus depends ultimately on a determination of responsiveness to injected vasopressin, with a dramatic decrease in urine volume and increase in urine osmolality in the former and little or no change in the latter. In central diabetes insipidus, circulating vasopressin levels are low for a given plasma osmolality, whereas in nephrogenic diabetes insipidus they are high.
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Polyuria in nephrogenic diabetes insipidus results from an inability to conserve water in the distal nephron because of a lack of vasopressin-dependent water channels. These channels, which reside within vesicles in the cytoplasm of collecting duct cells, are normally inserted into the apical plasma membrane in response to vasopressin stimulation, permitting increased reabsorption of water. Up to 13% of the volume of the glomerular filtrate can be reclaimed in this manner.
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In diabetes insipidus of either central or nephrogenic origin, if the patient is unable to maintain sufficient water intake to offset polyuria, dehydration with consequent hypernatremia develops. Hypernatremia leads to a number of neurologic manifestations, including progressive obtundation (decreased responsiveness to verbal and physical stimuli), myoclonus, seizures, focal deficits, and coma. These neurologic manifestations result from cell shrinkage and volume loss as a result of osmotic forces, sometimes complicated by intracranial hemorrhage because of stretching and rupture of small blood vessels. Barring structural changes such as those leading to hemorrhage, the neurologic consequences of hypernatremia are reversible on resolution of the underlying metabolic disorder.
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The time course of hypernatremia is an important variable in the development of neurologic symptoms in that, over time, neurons generate “idiogenic osmoles” (ie, amino acids and other metabolites that serve to raise intracellular osmolality to the level in the blood and thereby minimize fluid shifts out of the cells of the brain). Thus, the more slowly hypernatremia develops, the less likely are neurologic complications resulting from fluid shifts in the brain or from a vascular catastrophe.
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Checkpoint
What clues would suggest diabetes insipidus in a new patient?
How would you make a definitive diagnosis of diabetes insipidus?
What are the pathophysiologic differences between central and nephrogenic diabetes insipidus?
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Syndrome of Inappropriate Vasopressin Secretion (Siadh)
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The syndrome of inappropriate ADH (vasopressin) secretion (SIADH) is one of several causes of a hypotonic state (Table 19–11). SIADH is due to the secretion of vasopressin in excess of what is appropriate for hyperosmolality or intravascular volume depletion.
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Clinical Presentation
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The cardinal clinical presentation of SIADH is hyponatremia without edema. Depending on the rapidity of onset and the severity, the neurologic consequences of hyponatremia include confusion, lethargy and weakness, myoclonus, asterixis, generalized seizures, and coma.
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A variety of vasopressin-secreting tumors, CNS disorders, pulmonary disorders, and drugs have been associated with SIADH (Table 19–12). Therefore, it is worth mentioning that the hypothalamic neurons and the posterior pituitary are not always the source of vasopressin secretion. In fact, the hypothalamus and pituitary account for elevated vasopressin levels in only one-third of patients with SIADH, and it is important to regard SIADH as not necessarily a disorder of the hypothalamic-pituitary system. Several metabolic disorders can produce hyponatremia and must be investigated and ruled out before the diagnosis of true SIADH is made. In particular, adrenal insufficiency and hypothyroidism are often associated with hyponatremia. In these conditions, sodium deficiency and subsequent volume depletion trigger vasopressin secretion. Hyponatremia accompanying CNS disorders is caused either by SIADH or by cerebral salt wasting (CSW) with an increased release of natriuretic peptides (eg, BNP, ANP). A major difference between these two disorders is in the total extracellular volume, which is increased in SIADH and reduced in CSW.
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The serum sodium concentration (and hence osmolarity) is normally determined by the balance of water intake, renal solute delivery (a necessary step in water excretion), and vasopressin-mediated distal renal tubular water retention. Disorders in any one of these features of normal sodium balance, or factors controlling them, can result in hyponatremia. Hyponatremia occurs when the magnitude of the disorder exceeds the capacity of homeostatic mechanisms to compensate for dysfunction. Thus, simple excess water ingestion is generally compensated for by renal water diuresis. The exceptions are (1) when water ingestion is extreme (greater than the approximately 18 L daily that can be excreted via the kidney) or (2) when renal solute delivery is limited (eg, in salt depletion), thereby limiting the ability of the kidney to excrete free water.
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In hypoadrenal states, renal sodium loss resulting from lack of aldosterone has two consequences. Most importantly, volume depletion as a consequence of renal sodium loss results in the release of vasopressin; although the primary stimulus for ADH secretion is an elevated plasma osmolarity, ADH release is stimulated by low intravascular volume as well. Second, diminished renal solute delivery impairs the ability of the kidney to excrete a water load, in the case in which ingestion of water exceeds nonrenal water loss.
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In hypothyroidism, both renal solute delivery and function of the osmostat to which vasopressin secretion is coupled appear to be impaired, resulting in hyponatremia.
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True causes of hyponatremia, including SIADH, must also be distinguished from so-called pseudohyponatremia. Pseudohyponatremia occurs in two groups of conditions (Table 19–13). First, there are those in which infusion of hyperosmolar solutions (eg, glucose) pulls water out of cells, thereby diluting the sodium. The key feature of these conditions is hyponatremia without hypo-osmolality. Second, pseudohyponatremia occurs when the nonaqueous fraction of plasma is larger than normal. Sodium only equilibrates with, and is regulated in, the aqueous fraction of plasma, and calculations of serum sodium concentration typically correct for total plasma volume because the nonaqueous fraction of plasma volume is normally negligible. In those relatively rare conditions in which the nonaqueous fraction is significant (eg, severe hyperlipidemic states, multiple myeloma, and other conditions with higher than normal serum lipid or protein concentrations), the calculated sodium concentration will, therefore, be misleadingly low.
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The pathophysiologic mechanisms behind most cases of SIADH are not well understood. It has been proposed that baroreceptor input from the lung is impaired in those pulmonary disorders that result in SIADH. CNS lesions causing SIADH are presumed to interrupt the vasopressin-inhibiting neural pathways. Regardless of the mechanism, in most cases the hyponatremia of SIADH is partially limited by secretion of atrial natriuretic peptide. Thus, severe hyponatremia develops only when water intake is relatively increased, and edema formation is rare. The simplest therapy is restriction of free water intake and, in the case of CNS or pulmonary lesions, treatment of the underlying disease.
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Clinical Manifestations
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The clinical manifestations of SIADH are in part determined by the nature and course of any underlying disorder (eg, CNS or pulmonary disease), by the severity of hyponatremia, and by the rapidity with which hyponatremia develops. Regardless of its cause, SIADH can have neurologic manifestations, including confusion, asterixis, myoclonus, generalized seizures, and coma. These occur as a result of osmotic fluid shifts and resulting brain edema and elevated intracranial pressures; brain swelling is limited by the size of the skull. Physiologic mechanisms to counter this swelling include depletion of intracellular osmoles, especially potassium ions. The more rapid the progression of hyponatremia, the more likely it is that brain edema and increased intracranial pressure will develop and that the neurologic complications and herniation will lead to permanent damage. However, even when hyponatremia develops slowly, it can in extreme cases (eg, serum sodium <110 mEq/L) result in seizures and altered mental status. Central pontine myelinolysis can develop and cause permanent neurologic damage in patients whose hyponatremia is corrected too rapidly.
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Checkpoint
What conditions are associated with SIADH?
How would you distinguish SIADH from other causes of hyponatremia?
What are the neurologic consequences of SIADH, and how may they be prevented?