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InternalMed_Harrison. FIGURE 403-7 Management of a nonfunctioning pituitary mass. MRI, magnetic resonance imaging. possible to remove all adenoma tissue surgically, vision improves in 70% of patients with preoperative visual field defects. Preexisting hypopituitarism that results from tumor mass effects may improve or resolve completely. Beginning about 6 months postoperatively, MRI scans should be performed yearly to detect tumor regrowth. Within 5–6 years after successful surgical resection, ~15% of non-functioning tumors recur. When substantial tumor remains after transsphenoidal surgery, adjuvant radiotherapy may be indicated to prevent tumor regrowth. Radiotherapy may be deferred if no postoperative residual mass is evident. Nonfunctioning pituitary tumors respond poorly to dopamine agonist treatment and somatostatin analogues are largely ineffective for shrinking these tumors. The selective GnRH antagonist Nal-Glu GnRH suppresses FSH hypersecretion but has no effect on adenoma size.


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InternalMed_Harrison. TSH-producing macroadenomas are very rare but are often large and locally invasive when they occur. Patients usually present with thyroid goiter and hyperthyroidism, reflecting overproduction of TSH. Diagnosis is based on demonstrating elevated serum free T4 levels, inappropriately normal or high TSH secretion, and MRI evidence of a pituitary adenoma. Elevated uncombined α subunits are seen in many patients.


InternalMed_Harrison

InternalMed_Harrison. It is important to exclude other causes of inappropriate TSH secretion, such as resistance to thyroid hormone, an autosomal dominant disorder caused by mutations in the thyroid hormone β receptor (Chap. 405). The presence of a pituitary mass and elevated β subunit levels are suggestive of a TSH-secreting tumor. Dysalbuminemic hyperthyroxinemia syndromes, caused by mutations in serum thyroid hormone binding proteins, are also characterized by elevated thyroid hormone levels, but with normal rather than suppressed TSH levels. Moreover, free thyroid hormone levels are normal in these disorders, most of which are familial.


InternalMed_Harrison

InternalMed_Harrison. The initial therapeutic approach is to remove or debulk the tumor mass surgically, usually using a transsphenoidal approach. Total resection is not often achieved as most of these adenomas are large and locally invasive. Normal circulating thyroid hormone levels are achieved in about two-thirds of patients after surgery. Thyroid ablation or antithyroid drugs (methimazole and propylthiouracil) can be used to reduce thyroid hormone levels. Somatostatin analogue treatment effectively normalizes TSH and α subunit hypersecretion, shrinks the tumor mass in 50% of patients, and improves visual fields in 75% of patients; euthyroidism is restored in most patients. Because somatostatin analogues markedly suppress TSH, biochemical hypothyroidism often requires concomitant thyroid hormone replacement, which may also further control tumor growth. Disorders of the neurohypophysis Gary L. Robertson


InternalMed_Harrison

InternalMed_Harrison. Disorders of the neurohypophysis Gary L. Robertson The neurohypophysis, or posterior pituitary, is formed by axons that originate in large cell bodies in the supraoptic and paraventricular nuclei of the hypothalamus. It produces two hormones: (1) arginine vasopressin (AVP), also known as antidiuretic hormone, and (2) oxytocin. AVP acts on the renal tubules to reduce water loss by concentrating the urine. Oxytocin stimulates postpartum milk letdown in response to suckling. A deficiency of AVP secretion or action causes diabetes insipidus (DI), a syndrome characterized by the production of large amounts of dilute urine. Excessive or inappropriate AVP production impairs urinary water excretion and predisposes to hyponatremia if water intake is not reduced in parallel with urine output.


InternalMed_Harrison

InternalMed_Harrison. AVP is a nonapeptide composed of a six-member disulfide ring and a tripeptide tail (Fig. 404-1). It is synthesized via a polypeptide precursor that includes AVP, neurophysin, and copeptin, all encoded by a single gene on chromosome 20. After preliminary processing and folding, the precursor is packaged in neurosecretory vesicles, where it is transported down the axon; further processed to AVP, neurophysin, and copeptin; and stored in neurosecretory vesicles until released by exocytosis into peripheral blood. AVP secretion is regulated primarily by the “effective” osmotic pressure of body fluids. This control is mediated by specialized hypothalamic cells known as osmoreceptors, which are extremely sensitive FIGURE 404-1 Primary structures of arginine vasopressin (AVP), oxytocin, and desmopressin (DDAVP).


InternalMed_Harrison

InternalMed_Harrison. to small changes in the plasma concentration of sodium and its anions but normally are insensitive to other solutes such as urea and glucose. The osmoreceptors appear to include inhibitory as well as stimulatory components that function in concert to form a threshold, or set point, control system. Below this threshold, plasma AVP is suppressed to levels that permit the development of a maximum water diuresis. Above it, plasma AVP rises steeply in direct proportion to plasma osmolarity, quickly reaching levels sufficient to effect a maximum antidiuresis. The absolute levels of plasma osmolarity/sodium at which minimally and maximally effective levels of plasma AVP occur, vary appreciably from person to person, apparently due to genetic influences on the set and sensitivity of the system. However, the average threshold, or set point, for AVP release corresponds to a plasma osmolarity or sodium of about 280 mosmol/L or 135 meq/L, respectively; levels only 2–4% higher normally result in


InternalMed_Harrison

InternalMed_Harrison. However, the average threshold, or set point, for AVP release corresponds to a plasma osmolarity or sodium of about 280 mosmol/L or 135 meq/L, respectively; levels only 2–4% higher normally result in maximum antidiuresis.


InternalMed_Harrison

InternalMed_Harrison. Although it is relatively stable in a healthy adult, the set point of the osmoregulatory system can be lowered by pregnancy, the menstrual cycle, estrogen, and relatively large, acute reductions in blood pressure or volume. Those reductions are mediated largely by neuronal afferents that originate in transmural pressure receptors of the heart and large arteries and project via the vagus and glossopharyngeal nerves to the brainstem, from which postsynaptic projections ascend to the hypothalamus. These pathways maintain a tonic inhibitory tone that decreases when blood volume or pressure falls by >10–20%. This baroregulatory system is probably of minor importance in the physiology of AVP secretion because the hemodynamic changes required to affect it usually do not occur during normal activities. However, the baroregulatory system undoubtedly plays an important role in AVP secretion in patients with disorders that produce large, acute disturbances of hemodynamic function. However, the


InternalMed_Harrison

InternalMed_Harrison. However, the baroregulatory system undoubtedly plays an important role in AVP secretion in patients with disorders that produce large, acute disturbances of hemodynamic function. However, the baroregulatory system undoubtedly plays an important role in AVP secretion in patients with disorders that produce large, acute disturbances of hemodynamic function.


InternalMed_Harrison

InternalMed_Harrison. AVP secretion also can be stimulated by nausea, acute hypoglycemia, glucocorticoid deficiency, smoking, and, possibly, hyperangiotensinemia. The emetic stimuli are extremely potent since they typically elicit immediate, 50to 100-fold increases in plasma AVP even when the nausea is transient and is not associated with vomiting or other symptoms. They appear to act via the emetic center in the medulla and can be blocked completely by treatment with antiemetics such as fluphenazine. There is no evidence that pain or other noxious stresses have any effect on AVP unless they elicit a vasovagal reaction with its associated nausea and hypotension.


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InternalMed_Harrison. The most important, if not the only, physiologic action of AVP is to reduce water excretion by promoting concentration of urine. This antidiuretic effect is achieved by increasing the hydroosmotic permeability of cells that line the distal tubule and medullary collecting ducts of the kidney (Fig. 404-2). In the absence of AVP, these cells are impermeable to water and reabsorb little, if any, of the relatively large volume of dilute filtrate that enters from the proximal nephron. The lack of reabsorption results in the excretion of very large volumes (as much as 0.2 mL/kg per min) of maximally dilute urine (specific gravity and osmolarity ~1.000 and 50 mosmol/L, respectively), a condition known as water diuresis. In the presence of AVP, these cells become selectively permeable to water, allowing the water to diffuse back down the osmotic gradient created by the hypertonic renal medulla. As a result, the dilute fluid passing through the tubules is concentrated and the rate of urine flow


InternalMed_Harrison

InternalMed_Harrison. the water to diffuse back down the osmotic gradient created by the hypertonic renal medulla. As a result, the dilute fluid passing through the tubules is concentrated and the rate of urine flow decreases.


InternalMed_Harrison

InternalMed_Harrison. The magnitude of this effect varies in direct proportion to the plasma 2275 AVP concentration and the rate of solute excretion. At maximum levels of AVP and normal rates of solute excretion, it approximates a urine flow rate as low as 0.35 mL/min and a urine osmolarity as high as 1200 mosmol/L. This effect is reduced by a solute diuresis such as glucosuria in diabetes mellitus. Antidiuresis is mediated via binding to G protein– coupled V2 receptors on the serosal surface of the cell, activation of adenyl cyclase, and insertion into the luminal surface of water channels composed of a protein known as aquaporin 2 (AQP2). The V2 receptors and aquaporin 2 are encoded by genes on chromosomes Xq28 and 12q13, respectively.


InternalMed_Harrison

InternalMed_Harrison. At high concentrations, AVP also causes contraction of smooth muscle in blood vessels in the skin and gastrointestinal tract, induces glycogenolysis in the liver, and potentiates adrenocorticotropic hormone (ACTH) release by corticotropin-releasing factor. These effects are mediated by V1a or V1b receptors that are coupled to phospholipase C. Their role, if any, in human physiology/pathophysiology is uncertain. AVP distributes rapidly into a space roughly equal to the extracellular fluid volume. It is cleared irreversibly with a half-life (t 1/2) of 10–30 min. Most AVP clearance is due to degradation in the liver and kidneys. During pregnancy, the metabolic clearance of AVP is increased three-to fourfold due to placental production of an N-terminal peptidase.


InternalMed_Harrison

InternalMed_Harrison. Because AVP cannot reduce water loss below a certain minimum level obligated by urinary solute load and evaporation from skin and lungs, a mechanism for ensuring adequate intake is essential for preventing dehydration. This vital function is performed by the thirst mechanism. Like AVP, thirst is regulated primarily by an osmostat that is situated in the anteromedial hypothalamus and is able to detect very small changes in the plasma concentration of sodium and its anions. The thirst osmostat appears to be “set” about 3% higher than the AVP osmostat. This arrangement ensures that thirst, polydipsia, and dilution of body fluids do not occur until plasma osmolarity/sodium starts to exceed the defensive capacity of the antidiuretic mechanism.


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InternalMed_Harrison. Oxytocin is also a nonapeptide that differs from AVP only at positions 3 and 8 (Fig. 404-1). However, it has relatively little antidiuretic effect and seems to act mainly on mammary ducts to facilitate milk letdown during nursing. It also may help initiate or facilitate labor by stimulating contraction of uterine smooth muscle, but it is not clear if this action is physiologic or necessary for normal delivery.


InternalMed_Harrison

InternalMed_Harrison. DIABETES INSIPIDUS Clinical Characteristics A decrease of 75% or more in the secretion or action of AVP usually results in DI, a syndrome characterized by the production of abnormally large volumes of dilute urine. The 24-h urine volume exceeds 50 mL/kg body weight, and the osmolarity is less than 300 mosmol/L. The polyuria produces symptoms of urinary frequency, enuresis, and/or nocturia, which may disturb sleep and cause mild daytime fatigue or somnolence. It also results in a slight rise in plasma osmolarity that stimulates thirst and a commensurate increase in fluid intake (polydipsia). Overt clinical signs of dehydration are uncommon unless thirst and/or the compensatory increase of fluid intake are also impaired.


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InternalMed_Harrison. Etiology A primary deficiency of AVP secretion usually results from agenesis or irreversible destruction of the neurohypophysis. It is referred to variously as neurohypophyseal DI, neurogenic DI, pituitary DI, cranial DI, or central DI. It can be caused by a variety of congenital, acquired, or genetic disorders, but in about one-half of all adult patients, it is idiopathic (Table 404-1). Pituitary DI caused by surgery in or around the neurohypophysis usually appears within 24 h. After a few days, it may transition to a 2to 3-week period of inappropriate antidiuresis, after which the DI may or may not recur permanently. Disorders of the Neurohypophysis


InternalMed_Harrison

InternalMed_Harrison. FIGURE 404-2 Antidiuretic effect of arginine vasopressin (AVP) in the regulation of urine volume. In a typical 70-kg adult, the kidney filters ~180 L/d of plasma. Of this, ~144 L (80%) is reabsorbed isosmotically in the proximal tubule and another 8 L (4–5%) is reabsorbed without solute in the descending limb of Henle’s loop. The remainder is diluted to an osmolarity of ~60 mmol/kg by selective reabsorption of sodium and chloride in the ascending limb. In the absence of AVP, the urine issuing from the loop passes largely unmodified through the distal tubules and collecting ducts, resulting in a maximum water diuresis. In the presence of AVP, solute-free water is reabsorbed osmotically through the principal cells of the collecting ducts, resulting in the excretion of a much smaller volume of concentrated urine. This antidiuretic effect is mediated via a G protein–coupled V2 receptor that increases intracellular cyclic AMP, thereby inducing translocation of aquaporin 2 (AQP 2) water


InternalMed_Harrison

InternalMed_Harrison. of concentrated urine. This antidiuretic effect is mediated via a G protein–coupled V2 receptor that increases intracellular cyclic AMP, thereby inducing translocation of aquaporin 2 (AQP 2) water channels into the apical membrane. The resultant increase in permeability permits an influx of water that diffuses out of the cell through AQP 3 and AQP 4 water channels on the basal-lateral surface. The net rate of flux across the cell is determined by the number of AQP 2 water channels in the apical membrane and the strength of the osmotic gradient between tubular fluid and the renal medulla. Tight junctions on the lateral surface of the cells serve to prevent unregulated water flow.


InternalMed_Harrison

InternalMed_Harrison. Five genetic forms of pituitary DI are now known. By far, the most common is transmitted in an autosomal dominant mode and is caused by diverse mutations in the coding region of one allele of the AVP– neurophysin II (or AVP-NPII) gene. All the mutations alter one or more amino acids known to be critical for correct processing and/or folding of the prohormone, thus interfering with its trafficking through the endoplasmic reticulum. The misfolded mutant precursor accumulates and interferes with production of AVP by the normal allele, eventually destroying the magnocellular neurons in which it is produced. The AVP deficiency and DI are usually not present at birth but develop gradually over a period of several months to years, progressing from partial to severe at different rates depending on the mutation. Once established, the deficiency of AVP is permanent, but for unknown reasons, the DI occasionally improves or remits spontaneously in late middle age. The parvocellular neurons that


InternalMed_Harrison

InternalMed_Harrison. on the mutation. Once established, the deficiency of AVP is permanent, but for unknown reasons, the DI occasionally improves or remits spontaneously in late middle age. The parvocellular neurons that make AVP and the magnocellular neurons that make oxytocin appear to be unaffected. There are also rare autosomal recessive forms of pituitary DI. One is due to an inactivating mutation in the AVP portion of the gene; another is due to a large deletion involving the majority of the AVP gene and regulatory sequences in the intergenic region. A third form is caused by mutations of the WFS 1 gene responsible for Wolfram’s syndrome (DI, diabetes mellitus, optic atrophy, and neural deafness [DIDMOAD]). An X-linked recessive form linked to a region on Xq28 has also been described.


InternalMed_Harrison

InternalMed_Harrison. A primary deficiency of plasma AVP also can result from increased metabolism by an N-terminal aminopeptidase produced by the placenta. It is referred to as gestational DI because the signs and symptoms manifest during pregnancy and usually remit several weeks after delivery.


InternalMed_Harrison

InternalMed_Harrison. Secondary deficiencies of AVP secretion result from inhibition by excessive intake of fluids. They are referred to as primary polydipsia and can be divided into three subcategories. One of them, dipsogenic DI, is characterized by inappropriate thirst caused by a reduction in the set of the osmoregulatory mechanism. It sometimes occurs in association with multifocal diseases of the brain such as neurosarcoid, tuberculous meningitis, and multiple sclerosis but is often idiopathic. The second subtype, psychogenic polydipsia, is not associated with thirst, and the polydipsia seems to be a feature of psychosis or obsessive compulsive disorder. The third subtype, iatrogenic polydipsia, results from recommendations to increase fluid intake for its presumed health benefits.


InternalMed_Harrison

InternalMed_Harrison. Primary deficiencies in the antidiuretic action of AVP result in nephrogenic DI. The causes can be genetic, acquired, or drug induced (Table 404-1). The most common genetic form is transmitted in a semirecessive X-linked manner. It is caused by mutations in the coding region of the V2 receptor gene that impair trafficking and/or ligand binding of the mutant receptor. There are also autosomal recessive or dominant forms of nephrogenic DI. They are caused by AQP2 gene mutations that result in complete or partial defects in trafficking and function of the water channels that mediate antidiuresis in the distal and collecting tubules of the kidney. Secondary deficiencies in the antidiuretic response to AVP result from polyuria per se. They are caused by washout of the medullary concentration gradient and/or suppression of aquaporin function. They usually resolve 24–48 h after the polyuria is corrected but can complicate interpretation of some acute tests used for differential diagnosis.


InternalMed_Harrison

InternalMed_Harrison. Pathophysiology In pituitary, gestational, or nephrogenic DI, the polyuria results in a small (1–2%) decrease in body water and a commensurate increase in plasma osmolarity and sodium that stimulates thirst and a compensatory increase in water intake. As a result, hypernatremia and other overt physical or laboratory signs of dehydration do not develop unless the patient also has a defect in thirst or fails to increase fluid intake for some other reason. CAuSES of DiAbETES inSiPiDuS Metastatic (lung, breast) Hematologic (lymphoma, leukemia) Inflammatory Lymphocytic infundibuloneurohypophysitis Granulomatosis with polyangiitis (Wegener’s) Lupus erythematosus Scleroderma Congenital malformations Septo-optic dysplasia Midline craniofacial defects Holoprosencephaly Hypogenesis, ectopia of pituitary


InternalMed_Harrison

InternalMed_Harrison. Metabolic Hypercalcemia, hypercalciuria Hypokalemia causes excessive intake of fluids and an increase in 2277 body water that reduces plasma osmolarity/sodium, AVP secretion, and urinary concentration. Dilution of the urine, in turn, results in a compensatory increase in urinary free-water excretion that usually offsets the increase in intake and stabilizes plasma osmolarity/sodium at a level only 1–2% below basal. Thus, hyponatremia or clinically appreciable overhydration is uncommon unless the polydipsia is very severe or the compensatory water diuresis is impaired by a drug or disease that stimulates or mimics the antiduretic effect of endogenous AVP. A rise in plasma osmolarity and sodium produced by fluid deprivation or hypertonic saline infusion increases plasma AVP normally. However, the resultant increase in urine concentration is often subnormal because polyuria per se temporarily reduces the capacity of the kidney to concentrate the urine. Thus, the maximum level of urine


InternalMed_Harrison

InternalMed_Harrison. the resultant increase in urine concentration is often subnormal because polyuria per se temporarily reduces the capacity of the kidney to concentrate the urine. Thus, the maximum level of urine osmolarity achieved during fluid deprivation is often indistinguishable from that in patients with partial pituitary or partial nephrogenic DI.


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InternalMed_Harrison. Differential Diagnosis When symptoms of urinary frequency, enuresis, nocturia, and/or persistent thirst are present in the absence of glucosuria, the possibility of DI should be evaluated by collecting a 24-h urine on ad libitum fluid intake. If the volume exceeds 50 mL/kg per day (3500 mL in a 70-kg male) and the osmolarity is below 300 mosmol/L, DI is confirmed and the patient should be evaluated further to determine the type in order to select the appropriate therapy.


InternalMed_Harrison

InternalMed_Harrison. The type of DI can sometimes be inferred from the clinical setting or medical history. Often, however, such information is lacking, ambiguous, or misleading, and other approaches to differential diagnosis are needed. If basal plasma osmolarity and sodium are within normal limits, the traditional approach is to determine the effect of fluid deprivation and injection of antidiuretic hormone on urine osmolarity. This approach suffices for differential diagnosis if fluid deprivation raises plasma osmolarity and sodium above the normal range without inducing concentration of the urine. In that event, primary polydipsia and partial defects in AVP secretion and action are excluded, and the effect on urine osmolarity of injecting 2 μg of the AVP analogue, desmopressin, indicates whether the patient has severe pituitary DI or severe nephrogenic DI. However, this approach is of little or no diagnostic value if fluid deprivation results in concentration of the urine because the increases in


InternalMed_Harrison

InternalMed_Harrison. has severe pituitary DI or severe nephrogenic DI. However, this approach is of little or no diagnostic value if fluid deprivation results in concentration of the urine because the increases in urine osmolarity achieved both before and after the injection of desmopressin are similar in patients with partial pituitary DI,


InternalMed_Harrison

Disorders of the Neurohypophysis

InternalMed_Harrison. Disorders of the Neurohypophysis


InternalMed_Harrison

InternalMed_Harrison. In pituitary and nephrogenic DI, the severity of the defect in AVP partial nephrogenic DI, and primary polydipsia. These disorders can secretion or action varies significantly from patient to patient. In some, the be differentiated by measuring plasma AVP during fluid deprivation defect is so severe that it cannot be overcome by even an intense stimulus and relating it to the concurrent level of plasma and urine osmolarity such as nausea or severe dehydration. In others, the defect in AVP secre-(Fig. 404-3). However, this approach does not always differentiate tion or action is incomplete, and a modest stimulus such as a few hours clearly between partial pituitary DI and primary polydipsia unless of fluid deprivation, smoking, or a vasovagal reaction can raise urine the measurement is made when plasma osmolarity and sodium are at osmolarity as high as 800 mosmol/L. However, even when the defects are or above the normal range. This level is difficult to achieve by fluid partial, the


InternalMed_Harrison

InternalMed_Harrison. when plasma osmolarity and sodium are at osmolarity as high as 800 mosmol/L. However, even when the defects are or above the normal range. This level is difficult to achieve by fluid partial, the relation of urine osmolarity to plasma AVP in patients with deprivation alone once urinary concentration occurs. Therefore it nephrogenic DI (Fig. 404-3A) or of plasma AVP to plasma osmolarity is usually necessary to give a short infusion of 3% saline condition and sodium in patients with pituitary DI (Fig. 404-3B) is subnormal. (0.1 mL/kg body weight per minute for 60 to 90 minutes) and repeat


InternalMed_Harrison

InternalMed_Harrison. In primary polydipsia, the pathogenesis of the polydipsia and the measurement of plasma AVP. polyuria is the reverse of that in pituitary, nephrogenic, and gesta-A simpler but equally reliable way to differentiate between pituitary tional DI. In primary polydipsia, an abnormality in cognition or thirst DI, nephrogenic DI, and primary polydipsia is to measure basal plasma Urine osmolarity, mosmol/L 0.1 0.5 1 3 B60 40 20 15 10 5 0 Plasma vasopressin, pg/mL Plasma vasopressin, pg/mL Plasma osmolarity, mosmol/L FIGURE 404-3 Relationship of plasma AVP to urine osmolarity (A) and plasma osmolarity (B) before and during fluid deprivation–hypertonic saline infusion test in patients who are normal or have primary polydipsia (blue zones), pituitary diabetes insipidus (green zones), or nephrogenic diabetes insipidus (pink zones).


InternalMed_Harrison

InternalMed_Harrison. AVP to determine if a brain magnetic resonance imaging (MRI) is needed and sufficient for diagnosis (Fig. 404-4). If plasma AVP on ad libitum fluid intake is normal or elevated (>1 pg/mL) when measured by a sensitive and specific assay, both primary polydipsia and pituitary DI are excluded and the diagnosis of nephrogenic DI can be confirmed, if desired, by a 1to 2-day outpatient trial of desmopressin therapy. If, however, basal plasma AVP is low or undetectable (<1 pg/ mL), nephrogenic DI is very unlikely and MRI of the brain can be used to differentiate pituitary DI from primary polydipsia. In most healthy adults and children, the posterior pituitary emits a hyperintense signal visible in T1-weighted midsagittal images. This “bright spot” is almost always present in patients with primary polydipsia but is always absent or abnormally small in patients with pituitary DI, even if their AVP deficiency is partial. The MRI is also useful in searching for pathology responsible for


InternalMed_Harrison

InternalMed_Harrison. primary polydipsia but is always absent or abnormally small in patients with pituitary DI, even if their AVP deficiency is partial. The MRI is also useful in searching for pathology responsible for pituitary DI or the dipsogenic form of primary polydipsia (Fig. 404-2). The principal caveat is that MRI is not reliable for differential diagnosis of DI in patients with empty sella because they typically lack a bright spot even when their AVP secretion and action are normal. MRI also cannot be used to differentiate pituitary from nephrogenic DI because many patients with nephrogenic DI also lack a posterior pituitary bright spot, probably because they have an abnormally high rate of AVP secretion and turnover.


InternalMed_Harrison

InternalMed_Harrison. Brain MRI Urinary frequency, nocturia, enuresis 24-h urine volume and osmolarity on unrestrictedfluid intake Volume >40 mL/kg Osmolarity <300 mosm/L Basal plasma AVP >1 pg/mL <1 pg/mL Pituitary bright spot Present Absent Anatomy Pathology? GU evaluation Volume <40 mL/kg Osmolarity >300 mosm/L If MRI and/or AVP assays with the requisite sensitivity and specificity are unavailable and a fluid deprivation test is impractical or undesirable, a third way to differentiate between pituitary DI, nephrogenic DI, and primary polydipsia is a trial of desmopressin therapy. Such a trial should be conducted with very close monitoring of serum sodium as well as urine output, preferably in hospital, because desmopressin will produce hyponatremia in 8–24 h if the patient has primary polydipsia.


InternalMed_Harrison

InternalMed_Harrison. The signs and symptoms of uncomplicated pituitary DI can be eliminated by treatment with desmopressin (DDAVP), a synthetic analogue of AVP (Fig. 404-1). DDAVP acts selectively at V2 receptors to increase urine concentration and decrease urine flow in a dose-dependent manner. It is also more resistant to degradation than is AVP and has a threeto fourfold longer duration of action. DDAVP can be given by IV or SC injection, nasal inhalation, or orally by means of a tablet of melt. The doses required to control pituitary DI completely vary widely, depending on the patient and the route of administration. However, among adults, they usually range from 1–2 μg qd or bid by injection, 10–20 μg bid or tid by nasal spray, or 100–400 μg bid or tid orally. The onset of antidiuresis is rapid, ranging from as little as 15 min after injection to 60 min after oral administration. When given in a dose that normalizes 24-h urinary osmolarity (400–800 mosmol/L) and volume (15–30 mL/kg body weight),


InternalMed_Harrison

InternalMed_Harrison. from as little as 15 min after injection to 60 min after oral administration. When given in a dose that normalizes 24-h urinary osmolarity (400–800 mosmol/L) and volume (15–30 mL/kg body weight), DDAVP produces a slight (1–3%) increase in total body water and a decrease in plasma osmolarity/sodium that rapidly eliminates thirst and polydipsia (Fig. 404-5). Consequently, water balance is maintained within the normal range. Hyponatremia does not develop unless urine volume is reduced too far (to less than 10 mL/kg per day) or fluid intake is excessive due to an associated


InternalMed_Harrison

InternalMed_Harrison. FIGURE 404-4 Simplified approach to the differential diagnosis of diabetes insipidus. When symptoms suggest diabetes insipidus (DI), the syndrome should be differentiated from a genitourinary (GU) abnormality by measuring the 24-h urine volume and osmolarity on unrestricted fluid intake. If DI is confirmed, basal plasma arginine vasopressin (AVP) should be measured on unrestricted fluid intake. If AVP is normal or elevated (>1 pg/mL), the patient probably has nephrogenic DI. However, if plasma AVP is low or undetectable, the patient has either pituitary DI or primary polydipsia. In that case, magnetic resonance imaging (MRI) of the brain can be performed to differentiate between these two conditions by determining whether or not the normal posterior pituitary bright spot is visible on T1-weighted midsagittal images. In addition, the MRI anatomy of the pituitary hypothalamic area can be examined to look for evidence of pathology that sometimes causes pituitary DI or the dipsogenic form


InternalMed_Harrison

InternalMed_Harrison. midsagittal images. In addition, the MRI anatomy of the pituitary hypothalamic area can be examined to look for evidence of pathology that sometimes causes pituitary DI or the dipsogenic form of primary polydipsia. MRI is not reliable for differential diagnosis unless nephrogenic DI has been excluded because the bright spot is also absent, small, or faint in this condition.


InternalMed_Harrison

InternalMed_Harrison. of hypovolemia such as tachycardia, postural hypotension, azotemia, 2279 hyperuricemia, and hypokalemia due to secondary hyperaldosteronism. Muscle weakness, pain, rhabdomyolysis, hyperglycemia, hyperlipidemia, and acute renal failure may also occur. Obtundation or coma may be present but are often absent. Despite inappropriately low levels of plasma AVP, DI usually is not evident at presentation but may develop during rehydration as blood volume, blood pressure, and plasma osmolarity/ sodium return toward normal, further reducing plasma AVP. Etiology Hypodipsia is usually due to hypogenesis or destruction of the osmoreceptors in the anterior hypothalamus that regulate thirst. These defects can result from various congenital malformations of midline brain structures or may be acquired due to diseases such as occlusions of the anterior communicating artery, primary or Days of treatment


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InternalMed_Harrison. FIGURE 404-5 Effect of desmopressin therapy on fluid intake (blue bars), urine output (orange bars), and plasma osmolarity (red line) in a patient with uncomplicated pituitary diabetes insipidus. Note metastatic tumors in the hypothalamus, head trauma, surgery, granulomatous diseases such as sarcoidosis and histiocytosis, AIDS, and cytomegalovirus encephalitis. Because of their proximity, the osmoreceptors that regulate AVP secretion also are usually impaired. Thus, AVP secretion responds poorly or not at all to hyperosmotic stimulation (Fig. 404-6) but, in most cases, increases normally to nonosmotic that treatment rapidly reduces fluid intake and urine output to normal, with only a slight increase in body water as evidenced by the 20 slight decrease in plasma osmolarity. 18 abnormality in thirst or cognition. Fortunately, thirst abnormalities are rare, and if the patient is taught to drink only when truly thirsty, DDAVP can be given safely in doses sufficient to normalize urine


InternalMed_Harrison

InternalMed_Harrison. in thirst or cognition. Fortunately, thirst abnormalities are rare, and if the patient is taught to drink only when truly thirsty, DDAVP can be given safely in doses sufficient to normalize urine output (~15– 30 mL/kg per day) without the need for allowing intermittent escape to prevent water intoxication.


InternalMed_Harrison

InternalMed_Harrison. Primary polydipsia cannot be treated safely with DDAVP or any other antidiuretic drug because eliminating the polyuria does not eliminate the urge to drink. Therefore, it invariably produces hypona tremia and/or other signs of water intoxication, usually within 8–24 Plasma vasopressin, pg/mL h if urine output is normalized completely. There is no consistently 2 effective way to correct dipsogenic or psychogenic polydipsia, but the iatrogenic form may respond to patient education. To minimize the 0 risk of water intoxication, all patients should be warned about the use Disorders of the Neurohypophysis of other drugs such as thiazide diuretics or carbamazepine (Tegretol) that can impair urinary free-water excretion directly or indirectly.


InternalMed_Harrison

InternalMed_Harrison. Disorders of the Neurohypophysis of other drugs such as thiazide diuretics or carbamazepine (Tegretol) that can impair urinary free-water excretion directly or indirectly. The polyuria and polydipsia of nephrogenic DI are not affected by treatment with standard doses of DDAVP. If resistance is partial, it may be overcome by tenfold higher doses, but this treatment is too expensive and inconvenient for long-term use. However, treatment with conventional doses of a thiazide diuretic and/or amiloride in conjunction with a low-sodium diet and a prostaglandin synthesis inhibitor (e.g., indomethacin) usually reduces the polyuria and polydipsia by 30–70% and may eliminate them completely in some patients. Side effects such as hypokalemia and gastric irritation can be minimized by the use of amiloride or potassium supplements and by taking medications with meals.


InternalMed_Harrison

InternalMed_Harrison. An increase in plasma osmolarity/sodium above the normal range (hypertonic hypernatremia) can be caused by either a decrease in total body water or an increase in total body sodium. The former results from a failure to drink enough to replace normal or increased urinary and insensible water loss. The deficient intake can be due either to water deprivation or a lack of thirst (hypodipsia). The most common cause of an increase in total body sodium is primary hyperaldosteronism (Chap. 406). Rarely, it can also result from ingestion of hypertonic saline in the form of sea water or incorrectly prepared infant formula. However, even in these forms of hypernatremia, inadequate intake of water also contributes. This chapter focuses on hypodipsic hypernatremia, the form of hypernatremia due to a primary defect in the thirst mechanism.


InternalMed_Harrison

InternalMed_Harrison. Clinical Characteristics Hypodipsic hypernatremia is a syndrome characterized by chronic or recurrent hypertonic dehydration. The hypernatremia varies widely in severity and usually is associated with signs adipsic hypernatremia (AH) and the syndrome of inappropriate antidiuresis (SIAD). Each line depicts schematically the relationship of plasma arginine vasopressin (AVP) to plasma osmolarity during water loading and/or infusion of 3% saline in a patient with either AH (open symbols) or SIAD (closed symbols). The shaded area indicates the normal range of the relationship. The horizontal broken line indicates the plasma AVP level below which the hormone is undetectable and urinary concentration usually does not occur. Lines P and T represent patients with a selective deficiency in the osmoregulation of thirst and AVP that is either partial ( ) or total ( ). In the latter, plasma AVP does not change in response to increases or decreases in plasma osmolarity but remains within a range


InternalMed_Harrison

InternalMed_Harrison. of thirst and AVP that is either partial ( ) or total ( ). In the latter, plasma AVP does not change in response to increases or decreases in plasma osmolarity but remains within a range sufficient to concentrate the urine even if overhydration produces hypotonic hyponatremia. In contrast, if the osmoregulatory deficiency is partial ( ), rehydration of the patient suppresses plasma AVP to levels that result in urinary dilution and polyuria before plasma osmolarity and sodium are reduced to normal. Lines a –d represent different defects in the osmoregulation of plasma AVP observed in patients with SIADH or SIAD. In a ( ), plasma AVP is markedly elevated and fluctuates widely without relation to changes in plasma osmolarity, indicating complete loss of osmoregulation. In b ( ), plasma AVP remains fixed at a slightly elevated level until plasma osmolarity reaches the normal range, at which point it begins to rise appropriately, indicating a selective defect in the inhibitory component of


InternalMed_Harrison

InternalMed_Harrison. fixed at a slightly elevated level until plasma osmolarity reaches the normal range, at which point it begins to rise appropriately, indicating a selective defect in the inhibitory component of the osmoregulatory mechanism. In c ( ), plasma AVP rises in close correlation with plasma osmolarity before the latter reaches the normal range, indicating downward resetting of the osmostat. In d ( ), plasma AVP appears to be osmoregulated normally, suggesting that the inappropriate antidiuresis is caused by some other abnormality.


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InternalMed_Harrison. 2280 stimuli such as nausea or large reductions in blood volume or blood pressure, indicating that the neurohypophysis is intact.


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InternalMed_Harrison. Pathophysiology Hypodipsia results in a failure to drink enough water to replenish obligatory renal and extrarenal losses. Consequently, plasma osmolarity and sodium rise often to extremely high levels before the disorder is recognized. In most cases, urinary loss of water contributes little, if any, to the dehydration because AVP continues to be secreted in the small amounts necessary to concentrate the urine. In some patients this appears to be due to hypovolemic stimulation and/or incomplete destruction of AVP osmoreceptors because plasma AVP declines and DI develops during rehydration (Fig. 404-6). In others, however, plasma AVP does not decline during rehydration even if they are overhydrated. Consequently, they develop a hyponatremic syndrome indistinguishable from inappropriate antidiuresis. This suggests that the AVP osmoreceptors normally provide inhibitory and stimulatory input to the neurohypophysis and the patients can no longer osmotically stimulate or suppress tonic


InternalMed_Harrison

InternalMed_Harrison. antidiuresis. This suggests that the AVP osmoreceptors normally provide inhibitory and stimulatory input to the neurohypophysis and the patients can no longer osmotically stimulate or suppress tonic secretion of the hormone because both inputs have been totally eliminated by the same pathology that destroyed the osmoregulation of thirst. In a few patients, the neurohypophysis is also destroyed, resulting in a combination of chronic pituitary DI and hypodipsia that is particularly difficult to manage.


InternalMed_Harrison

InternalMed_Harrison. Differential Diagnosis Hypodipsic hypernatremia usually can be distinguished from other causes of inadequate fluid intake (e.g., coma, paralysis, restraints, absence of fresh water) by the clinical history and setting. Previous episodes and/or denial of thirst and failure to drink spontaneously when the patient is conscious, unrestrained, and hypernatremic are virtually diagnostic. The hypernatremia caused by excessive retention or intake of sodium can be distinguished by the presence of thirst as well as the physical and laboratory signs of hypervolemia rather than hypovolemia.


InternalMed_Harrison

InternalMed_Harrison. Hypodipsic hypernatremia should be treated by administering water orally if the patient is alert and cooperative or by infusing hypotonic fluids (0.45% saline or 5% dextrose and water) if the patient is not. The amount of free water in liters required to correct the deficit (ΔFW) can be estimated from body weight in kg (BW) and the serum sodium concentration in mmol/L (SNa) by the formula ΔFW = 0.5BW × ([S – 140]/140). If serum glucose (S ) is elevated, the mea- sured S should be corrected (S *) by the formula S *= S + ([S – 90]/36).


InternalMed_Harrison

InternalMed_Harrison. This amount plus an allowance for continuing insensible and urinary losses should be given over a 24to 48-h period. Close monitoring of serum sodium as well as fluid intake and urinary output is essential because, depending on the extent of osmoreceptor deficiency, some patients will develop AVP-deficient DI, requiring DDAVP therapy to complete rehydration; others will develop hyponatremia and a syndrome of inappropriate antidiuresis (SIAD)-like picture if overhydrated. If hyperglycemia and/or hypokalemia are present, insulin and/or potassium supplements should be given with the expectation that both can be discontinued soon after rehydration is complete. Plasma urea/creatinine should be monitored closely for signs of acute renal failure caused by rhabdomyolysis, hypovolemia, and hypotension.


InternalMed_Harrison

InternalMed_Harrison. Once the patient has been rehydrated, an MRI of the brain and tests of anterior pituitary function should be performed to look for the cause and collateral defects in other hypothalamic functions. A long-term management plan to prevent or minimize recurrence of the fluid and electrolyte imbalance also should be developed. This should include a practical method to regulate fluid intake in accordance with variations in water balance as indicated by changes in body weight or serum sodium determined by home monitoring analyzers. Prescribing a constant fluid intake is ineffective and potentially dangerous because it does not take into account the large, uncontrolled variations in insensible loss that inevitably result from changes in ambient temperature and physical activity.


InternalMed_Harrison

InternalMed_Harrison. A decrease in plasma osmolarity/sodium below the normal range (hypotonic hyponatremia) can be due to any of three different types of salt and water imbalance: (1) an increase in total body water that exceeds the increase in total body sodium (hypervolemic hyponatremia); (2) a decrease in body sodium greater than the decrease in body water (hypovolemic hyponatremia); or (3) an increase in body water with little or no change in body sodium (euvolemic hyponatremia) (Chap. 63). All three forms are associated with a failure to fully dilute the urine and mount a water diuresis in the face of hypotonic hyponatremia. The hypervolemic form typically occurs in disorders like severe congestive heart failure or cirrhosis. The hypovolemic form typically occurs in disorders such as severe diarrhea, diuretic abuse, or mineralocorticoid deficiency. Euvolemic hyponatremia, however, is due mainly to expansion of total body water caused by excessive intake in the face of a defect in urinary dilution.


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InternalMed_Harrison. abuse, or mineralocorticoid deficiency. Euvolemic hyponatremia, however, is due mainly to expansion of total body water caused by excessive intake in the face of a defect in urinary dilution. The impaired dilution is usually caused by a defect in the osmotic suppression of AVP that can have either of two causes. One is a nonhemodynamic stimulus such as nausea or a cortisol deficiency, which can be corrected quickly by treatment with antiemetics or cortisol. The other is a primary defect in osmoregulation caused by another disorder such as malignancy, stroke, or pneumonia that cannot be easily or quickly corrected. The latter is commonly known as the syndrome of inappropriate antidiuretic hormone (SIADH). Much less often, euvolemic hyponatremia can also result from AVP-independent activation of renal V2 receptors, a variant known as nephrogenic inappropriate antidiuresis or NSIAD. Both of the latter will be discussed in this chapter.


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InternalMed_Harrison. Clinical Characteristics Antidiuresis of any cause decreases the volume and increases the concentration of urine. If not accompanied by a commensurate reduction in fluid intake or an increase in insensible loss, the reduction in urine output results in excess water retention which expands and dilutes body fluids. If the hyponatremia develops gradually or has been present for more than a few days, it may be largely asymptomatic. However, if it develops acutely, it is usually accompanied by symptoms and signs of water intoxication that may include mild headache, confusion, anorexia, nausea, vomiting, coma, and convulsions. Severe acute hyponatremia may be lethal. Other clinical signs and symptoms vary greatly, depending on the type of hyponatremia. The hypervolemic form is characterized by generalized edema and other signs of marked volume expansion. The opposite is evident in the hypovolemic form. However, overt signs of volume expansion or contraction are absent in SIADH, SIAD, and


InternalMed_Harrison

InternalMed_Harrison. generalized edema and other signs of marked volume expansion. The opposite is evident in the hypovolemic form. However, overt signs of volume expansion or contraction are absent in SIADH, SIAD, and other forms of euvolemic hyponatremia.


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InternalMed_Harrison. Etiology In SIADH, the inappropriate secretion of AVP can have many different causes. They include ectopic production of AVP by lung cancer or other neoplasms; eutopic release induced by various diseases or drugs; and exogenous administration of AVP, DDAVP, or large doses of oxytocin (Table 404-2). The ectopic forms result from abnormal expression of the AVP-NPII gene by primary or metastatic malignancies. The eutopic forms occur most often in patients with acute infections or strokes but have also been associated with many other neurologic diseases and injuries. The mechanisms by which these diseases interfere with osmotic suppression of AVP are not known. The defect in osmoregulation can take any of four distinct forms (Fig. 404-6). In one of the most common (reset osmostat), AVP secretion remains fully responsive to changes in plasma osmolarity/sodium, but the threshold, or set point, of the osmoregulatory system is abnormally low. These patients differ from those with the other


InternalMed_Harrison

InternalMed_Harrison. remains fully responsive to changes in plasma osmolarity/sodium, but the threshold, or set point, of the osmoregulatory system is abnormally low. These patients differ from those with the other types of SIADH in that they are able to maximally suppress plasma AVP and dilute their urine if their fluid intake is high enough to reduce their plasma osmolarity and/or sodium to the new set point. In most patients, SIADH is self-limited and remits spontaneously within 2–3 weeks, but about 10% of cases are chronic. Another, smaller subgroup (~10% of the total) has inappropriate antidiuresis without a demonstrable defect in the osmoregulation of plasma AVP (Fig. 404-6). In some of them, all young boys, the inappropriate antidiuresis has been traced to a constitutively activating mutation of the V2 receptor gene. This unusual variant may be referred to as familial nephrogenic SIAD (NSIAD) to distinguish it from


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InternalMed_Harrison. CAuSES of SynDRomE of inAPPRoPRiATE AnTiDiuRETiC HoRmonE (SiADH) Bladder, ureter Psychosis Pneumothorax Pneumonia, bacterial or viral Positive-pressure respiration Abscess, lung or brain Vasopressin or desmopressin Tuberculosis, lung or brain Serotonin reuptake inhibitors Meningitis, bacterial or viral Oxytocin, high dose Encephalitis Nicotine Cerebrovascular occlusions, other possible causes of the syndrome. The inappropriate antidiuresis in these patients appears to be permanent, although the hyponatremia is variable owing presumably to individual differences in fluid intake.


InternalMed_Harrison

InternalMed_Harrison. Pathophysiology Impaired osmotic suppression of antidiuresis results in excessive retention of water and dilution of body fluids only if water intake exceeds insensible and urinary losses. The excess intake is sometimes due to an associated defect in the osmoregulation of thirst (dipsogenic) but can also be psychogenic or iatrogenic, including excessive IV administration of hypotonic fluids. In SIADH and other forms of euvolemic hyponatremia, the decrease in plasma osmolarity/ sodium and the increase in extracellular and intracellular volume are proportional to the amount of water retained. Thus, an increase in body water of 10% (~4 L in a 70-kg adult) reduces plasma osmolarity and sodium by approximately 10% (~28 mosmol/L or 14 meq/L). An increase in body water of this magnitude is rarely detectable on physical examination but will be reflected in a weight gain of about 4 kg. It also increases glomerular filtration and atrial natriuretic hormone and suppresses plasma renin activity,


InternalMed_Harrison

InternalMed_Harrison. detectable on physical examination but will be reflected in a weight gain of about 4 kg. It also increases glomerular filtration and atrial natriuretic hormone and suppresses plasma renin activity, thereby increasing urinary sodium excretion. The resultant reduction in total body sodium decreases the expansion of extracellular volume but aggravates the hyponatremia and further expands intracellular volume. The latter further increases brain swelling and intracranial pressure, which probably produces most of the symptoms of acute water intoxication. Within a few days, this swelling may be counteracted by inactivation or elimination of intracellular solutes, resulting in the remission of symptoms even though the hyponatremia persists.


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InternalMed_Harrison. In type I (hypervolemic) or type II (hypovolemic) hyponatremia, osmotic suppression of AVP secretion appears to be counteracted by a hemodynamic stimulus resulting from a large reduction in cardiac output and/or effective blood volume. The resultant antidiuresis is enhanced by decreased distal delivery of glomerular filtrate that results from increased reabsorption of sodium in proximal nephron. 2281 If the reduction in urine output is not associated with a commensurate reduction in water intake or an increase in insensible loss, body fluids are expanded and diluted, resulting in hyponatremia despite an increase in body sodium. Unlike SIADH and other forms of euvolemic hyponatremia, however, glomerular filtration is reduced and plasma renin activity and aldosterone are elevated. Thus, the rate of urinary sodium excretion is low (unless sodium reabsorption is impaired by a diuretic), and the hyponatremia is usually accompanied by edema, hypokalemia, azotemia, and hyperuricemia. In type


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InternalMed_Harrison. rate of urinary sodium excretion is low (unless sodium reabsorption is impaired by a diuretic), and the hyponatremia is usually accompanied by edema, hypokalemia, azotemia, and hyperuricemia. In type II (hypovolemic) hyponatremia, sodium and water are also retained as an appropriate compensatory response to the severe depletion.


InternalMed_Harrison

InternalMed_Harrison. Differential Diagnosis SIADH is a diagnosis of exclusion that usually can be made from the history, physical examination, and basic laboratory data. If hyperglycemia is present, its contribution to the reduction in plasma sodium can be estimated either by measuring plasma osmolarity for a more accurate estimate of the true “effective” tonicity of body fluids or by correcting the measured plasma sodium for the reduction caused by the hyperglycemia using the simplified formula where P = plasma sodium in meq/L and P = plasma glucose in mg/dL.


InternalMed_Harrison

InternalMed_Harrison. If the plasma osmolarity and/or corrected plasma sodium are below normal limits, hypotonic hyponatremia is present and further evaluation to determine the type should be undertaken in order to administer safe and effective treatment. This differentiation is usually possible by evaluating standard clinical indicators of the extracellular fluid volume (Table 404-3). If these findings are ambiguous or contradictory, measuring plasma renin activity or the rate of urinary sodium excretion may be helpful provided that the hyponatremia is not in the recovery phase or is due to a primary defect in renal conservation of sodium, diuretic abuse, or hyporeninemic hypoaldosteronism. The latter may be suspected if serum potassium is elevated instead of low, as it usually is in types I and II hyponatremia. Measurements of plasma AVP are currently of no value in differentiating SIADH from the other types of hyponatremia since the plasma levels are elevated similarly in all. In patients who fulfill


InternalMed_Harrison

InternalMed_Harrison. Measurements of plasma AVP are currently of no value in differentiating SIADH from the other types of hyponatremia since the plasma levels are elevated similarly in all. In patients who fulfill the clinical criteria for type III (euvolemic) hyponatremia, morning plasma cortisol should also be measured to exclude secondary adrenal insufficiency. If it is normal and there is no history of nausea/vomiting, the diagnosis of SIADH is confirmed, and a careful search for occult lung cancer or other common causes of the syndrome (Table 404-2) should be undertaken.


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InternalMed_Harrison. SIAD due to an activating mutation of the V2 receptor gene should be suspected if the hyponatremia occurs in a child or several members of the family or is refractory to treatment with a vaptan (see below). In that case, plasma AVP should be measured to confirm that it is appropriately suppressed while the hyponatremia and antidiuresis are present, and the V2 receptor gene should be sequenced, if possible.


InternalMed_Harrison

InternalMed_Harrison. The management of hyponatremia differs depending on the type and the severity and duration of symptoms. In acute symptomatic SIADH, the aim should be to raise plasma osmolarity and/or plasma sodium at a rate approximating 1% an hour until they reach levels of about 270 mosmol/L or 130 meq/L, respectively. This can be accomplished in either of two ways. One is to infuse hypertonic (3%) saline at a rate of about 0.05 mL/kg body weight per minute. This treatment also has the advantage of correcting the sodium deficiency that is partly responsible for the hyponatremia and often produces a solute diuresis that serves to remove some of the excess water. The other treatment is to reduce body water by giving an AVP receptor-2 antagonist (vaptan) to block the antidiuretic effect of AVP and increase urine output (Fig. 404-7). One of the vaptans, a combined V2/V1a antagonist (Conivaptan), has been approved for short-term, in-hospital IV treatment of SIADH, and others are in various stages of


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InternalMed_Harrison. urine output (Fig. 404-7). One of the vaptans, a combined V2/V1a antagonist (Conivaptan), has been approved for short-term, in-hospital IV treatment of SIADH, and others are in various stages of development. With either approach, fluid intake should be restricted to less than urine


InternalMed_Harrison

InternalMed_Harrison. Disorders of the Neurohypophysis SIADH and SIAD Clinical Findings Type I, Hypervolemic Type II, Hypovolemic Type III, Euvolemic Euvolemic CHF, cirrhosis, or nephrosis Generalized edema, ascites BUN, creatinine


InternalMed_Harrison

InternalMed_Harrison. Urinary sodium (meq per unit of time)g aPostural hypotension may occur in secondary (ACTH-dependent) adrenal insufficiency even though extracellular fluid volume and aldosterone are usually normal. bSerum potassium may be high if hypovolemia is due to aldosterone deficiency. cSerum potassium may be low if vomiting causes alkalosis. dSerum cortisol is low if hypovolemia is due to primary adrenal insufficiency (Addison’s disease). eSerum cortisol will be normal or high if the cause is nausea and vomiting rather than secondary (ACTH-dependent) adrenal insufficiency. fPlasma renin activity may be high if the cause is secondary (ACTH) adrenal insufficiency. gUrinary sodium should be expressed as the rate of excretion rather than the concentration. In a hyponatremic adult, an excretion rate >25 meq/d (or 25 μeq/mg of creatinine) could be considered high. hThe rate of urinary sodium excretion may be high if the hypovolemia is due to diuretic abuse, primary adrenal insufficiency, or other


InternalMed_Harrison

InternalMed_Harrison. >25 meq/d (or 25 μeq/mg of creatinine) could be considered high. hThe rate of urinary sodium excretion may be high if the hypovolemia is due to diuretic abuse, primary adrenal insufficiency, or other causes of renal sodium wasting. iThe rate of urinary sodium excretion may be low if intake is curtailed by symptoms or treatment.


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InternalMed_Harrison. Abbreviations: ACTH, adrenocorticotropic hormone; BUN, blood urea nitrogen; CHF, congestive heart failure; SIAD, syndrome of inappropriate antidiuresis. output, and serum sodium should be checked at least once every 2h to ensure it is not raised too fast or too far. Doing so may result in central pontine myelinolysis, an acute, potentially fatal neurologic syndrome characterized by quadriparesis, ataxia, and abnormal extraocular movements.


InternalMed_Harrison

InternalMed_Harrison. In chronic and/or minimally symptomatic SIADH, the hyponatremia can and should be corrected more gradually. This can be achieved by restricting total fluid intake to less than the sum of urinary and insensible losses. Because the water derived from food (300–700 mL/d) usually approximates basal insensible losses in adults, the aim should be to reduce total discretionary intake (all liquids) to approximately 500 mL less than urinary output. Adherence to this regimen is often problematic and, even if achieved, usually reduces body water and increases serum sodium by only about 1–2% per day. Hence, additional approaches are usually desirable if not necessary. The best approach for treatment of chronic SIADH is the administration of an oral vaptan, tolvaptan, a selective V2 antagonist that also increases urinary water excretion by blocking the antidiuretic effect of AVP. Some restriction of fluid intake may also be necessary to achieve satisfactory control of the hyponatremia. It is


InternalMed_Harrison

InternalMed_Harrison. also increases urinary water excretion by blocking the antidiuretic effect of AVP. Some restriction of fluid intake may also be necessary to achieve satisfactory control of the hyponatremia. It is approved for treatment of nonemergent SIADH with initial in-hospital dosing. Other approaches include demeclocycline, 150–300 mg PO tid or qid, or fludrocortisone, 0.05–0.2 mg PO bid. The effect of the demeclocycline manifests in 7–14 days and is due to induc- tion of a reversible form of nephrogenic DI. Potential side effects include phototoxicity and azotemia. The effect of fludrocortisone also requires 1–2 weeks and is partly due to increased retention of sodium and possibly inhibition of thirst. It also increases urinary potassium excretion, which may require replacement through dietary adjustments or supplements and may induce hypertension, occasionally necessitating discontinuation of the treatment.


InternalMed_Harrison

InternalMed_Harrison. vomiting or isolated glucocorticoid deficiency (type III), all abnormalities can be corrected quickly and completely by giving an antiemetic or stress doses of hydrocortisone (for glucocorticoid deficiency). As with other treatments, care must be taken to ensure that serum sodium does not rise too quickly or too far. In SIAD due to an activating mutation of the V2 receptor, the V2 FIGURE 404-7 The effect of vaptan therapy on water balance in a patient with chronic syndrome of inappropriate antidiuretic hormone (SIADH). The periods of vaptan (V) therapy are indicated by the green shaded boxes at the top. Urine output is indicated by orange bars. Fluid intake is shown by the open bars. Intake was restricted to 1 L/d throughout. Serum sodium is indicated by the black line. Note that sodium increased progressively when vaptan increased urine output to levels that clearly exceeded fluid intake.


InternalMed_Harrison

InternalMed_Harrison. antagonists usually do not block the antidiuresis or raise plasma osmolarity/sodium. In that condition, use of an osmotic diuretic such as urea is reported to be effective in preventing or correcting hyponatremia. However, some vaptans may be effective in patients with a different type of activating mutation so the response to this therapy may be neither predictable nor diagnostic.


InternalMed_Harrison

InternalMed_Harrison. In hypervolemic hyponatremia, fluid restriction is also appropriate and somewhat effective if it can be maintained. However, infusion of hypertonic saline is contraindicated because it further increases total body sodium and edema and may precipitate cardiovascular decompensation. However, as in SIADH, the V2 receptor antagonists are also safe and effective in the treatment of hypervolemic hyponatremia caused by congestive heart failure. Tolvaptan is approved by the Food and Drug Administration for this indication with the caveat that treatment should be initiated or reinitiated in hospital. Its use should also be limited to 30 days at a time because of reports that longer periods may be associated with abnormal liver chemistries.


InternalMed_Harrison

InternalMed_Harrison. In hypovolemic hyponatremia, the defect in AVP secretion and water balance usually can be corrected easily and quickly by stopping the loss of sodium and water and/or replacing the deficits by mouth or IV infusion of normal or hypertonic saline. As with the treatment of other forms of hyponatremia, care must be taken to ensure that plasma sodium does not increase too rapidly or too far. Fluid restriction and administration of AVP antagonists are contraindicated in type II hyponatremia because they would only aggravate the underlying volume depletion and could result in hemodynamic collapse.


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InternalMed_Harrison. The incidence, clinical characteristics, etiology, pathophysiology, differential diagnosis, and treatments of fluid and electrolyte disorders in tropical and nonindustrialized countries differ in some respects from those in the United States and other industrialized parts of the world. Hyponatremia, for example, appears to be more common and is more likely to be due to infectious diseases such as cholera, shigellosis, and other diarrheal disorders. In these circumstances, hyponatremia is probably due to gastrointestinal losses of salt and water (hypovolemia type II), but other abnormalities, including undefined infectious toxins, also may contribute. The causes of DI are similar worldwide except that malaria and venoms from snake or insect bites are much more common.


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InternalMed_Harrison. Disorders of the Thyroid gland J. Larry Jameson, Susan J. Mandel, Anthony P. Weetman The thyroid gland produces two related hormones, thyroxine (T4) and triiodothyronine (T3) (Fig. 405-1). Acting through thyroid hormone receptors α and β, these hormones play a critical role in cell differentia-tion during development and help maintain thermogenic 405 and metabolic homeostasis in the adult. Autoimmune disorders of the thyroid gland can stimulate overproduction of thyroid hormones (thyrotoxicosis) or cause glandular destruction and hormone deficiency (hypothyroidism). In addition, benign nodules and various forms of thyroid cancer are relatively common and amenable to detection by physical examination. The thyroid (Greek thyreos, shield, plus eidos, form) consists of two lobes connected by an isthmus. It is located I anterior to the trachea between the cricoid cartilage and


InternalMed_Harrison

InternalMed_Harrison. The thyroid (Greek thyreos, shield, plus eidos, form) consists of two lobes connected by an isthmus. It is located I anterior to the trachea between the cricoid cartilage and The thyroid gland develops from the floor of the primitive pharynx 2283 during the third week of gestation. The developing gland migrates along the thyroglossal duct to reach its final location in the neck. This feature accounts for the rare ectopic location of thyroid tissue at the base of the tongue (lingual thyroid) as well as the occurrence of thyroglossal duct cysts along this developmental tract. Thyroid hormone synthesis normally begins at about 11 weeks’ gestation.


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InternalMed_Harrison. Neural crest derivatives from the ultimobranchial body give rise to thyroid medullary C cells that produce calcitonin, a calcium-lowering hormone. The C cells are interspersed throughout the thyroid gland, although their density is greatest in the juncture of the upper one-third and lower two-thirds of the gland. Calcitonin plays a minimal role in calcium homeostasis in humans but the C-cells are important because of their involvement in medullary thyroid cancer.


InternalMed_Harrison

InternalMed_Harrison. Thyroid gland development is orchestrated by the coordinated expression of several developmental transcription factors. Thyroid transcription factor (TTF)-1, TTF-2, and paired homeobox-8 (PAX-8) are expressed selectively, but not exclusively, in the thyroid gland. In combination, they dictate thyroid cell development and the induction of thyroid-specific genes such as thyroglobulin (Tg), thyroid peroxidase (TPO), the sodium iodide symporter (Na+/I–, NIS), and the thyroid-stimulating hormone receptor (TSH-R). Mutations in these developmental transcription factors or their downstream target genes are rare causes of thyroid agenesis or dyshormonogenesis, although the causes of most forms of congenital hypothyroidism remain unknown (Table 405-1). Because congenital hypothyroidism occurs in approximately 1 in 4000 newborns, neonatal screening is now performed in most industrialized countries (see below). Transplacental passage of maternal thyroid hormone occurs before the fetal thyroid


InternalMed_Harrison

InternalMed_Harrison. approximately 1 in 4000 newborns, neonatal screening is now performed in most industrialized countries (see below). Transplacental passage of maternal thyroid hormone occurs before the fetal thyroid gland begins to function and provides partial hormone support to a fetus with congenital hypothyroidism. Early thyroid hormone replacement in newborns with congenital hypothyroidism prevents potentially severe developmental abnormalities.


InternalMed_Harrison

InternalMed_Harrison. The thyroid gland consists of numerous spherical follicles composed of thyroid follicular cells that surround secreted colloid, a proteinaceous fluid containing large amounts of thyroglobulin, the protein precursor of thyroid hormones (Fig. 405-2). The thyroid follicular cells are polarized—the basolateral surface is apposed to the bloodstream and an apical surface faces the follicular lumen. Increased demand for thyroid hormone is regulated by thyroid-stimulating hormone (TSH), which binds to its receptor on the basolateral surface of the follicular cells. This binding leads to Tg reabsorption from the follicular lumen and proteolysis within the cytoplasm, yielding thyroid hormones for secretion into the bloodstream. TSH, secreted by the thyrotrope cells of the anterior pituitary, plays a pivotal role in control of the thyroid axis and serves as the most useful 3,5,3',5'-Tetraiodothyronine Disorders of the Thyroid Gland the suprasternal notch. The normal thyroid is 12–20 g HO


InternalMed_Harrison

InternalMed_Harrison. Disorders of the Thyroid Gland the suprasternal notch. The normal thyroid is 12–20 g HO CH2 CH COOH in size, highly vascular, and soft in consistency. Four parathyroid glands, which produce parathyroid hormone II (Chap. 424), are located posterior to each pole of the Triiodothyronine (T3) Reverse T3 (rT3) 3,5,3'-Triiodothyronine 3,3',5'-Triiodothyronine thyroid. The recurrent laryngeal nerves traverse the lateral borders of the thyroid gland and must be identified FIGURE 405-1 Structures of thyroid hormones. Thyroxine (T4) contains four during thyroid surgery to avoid injury and vocal cord iodine atoms. Deiodination leads to production of the potent hormone triiodothyparalysis. ronine (T ) or the inactive hormone reverse T . PROP-1 Autosomal recessive Combined pituitary hormone deficiencies with preservation of adrenocorticotropic hormone PIT-1 Autosomal recessive Combined deficiencies of growth hormone, prolactin, thyroid-


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InternalMed_Harrison. PIT-1 Autosomal recessive Combined deficiencies of growth hormone, prolactin, thyroid- TTF-1 (TITF-1) Autosomal dominant Variable thyroid hypoplasia, choreoathetosis, pulmonary problems hereditary osteodystrophy) Na+/Isymporter Autosomal recessive Inability to transport iodide DUOX2 (THOX2) Autosomal dominant Organification defect physiologic marker of thyroid hormone action. TSH is a 31-kDa hormone composed of α and β subunits; the α subunit is common to the other glycoprotein hormones (luteinizing hormone, follicle-stimulating hormone, human chorionic gonadotropin [hCG]), whereas the TSH β subunit is unique to TSH. The extent and nature of carbohydrate modification are modulated by thyrotropin-releasing hormone (TRH) stimulation and influence the biologic activity of the hormone.


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InternalMed_Harrison. The thyroid axis is a classic example of an endocrine feedback loop. Hypothalamic TRH stimulates pituitary production of TSH, which, in turn, stimulates thyroid hormone synthesis and secretion. Thyroid hormones act via negative feedback predominantly through thyroid hormone receptor β2 (TRβ2) to inhibit TRH and TSH production (Fig. 405-2). The “set-point” in this axis is established by TSH. TRH is the major positive regulator of TSH synthesis and secretion. Peak TSH secretion occurs ~15 min after administration of exogenous TRH. Dopamine, glucocorticoids, and somatostatin suppress TSH but are not of major physiologic importance except when these agents are administered in pharmacologic doses. Reduced levels of thyroid hormone increase basal TSH production and enhance TRH-mediated stimulation of TSH. High thyroid hormone levels rapidly and directly suppress TSH gene expression secretion and inhibit TRH stimulation of TSH, indicating that thyroid hormones are the dominant regulator of


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InternalMed_Harrison. of TSH. High thyroid hormone levels rapidly and directly suppress TSH gene expression secretion and inhibit TRH stimulation of TSH, indicating that thyroid hormones are the dominant regulator of TSH production. Like other pituitary hormones, TSH is released in a pulsatile manner and exhibits a diurnal rhythm; its highest levels occur at night. However, these TSH excursions are modest in comparison to those of other pituitary hormones, in part, because TSH has a relatively long plasma half-life (50 min). Consequently, single measurements of TSH are adequate for assessing its circulating level. TSH is measured using immunoradiometric assays that are highly sensitive and specific. These assays readily distinguish between normal and suppressed TSH values; thus, TSH can be used for the diagnosis of hyperthyroidism (low TSH) as well as hypothyroidism (high TSH).


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InternalMed_Harrison. THYROID HORMONE SYNTHESIS, METABOLISM, AND ACTION Thyroid hormones are derived from Tg, a large iodinated glycoprotein. After secretion into the thyroid follicle, Tg is iodinated on tyrosine FIGURE 405-2 Regulation of thyroid hormone synthesis. Left. Thyroid hormones T4 and T3 feed back to inhibit hypothalamic production of thyrotropin-releasing hormone (TRH) and pituitary production of thyroid-stimulating hormone (TSH). TSH stimulates thyroid gland production of T4 and T3. Right. Thyroid follicles are formed by thyroid epithelial cells surrounding proteinaceous colloid, which contains thyroglobulin. Follicular cells, which are polarized, synthesize thyroglobulin and carry out thyroid hormone biosynthesis (see text for details). DIT, diiodotyrosine; MIT, monoiodotyrosine; NIS, sodium iodide symporter; Tg, thyroglobulin; TPO, thyroid peroxidase; TSH-R, thyroid-stimulating hormone receptor.


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InternalMed_Harrison. residues that are subsequently coupled via an ether linkage. Reuptake of Tg into the thyroid follicular cell allows proteolysis and the release of newly synthesized T4 and T3.


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InternalMed_Harrison. Iodine Metabolism and Transport Iodide uptake is a critical first step in thyroid hormone synthesis. Ingested iodine is bound to serum proteins, particularly albumin. Unbound iodine is excreted in the urine. The thyroid gland extracts iodine from the circulation in a highly efficient manner. For example, 10–25% of radioactive tracer (e.g., 123I) is taken up by the normal thyroid gland over 24 h; this value can rise to 70–90% in Graves’ disease. Iodide uptake is mediated by NIS, which is expressed at the basolateral membrane of thyroid follicular cells. NIS is most highly expressed in the thyroid gland, but low levels are present in the salivary glands, lactating breast, and placenta. The iodide transport mechanism is highly regulated, allowing adaptation to variations in dietary supply. Low iodine levels increase the amount of NIS and stimulate uptake, whereas high iodine levels suppress NIS expression and uptake. The selective expression of NIS in the thyroid allows isotopic


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InternalMed_Harrison. Low iodine levels increase the amount of NIS and stimulate uptake, whereas high iodine levels suppress NIS expression and uptake. The selective expression of NIS in the thyroid allows isotopic scanning, treatment of hyperthyroidism, and ablation of thyroid cancer with radioisotopes of iodine, without significant effects on other organs. Mutation of the NIS gene is a rare cause of congenital hypothyroidism, underscoring its importance in thyroid hormone synthesis. Another iodine transporter, pendrin, is located on the apical surface of thyroid cells and mediates iodine efflux into the lumen. Mutation of the pendrin gene causes Pendred syndrome, a disorder characterized by defective organification of iodine, goiter, and sensorineural deafness.


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InternalMed_Harrison. Iodine deficiency is prevalent in many mountainous regions and in central Africa, central South America, and northern


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InternalMed_Harrison. Asia (Fig. 405-3). Europe remains mildly iodine-deficient, and health surveys indicate that iodine intake has been falling in the United States and Australia. The World Health Organization (WHO) estimates that about 2 billion people are iodine-deficient, based on urinary excretion data. In areas of relative iodine deficiency, there is an increased prevalence of goiter and, when deficiency is severe, hypothyroidism and cretinism. Cretinism is characterized by mental and growth retardation and occurs when children who live in iodine-deficient regions are not treated with iodine or thyroid hormone to restore normal thyroid hormone levels during early life. These children are often born to mothers with iodine deficiency, and it is likely that maternal thyroid hormone deficiency worsens the condition. Concomitant selenium deficiency may also contribute to the neurologic manifestations of cretinism. Iodine supplementation of salt, bread, and other food substances has markedly reduced the


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InternalMed_Harrison. condition. Concomitant selenium deficiency may also contribute to the neurologic manifestations of cretinism. Iodine supplementation of salt, bread, and other food substances has markedly reduced the prevalence of cretinism. Unfortunately, however, iodine deficiency remains the most common cause of preventable mental deficiency, often because of societal resistance to food additives or the cost of supplementation. In addition to overt cretinism, mild iodine deficiency can lead to subtle reduction of IQ. Oversupply of iodine, through supplements or foods enriched in iodine (e.g., shellfish, kelp), is associated with an increased incidence of autoimmune thyroid disease. The recommended average daily intake of iodine is 150–250 μg/d for adults, 90–120 μg/d for children, and 250 μg/d for pregnant and lactating women. Urinary iodine is >10 μg/dL in iodine-sufficient populations.


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InternalMed_Harrison. Organification, Coupling, Storage, and Release After iodide enters the thyroid, it is trapped and transported to the apical membrane of thyroid follicular cells, where it is oxidized in an organification reaction that involves TPO and hydrogen peroxide produced by dual oxidase (DUOX) and DUOX maturation factor (DUOXA). The reactive iodine atom is added to selected tyrosyl residues within Tg, a large (660 kDa) dimeric protein that consists of 2769 amino acids. The iodotyrosines in Tg are then coupled via an ether linkage in a reaction that is also catalyzed by TPO. Either T4 or T3 can be produced by this reaction, depending on the number of iodine atoms present in the iodotyrosines. After coupling, Tg is taken back into the thyroid cell, where it is processed in lysosomes to release T4 and T3. Uncoupled monoand diiodotyrosines (MIT, DIT) are deiodinated by the enzyme dehalogenase, thereby recycling any iodide that is not converted into thyroid hormones.


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InternalMed_Harrison. Disorders of thyroid hormone synthesis are rare causes of con-2285 genital hypothyroidism. The vast majority of these disorders are due to recessive mutations in TPO or Tg, but defects have also been identified in the TSH-R, NIS, pendrin, hydrogen peroxide generation, and dehalogenase. Because of the biosynthetic defect, the gland is incapable of synthesizing adequate amounts of hormone, leading to increased TSH and a large goiter.


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InternalMed_Harrison. TSH Action TSH regulates thyroid gland function through the TSHR, a seven-transmembrane G protein–coupled receptor (GPCR). The TSH-R is coupled to the α subunit of stimulatory G protein (GSα), which activates adenylyl cyclase, leading to increased production of cyclic adenosine monophosphate (AMP). TSH also stimulates phosphatidylinositol turnover by activating phospholipase C. The functional role of the TSH-R is exemplified by the consequences of naturally occurring mutations. Recessive loss-of-function mutations cause thyroid hypoplasia and congenital hypothyroidism. Dominant gain-of-function mutations cause sporadic or familial hyperthyroidism that is characterized by goiter, thyroid cell hyperplasia, and autonomous function. Most of these activating mutations occur in the transmembrane domain of the receptor. They mimic the conformational changes induced by TSH binding or the interactions of thyroid-stimulating immunoglobulins (TSI) in Graves’ disease. Activating TSH-R mutations


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InternalMed_Harrison. domain of the receptor. They mimic the conformational changes induced by TSH binding or the interactions of thyroid-stimulating immunoglobulins (TSI) in Graves’ disease. Activating TSH-R mutations also occur as somatic events, leading to clonal selection and expansion of the affected thyroid follicular cell and autonomously functioning thyroid nodules (see below).


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InternalMed_Harrison. Other Factors That Influence Hormone Synthesis and Release Although TSH is the dominant hormonal regulator of thyroid gland growth and function, a variety of growth factors, most produced locally in the thyroid gland, also influence thyroid hormone synthesis. These include insulin-like growth factor I (IGF-I), epidermal growth factor, transforming growth factor β (TGF-β), endothelins, and various cytokines. The quantitative roles of these factors are not well understood, but they are important in selected disease states. In acromegaly, for example, increased levels of growth hormone and IGF-I are associated with goiter and predisposition to multinodular goiter (MNG). Certain cytokines and interleukins (ILs) produced in association with autoimmune thyroid disease induce thyroid growth, whereas others lead to apoptosis. Iodine deficiency increases thyroid blood flow and upregulates the NIS, stimulating more efficient iodine uptake. Excess iodide transiently inhibits thyroid iodide


InternalMed_Harrison

InternalMed_Harrison. whereas others lead to apoptosis. Iodine deficiency increases thyroid blood flow and upregulates the NIS, stimulating more efficient iodine uptake. Excess iodide transiently inhibits thyroid iodide organification, a phenomenon known as the Wolff-Chaikoff effect. In individuals with a normal thyroid, the gland escapes from this inhibitory effect and iodide organification resumes; the suppressive action of high iodide may persist, however, in patients with underlying autoimmune thyroid disease.


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InternalMed_Harrison. THYROID HORMONE TRANSPORT AND METABOLISM Serum Binding Proteins T4 is secreted from the thyroid gland in about twentyfold excess over T3 (Table 405-2). Both hormones are bound to plasma proteins, including thyroxine-binding globulin (TBG), transthyretin (TTR, formerly known as thyroxinebinding prealbumin, or TBPA), and albumin. The plasma-binding proteins increase the pool of circulating hormone, delay hormone clearance, and may modulate hormone delivery to selected tissue sites. The concentration of TBG is relatively low (1–2 mg/dL), but because of its high affinity for thyroid hormones (T4 > T3), it carries about 80% of the bound hormones. Albumin has relatively low affinity for thyroid hormones CHAPTER 405 Disorders of the Thyroid Gland until a new steady state is reached, thereby restoring euthyroidism. Circulating factors associated with acute illness may also displace thyroid hormone from binding proteins (see “Sick Euthyroid Syndrome,” below).


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InternalMed_Harrison. Total hormone 8 μg/dL 0.14 μg/dL Deiodinases T4 may be thought of as a precursor for the more potent Fraction of total hormone in the unbound form 0.02% 0.3% T . T is converted to T by the deiodinase enzymes (Fig. 405-1). Type I deiodinase, which is located primarily in thyroid, liver, and kidneys, Serum half-life 7 d 2 d has a relatively low affinity for T4. Type II deiodinase has a higher affin-Fraction directly from the thyroid 100% 20% ity for T4 and is found primarily in the pituitary gland, brain, brown fat, Production rate, including peripheral conversion 90 μg/d 32 μg/d and thyroid gland. Expression of type II deiodinase allows it to regulate T concentrations locally, a property that may be important in the context of levothyroxine (T ) replacement. Type II deiodinase is also


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InternalMed_Harrison. T concentrations locally, a property that may be important in the context of levothyroxine (T ) replacement. Type II deiodinase is also Relative metabolic potency 0.3 1 4 regulated by thyroid hormone; hypothyroidism induces the enzyme, resulting in enhanced T4 → T3 conversion in tissues such as brain and pituitary. T4 → T3 conversion is impaired by fasting, systemic illness When the effects of the various binding proteins are combined, or acute trauma, oral contrast agents, and a variety of medications approximately 99.98% of T and 99.7% of T are protein-bound. (e.g., propylthiouracil, propranolol, amiodarone, glucocorticoids). Because T is less tightly bound than T , the fraction of unbound T Type III deiodinase inactivates T and T and is the most important is greater than unbound T , but there is less unbound T in the cir-source of reverse T3 (rT3), including in the sick euthyroid syndrome.


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InternalMed_Harrison. culation because it is produced in smaller amounts and cleared more This enzyme is expressed in the human placenta but is not active in rapidly than T . The unbound or “free” concentrations of the hor-healthy individuals. In the sick euthyroid syndrome, especially with mones are ~2 × 10−11 M for T and ~6 × 10−12 M for T , which roughly hypoperfusion, the type III deiodinase is activated in muscle and liver. correspond to the thyroid hormone receptor binding constants for Massive hemangiomas that express type III deiodinase are a rare cause these hormones (see below). The unbound hormone is thought to be of hypothyroidism in infants. biologically available to tissues. Nonetheless, the homeostatic mechanisms that regulate the thyroid axis are directed toward maintenance THYROID HORMONE ACTION of normal concentrations of unbound hormones. Thyroid Hormone Transport Circulating thyroid hormones enter cells by passive diffusion and via specific transporters such as the mono-


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InternalMed_Harrison. Abnormalities of Thyroid Hormone Binding Proteins A number of inher carboxylate 8 transporter (MCT8), MCT10, and organic anionited and acquired abnormalities affect thyroid hormone binding transporting polypeptide 1C1. Mutations in the MCT8 gene have been proteins. X-linked TBG deficiency is associated with very low levels identified in patients with X-linked psychomotor retardation andof total T4 and T3. However, because unbound hormone levels are thyroid function abnormalities (low T4, high T3, and high TSH). Afternormal, patients are euthyroid and TSH levels are normal. It is imporentering cells, thyroid hormones act primarily through nuclear receptant to recognize this disorder to avoid efforts to normalize total T4 tors, although they also have nongenomic actions through stimulatinglevels, because this leads to thyrotoxicosis and is futile because of rapid mitochondrial enzymatic responses and may act directly on blood veshormone clearance in the absence of TBG. TBG levels are


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InternalMed_Harrison. because this leads to thyrotoxicosis and is futile because of rapid mitochondrial enzymatic responses and may act directly on blood veshormone clearance in the absence of TBG. TBG levels are elevated sels and the heart through integrin receptors.


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InternalMed_Harrison. by estrogen, which increases sialylation and delays TBG clearance. Consequently, in women who are pregnant or taking estrogen-Nuclear Thyroid Hormone Receptors Thyroid hormones bind with high containing contraceptives, elevated TBG increases total T4 and T3 levels; affinity to nuclear thyroid hormone receptors (TRs) α and β. Both TRα and however, unbound T4 and T3 levels are normal. These features are TRβ are expressed in most tissues, but their relative expression levels vary part of the explanation for why women with hypothyroidism require increased amounts of L-thyroxine replacement as TBG levels are increased by pregnancy or estrogen treatment. Mutations in TBG, TTR, and albumin may increase the bind-ing affinity for T4 and/or T3 and cause TAblE 405-3 ConDiTionS ASSoCiATED wiTH EuTHyRoiD HyPERTHyRoxinEmiA Disorder Cause Transmission Characteristics Familial dysalbuminemic hyperthyroxinemia (FDH) Albumin mutations, usually R218H AD Increased T4 Normal unbound T4


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InternalMed_Harrison. Rarely increased T3 roxinemia or familial dysalbuminemic TBG hyperthyroxinemia (FDH) (Table 405-3). Familial excess Increased TBG production XL Increased total T4, T3 disorders known as euthyroid hyperthy- Normal unbound T , T and/or T , but unbound hormone lev T4 3 Acquired excess Medications (estrogen), Acquired Increased total T4, T43 3 els are normal. The familial nature of the pregnancy, cirrhosis, Normal unbound T4, T3 disorders, and the fact that TSH levels are normal rather than suppressed, should suggest this diagnosis. Unbound hor- Excess Islet tumors Acquired Usually normal T4, T3 Mutations Increased affinity for T4 AD Increased total T4, T3 are normal in FDH. The diagnosis can be


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InternalMed_Harrison. Excess Islet tumors Acquired Usually normal T4, T3 Mutations Increased affinity for T4 AD Increased total T4, T3 are normal in FDH. The diagnosis can be Normal unbound T4, T3 confirmed by using tests that measure the affinities of radiolabeled hormone bind-Medications: propranolol, ipo-Decreased T4 → T3 Acquired Increased T4 ing to specific transport proteins or by date, iopanoic acid, amiodarone conversion performing DNA sequence analyses of the abnormal transport protein genes. Resistance to thyroid hormone Thyroid hormone receptor AD Increased unbound T4, T3Certain medications, such as salicylates (RTH) β mutations and salsalate, can displace thyroid hor- mones from circulating binding proteins. aAlso known as thyroxine-binding prealbumin (TBPA). the thyroid axis by increasing free thyroid hormone levels, TSH is suppressed Abbreviations: AD, autosomal dominant; TBG, thyroxine-binding globulin; TSH, thyroid-stimulating hormone; XL, X-linked.


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InternalMed_Harrison. the thyroid axis by increasing free thyroid hormone levels, TSH is suppressed Abbreviations: AD, autosomal dominant; TBG, thyroxine-binding globulin; TSH, thyroid-stimulating hormone; XL, X-linked. among organs; TRα is particularly abundant in brain, kidneys, gonads, muscle, and heart, whereas TRβ expression is relatively high in the pituitary and liver. Both receptors are variably spliced to form unique isoforms. The TRβ2 isoform, which has a unique amino terminus, is selectively expressed in the hypothalamus and pituitary, where it plays a role in feedback control of the thyroid axis (see above). The TRα2 isoform contains a unique carboxy terminus that precludes thyroid hormone binding; it may function to block the action of other TR isoforms.


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InternalMed_Harrison. The TRs contain a central DNA-binding domain and a C-terminal ligand-binding domain. They bind to specific DNA sequences, termed thyroid response elements (TREs), in the promoter regions of target genes (Fig. 405-4). The receptors bind as homodimers or, more commonly, as heterodimers with retinoic acid X receptors (RXRs) (Chap. 400e). The activated receptor can either stimulate gene transcription (e.g., myosin heavy chain α) or inhibit transcription (e.g., TSH β-subunit gene), depending on the nature of the regulatory elements in the target gene.


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InternalMed_Harrison. Thyroid hormones (T3 and T4) bind with similar affinities to TRα and TRβ. However, structural differences in the ligand binding domains provide the potential for developing receptor-selective agonists or antagonists, and these are under investigation. T3 is bound with 10–15 times greater affinity than T4, which explains its increased hormonal potency. Although T4 is produced in excess of T3, receptors are occupied mainly by T3, reflecting T4 → T3 conversion by peripheral tissues, greater T3 bioavailability in the plasma, and the greater affinity of receptors for T3. After binding to TRs, thyroid hormone induces conformational changes in the receptors that modify its interactions with accessory transcription factors. Importantly, in the absence of thyroid hormone binding, the aporeceptors bind to co-repressor proteins that inhibit gene transcription. Hormone binding dissociates the co-repressors and allows the recruitment of co-activators that enhance transcription. The discovery of TR


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InternalMed_Harrison. to co-repressor proteins that inhibit gene transcription. Hormone binding dissociates the co-repressors and allows the recruitment of co-activators that enhance transcription. The discovery of TR interactions with co-repressors explains the fact that TR silences gene expression in the absence of hormone binding. Consequently, hormone deficiency has a profound effect on gene expression because it causes gene repression as well as loss of hormone-induced stimulation. This concept has been corroborated by the finding that targeted deletion of the TR genes in mice has a less pronounced phenotypic effect than hormone deficiency.


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InternalMed_Harrison. FIGURE 405-4 Mechanism of thyroid hormone receptor action. The thyroid hormone receptor (TR) and retinoid X receptor (RXR) form heterodimers that bind specifically to thyroid hormone response elements (TRE) in the promoter regions of target genes. In the absence of hormone, TR binds co-repressor (CoR) proteins that silence gene expression. The numbers refer to a series of ordered reactions that occur in response to thyroid hormone: (1) T4 or T3 enters the nucleus; (2) T3 binding dissociates CoR from TR; (3) co-activators (CoA) are recruited to the T3-bound receptor; and (4) gene expression is altered.


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InternalMed_Harrison. Thyroid Hormone Resistance Resistance to thyroid hormone (RTH) 2287 is an autosomal dominant disorder characterized by elevated thyroid hormone levels and inappropriately normal or elevated TSH. Individuals with RTH do not, in general, exhibit signs and symptoms that are typical of hypothyroidism because hormone resistance is partial and is compensated by increased levels of thyroid hormone. The clinical features of RTH can include goiter, attention deficit disorder, mild reduction in IQ, delayed skeletal maturation, tachycardia, and impaired metabolic responses to thyroid hormone.


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InternalMed_Harrison. Classical forms of RTH are caused by mutations in the TRβ gene. These mutations, located in restricted regions of the ligand-binding domain, cause loss of receptor function. However, because the mutant receptors retain the capacity to dimerize with RXRs, bind to DNA, and recruit co-repressor proteins, they function as antagonists of the remaining normal TRβ and TRα receptors. This property, referred to as “dominant negative” activity, explains the autosomal dominant mode of transmission. The diagnosis is suspected when unbound thyroid hormone levels are increased without suppression of TSH. Similar hormonal abnormalities are found in other affected family members, although the TRβ mutation arises de novo in about 20% of patients. DNA sequence analysis of the TRβ gene provides a definitive diagnosis. RTH must be distinguished from other causes of euthyroid hyperthyroxinemia (e.g., FDH) and inappropriate secretion of TSH by TSH-secreting pituitary adenomas (Chap. 403). In most patients,


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InternalMed_Harrison. diagnosis. RTH must be distinguished from other causes of euthyroid hyperthyroxinemia (e.g., FDH) and inappropriate secretion of TSH by TSH-secreting pituitary adenomas (Chap. 403). In most patients, no treatment is indicated; the importance of making the diagnosis is to avoid inappropriate treatment of mistaken hyperthyroidism and to provide genetic counseling.


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InternalMed_Harrison. A distinct form of RTH is caused by mutations in the TRα gene. Affected patients have many clinical features of congenital hypothyroidism including growth retardation, skeletal dysplasia, and severe constipation. In contrast to RTH caused by mutations in TRβ, thyroid function tests include normal TSH, low or normal T4, and normal or elevated T3 levels. These distinct clinical and laboratory features underscore the different tissue distribution and functional roles of TRβ and TRα. Optimal treatment of patients with RTH caused by TRα mutations has not been established.


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InternalMed_Harrison. In addition to the examination of the thyroid itself, the physical examination should include a search for signs of abnormal thyroid function and the extrathyroidal features of ophthalmopathy and dermopathy (see below). Examination of the neck begins by inspecting the seated patient from the front and side and noting any surgical scars, obvious masses, or distended veins. The thyroid can be palpated with both hands from behind or while facing the patient, using the thumbs to palpate each lobe. It is best to use a combination of these methods, especially when nodules are small. The patient’s neck should be slightly flexed to relax the neck muscles. After locating the cricoid cartilage, the isthmus, which is attached to the lower one-third of the thyroid lobes, can be identified and then followed laterally to locate either lobe (normally, the right lobe is slightly larger than the left). By asking the patient to swallow sips of water, thyroid consistency can be better appreciated as the


InternalMed_Harrison

InternalMed_Harrison. laterally to locate either lobe (normally, the right lobe is slightly larger than the left). By asking the patient to swallow sips of water, thyroid consistency can be better appreciated as the gland moves beneath the examiner’s fingers.