Charles A. Peloquin, PharmD

• Professor
• College of Pharmacy
• University of Florida

A number of disorders impairing renal tubular sodium or water conservation can lead to volume contraction anxiety and sleep buy cymbalta 30mg visa. First anxiety knee pain generic cymbalta 30 mg otc, various tubular nephropathies are characterized by specific deficits in salt or water absorption anxiety symptoms vs heart attack symptoms generic cymbalta 20mg on line. As mentioned earlier anxiety symptoms and causes cymbalta 20mg low price, nephrogenic diabetes insipidus and interstitial renal disease may produce water or sodium wasting, respectively. However, the general term renal tubular acidosis also includes other sodium-wasting disorders accompanied by hyperchloremic acidosis, such as proximal tubular acidosis, a specific proximal defect in bicarbonate reabsorption, and gradient-limited distal renal tubular acidosis, a specific defect in distal tubular sodium bicarbonate regeneration (see Chapter 107). Inhibition of tubular sodium absorptive processes due to chronic diuretic abuse also may lead to salt wasting, volume contraction, and specific metabolic acid-base abnormalities. Profound but reversible defects in tubular salt and water absorption may occur during postobstructive diuresis, that is, shortly after relief of partial or complete urinary tract obstruction. Salt and water losses also may occur in the diuretic phase of acute tubular necrosis. Third, glomerular filtration of large amounts of non-electrolytes may produce volume deficits by overwhelming renal tubular reabsorptive capacity for salt and water; in this instance, water losses predominate so that hypernatremia generally occurs. In addition to hemorrhage, two other classes of extrarenal losses account for volume contraction. Simple dehydration may result from increased insensible water loss in excessive sweating due to high ambient temperatures or to fever. Finally, gastrointestinal volume losses occur when portions of the 8 to 10 L of normal gastrointestinal secretions are lost, particularly in secretory diarrheas. Volume depletion is most commonly the consequence of vomiting, gastric drainage, or diarrhea but may occur with any type of bowel fistula. Loss of hydrochloric acid from the stomach may produce metabolic alkalosis, whereas loss of sodium bicarbonate from pancreatic secretions lost through the lower gastrointestinal tract, as in diarrhea, may produce metabolic acidosis. The clinical findings in states of true volume contraction are due both to underfilling of the arterial tree and to the subsequent renal and hemodynamic responses. In mild or partially compensated volume contraction, particularly when the latter has occurred gradually, the patient may exhibit nothing more than mild postural giddiness, postural tachycardia, and weakness, whereas in severe volume contraction, life-threatening circulatory collapse may occur. The lack of physical findings does not exclude the presence of mild to moderate volume contraction in a given patient. In the postoperative period, 7 to 10% blood volume losses in patients are often accompanied by normal vital signs and by only slight decreases in the central venous pressure or the pulmonary capillary wedge pressure. Skin turgor and the moistness of mucous membranes are valuable indices to the volume of body water in infants but are unreliable in adults. In young adults, reductions in skin turgor do not occur unless profound volume contraction is present, and normal loss of skin elasticity makes skin turgor difficult to assess in older patients. Similarly, mouth breathing and other factors affect the oral mucosa independently of external volume balances. Consequently, the clinical findings in volume contraction depend primarily on the interplay among four major factors: (1) the magnitude of the volume loss; (2) the rate of volume loss; (3) the nature of the fluid loss, that is, whether the fluid loss is primarily water, a combined sodium plus water loss, or a blood loss; and (4) the responsiveness of the vasculature to volume reduction. The clinical manifestations of volume contraction are obviously related intimately to the volume and rate of fluid loss. For example, an acute gastrointestinal hemorrhage of 1 L of blood can easily result in oliguria, coupled with the signs and symptoms of circulatory collapse, while the hematocrit remains constant. In other words, the hemorrhage is sufficiently acute that fluid flux from the interstitial to the vascular bed makes a negligible contribution to expanding the vascular bed. Second, the kind of fluid loss significantly affects the clinical findings in volume contraction. Consider, for example, a 1-L loss of different kinds of body fluids in a 70-kg man with a total body water of 40 L and a hematocrit of 45%. The acute loss of 1 L of predominantly solute-free water, as in diabetes insipidus, reduces the blood volume by 2. Lastly, the acute loss of 1 L of blood by hemorrhage reduces blood volume by 20%, thus resulting in profound oliguria and near circulatory collapse. Finally, peripheral vasoconstriction and tachycardia represent important physiologic responses to volume losses. Consequently, even modest signs and symptoms of volume contraction are amplified appreciably in patients with diminished myocardial reserve or reduced sympathetic nervous system function. The former occurs commonly in cardiomyopathies of any cause or in pericardial tamponade or pericardial constriction. The latter occurs commonly in patients on prolonged bed rest, in diabetic patients with autonomic neuropathy, and as a consequence of therapy with certain antihypertensive drugs. The pulse, blood pressure, and changes of these variables with position, together with a clinical estimate of the venous pressure and skin temperature, provide an initial assessment of circulatory dynamics. Wide variations exist in blood pressure and pulse changes to orthostatic measurements. A decrease in orthostatic diastolic blood pressure of 10 mm Hg is considered to be the most reliable indicator of significant volume depletion. Even then, a physician cannot be certain, and it is useful to consider a fluid challenge to evaluate patients in whom a volume deficit is thought to contribute to a reduced cardiac output. A convenient way of achieving this goal is to administer 500 mL of normal saline over 1 to 3 hours. In patients with a normal cardiac reserve, the effect of a fluid challenge may be monitored safely by evaluating the pulse, blood pressure, and urine flow. In patients with impaired cardiac function, using a flow-directed Swan-Ganz catheter to measure the pulmonary capillary wedge pressure or cardiac output, as estimated by thermal dilution, provides a more precise indicator to early volume overload secondary to a fluid challenge. Because volume contraction is associated with vasoconstriction, both in the venous and the arterial circuits, transient changes in the pulmonary capillary wedge 544 pressure may not accurately reflect volume status. The initial pressure elevation is due to fluid infusion into a vasoconstricted, low-capacity vascular bed and should not be misinterpreted to indicate adequacy of volume repletion. The subsequent reduction in wedge pressure coincides with decreases in arterial resistance coupled with increases in venous capacitance. Finally, central venous pressure measurements provide unreliable estimates of pulmonary vascular volume. The cardinal laboratory findings associated with volume contraction follow directly from the volume repletion mechanism summarized in Figure 102-2. The kidney initially responds to a decrease in effective circulating blood volume by reducing urine volume and sodium excretion. Severe degrees of volume contraction also reduce filtration rate and result in prerenal azotemia and a decrease in fractional excretion of sodium (see Chapter 100). The type of fluid, the route and rate of fluid administration, and the total amount of fluid to be given will vary with the particular circumstance. For example, a mild, non-persisting upper gastrointestinal hemorrhage may be treated appropriately by infusing normal saline, whereas a major, persisting upper gastrointestinal hemorrhage will generally require replacement with whole blood. If glucose metabolism is normal, infusing 5% dextrose in water (D5 W) is equivalent to administering solute-free water, which distributes uniformly in total body water. Because less than 10% of total body water is in the intravascular compartment, infusing 1 L of D5 W expands the intravascular volume by 75 to 100 mL, that is, by about 2%. Infusing 1 L of a normal saline solution increases blood volume by about 300 mL, or about 6%; the remaining portion is distributed in the interstitial compartment. Hypotonic sodium-containing salt solutions expand intravascular volume in a manner intermediate between that of D5 W and normal saline. Sodium-containing crystalloid solutions are indicated primarily in volume-contracted states secondary to renal or gastrointestinal sodium losses (see Table 102-2). Colloid-containing solutions, such as iso-oncotic albumin solutions and plasma, preferentially expand the intravascular compartment, because large molecules like albumin are mainly restricted to the intravascular space. This kind of fluid replacement is most helpful in burns, in which cutaneous protein losses are appreciable, and in circulatory collapse, in which rapid intravascular expansion is critical. In most other instances of volume contraction, using colloid-containing solutions is difficult to justify, since the half-life of infused albumin in ill patients is relatively short, only 4 to 6 hours, and the cost of colloid solutions such as iso-oncotic albumin is more than 50 times greater than that of an equal volume of crystalloid solution. Finally, blood-which contains formed elements-is the most potent expander of the intravascular space. In most hemorrhagic situations, the combination of packed red blood cells with either normal saline solutions or colloid solutions is adequate for volume replacement. Few circumstances occur in modern practice, with the possible exception of massive hemorrhagic shock, in which whole-blood therapy for volume expansion is used. In the preceding section we considered those disorders characterized by inadequate filling of the arterial tree that occurred because of true volume deficits.

Herpesvirus tends to produce vesicles or isolated superficial ulcers anxiety 7 cups of tea 60 mg cymbalta for sale, but extensive involvement can produce confluent ulcerations anxiety symptoms generic cymbalta 30 mg on-line. Biopsy of the ulcerated area usually shows either invasive hyphae of Candida or characteristic nuclear changes of the squamous cells when herpesvirus is present anxiety zap reviews buy cymbalta 40mg with mastercard. For mild anxiety 7 months pregnant effective cymbalta 20mg, noninvasive candidal disease, topical therapy with nystatin (250,000 units every 2 hours) or clotrimazole (dissolved in the mouth 5 times per day) suffices. For more serious infections, systemic treatment with oral fluconazole or occasionally ketoconazole is used. Low-dose intravenous amphotericin may be needed for patients who do not respond to oral treatment and those unable to swallow medications. Esophageal Injuries Caustic Ingestion Caustic burns of the esophagus occur in children by accident; adults usually suffer such burns because of suicide attempts. Lye crystals, and especially liquid lye preparations for drain cleaning, detergents, and bleach are the most common causes (see Chapter 98). The speed of lye injury is so great that attempts to neutralize the caustic are futile. The history is all-important, but the degree of esophageal injury must be assessed emergently by endoscopy. Significant esophageal damage has been seen even without oral burns; conversely, oral burns do not necessarily mean that the material has reached the esophagus. If no esophageal reaction is present after apparent caustic ingestion, further care directed toward the esophagus will not be necessary. Circumferential burns and ulcers in the esophagus may result in delayed perforation over several days or in stricture formation. The goals of therapy are to prevent perforation and to avoid progressive fibrosis and stricture of the esophagus. However, the accepted therapy of a definite lye or caustic burn remains unsupported by clinical trials. For burns with solid lye or other solid agents, corticosteroids have been recommended at an initial dose of 80 mg/day, tapering to 20 mg/day until the esophagus heals. For liquid lye, serious consideration should be given to emergent esophagogastrectomy because lesser measures have met with unacceptably high mortality. Damage by Medication Ingested pills may lodge in the esophagus and damage the mucosa in a localized area. Tetracycline, doxycycline, potassium tablets, ascorbic acid, quinidine, and nonsteroidal anti-inflammatory agents are the principal medications that cause pill-induced esophagitis, but the list is long. For example, the bisphosphonates, such as alendronate, also cause esophageal injury. Normal individuals can retain small capsules in the esophagus even when swallowing in the upright position. The clinical syndrome consists of steady burning or chest pain accompanied by local odynophagia occurring 4 to 6 hours after ingesting one of the offending capsules or tablets. Endoscopy usually shows a localized mucosal ulcer, which may heal without scar or lead to a stricture requiring dilation. Pills should be taken by the patient in the upright position, with several swallows of water taken both before and after pill ingestion. Esophageal Trauma the esophagus is well protected by the thoracic cage, but it can be involved either by blunt trauma. Iatrogenic perforation with an endoscope, dilator, or, very rarely, nasogastric tube can lead to similar complications. The mucosal lesion first described by Mallory and Weiss has been recognized much more frequently since the advent of emergency fiberoptic endoscopy. Classically, the patient has repeated attacks of retching, at first producing gastric contents and later bright red blood. One quarter of patients shown to have a Mallory-Weiss tear have no prior history of vomiting. The tear is usually in the gastric mucosa just below the gastroesophageal junction, although it can extend through the junction and up into the esophageal mucosa. Diagnosis is almost always made at endoscopy; the rent is usually seen as the endoscope is being withdrawn from the stomach into the esophagus. The majority of such lesions heal with conservative therapy, and angiographic or surgical therapy is necessary in fewer than 5% of cases. Bleeding can be stopped during endoscopy by directly applying electrocoagulation or by injecting epinephrine. It usually follows vomiting, but other marked increases in intra-abdominal pressure, such as from lifting a heavy weight or straining at stool, have been associated with this syndrome. The clinical diagnosis can be extremely difficult; often, patients with esophageal rupture are thought to have a myocardial infarction, pneumothorax, perforated viscus, or pancreatitis. Air in the mediastinum or the rapid appearance of a pleural effusion on the left usually leads to the correct diagnosis. The diagnosis of esophageal perforation can usually be established by a cautious radiographic examination with water-soluble material. Barium should be used only if a tear is not demonstrated by the water-soluble agent. Immediate surgical repair is the accepted method of treatment of esophageal perforation. In those too ill for surgery, treatment consists of nasogastric suction, administration of antibiotics, and subsequent mediastinal drainage if necessary. Soll the normal gastric mucosa has a remarkable ability to resist acid-peptic injury (see Chapter 126). Three conditions (severe physiologic stress, alcohol, and non-steroidal anti-inflammatory agents) that cause erosive or hemorrhagic damage have been traditionally included among disorders causing gastritis. This organism has three attributes that allow it to fill a unique ecologic niche (Table 125-2). The antrum is consistently involved, whereas inflammation in the acid-secreting, fundic or oxyntic gland mucosa (gastric body and fundus) is more variable (see later). Transmission is most likely by a fecal-oral route or by exposure to gastric juice of infected individuals (oral-gastric). Transmission has also occurred with contaminated nasogastric tubes and endoscopes. A large component of the increase in prevalence with age reflects an age cohort effect whereby older individuals, especially those older than 60, acquired the infection at a young age. The clinical correlate is that duodenal ulcer patients secrete acid at high-normal or high rates and have a lower risk of gastric cancer. In contrast to duodenal ulcer, patients with gastric ulcer tend to have more severe antral gastritis, more involvement with superficial fundic gland gastritis, and low-normal acid secretory rates. With time and increasing severity of pangastritis, fundic gland atrophy can occur and cause a decrease in maximal acid secretion with age. Atrophy of antral glands can also occur, often accompanied by pseudopyloric metaplasia (the parietal and chief cells of fundic glands are replaced by mucous glands indistinguishable from normal antrum) and intestinal metaplasia (mucin-containing goblet cells, absorptive cells, and occasionally rudimentary villi). Invasive testing includes biopsy for histologic examination, urease test on antral biopsies, or culture (which is not routinely available). In tests that depend on the number of organisms (testing breath and gastric biopsies for urease activity, histology, and culture), false-negative results occur especially when the organism has been suppressed by antibiotics, proton pump inhibitors (omeprazole or lansoprazole), or bismuth. Therapy may need to be discontinued for several weeks before these tests become positive. Individuals with gastritis are usually asymptomatic; the relation of pathologic gastritis to dyspepsia is mired in the vagaries of visceral sensation (see Chapter 126). The contribution of other factors to pathogenesis and the overlap with autoimmune gastritis and pernicious anemia remain to be established. This immune gastritis (type A) predominantly involves the fundic gland mucosa, is deep (encompassing the gastric glands that contain parietal and chief cells), and usually is atrophic (with decreased or absent glandular elements and mucosal thinning). Superficial inflammation is minimal, and deep inflammatory changes usually are most prominent along the greater curvature of the fundus and body. Even with sufficient fundic gland atrophy to produce histamine-fast achlorhydria, some patchy nests of parietal and chief cells may persist. The relative absence of glandular atrophy in the antrum accounts for the ability of many of these patients to develop marked hypergastrinemia when there is no feedback inhibition of acid on gastrin release. About 90% of patients with pernicious anemia have antibodies against parietal cells.

It is also due to the catabolism of filtered albumin by the proximal tubule as well as to redistribution of albumin within the body anxiety disorder definition buy cymbalta 20mg fast delivery. This anxiety symptoms pregnancy cheap cymbalta 20 mg online, in part anxiety symptoms 89 purchase cymbalta 40mg online, accounts for the inexact relationship between urinary protein loss anxiety symptoms 6 dpo order 20 mg cymbalta amex, the level of the serum albumin, and other secondary consequences of heavy albuminuria. The salt and volume retention in the nephrotic syndrome may occur through at least two different major mechanisms. In the classic theory, proteinuria leads to hypoalbuminemia, a low plasma oncotic pressure, and intravascular volume depletion. Subsequent underperfusion of the kidney stimulates the priming of sodium-retentive hormonal systems such as the renin-angiotensin-aldosterone axis, causing increased renal sodium and volume retention. In the peripheral capillaries with normal hydrostatic pressures and decreased oncotic pressure, the Starling forces lead to transcapillary fluid leakage and edema. In some patients, however, the intravascular volume has been measured and found to be increased along with suppression of the renin-angiotensin-aldosterone axis. An animal model of unilateral proteinuria shows evidence for primary renal sodium retention at a distal nephron site, perhaps due to altered responsiveness to hormones such as atrial natriuretic factor. Here only the proteinuric kidney retains sodium and volume and at a time when the animal is not yet hypoalbuminemic. Thus, local factors within the kidney may account for the volume retention of the nephrotic patient as well. Recent epidemiologic study clearly defines an increased risk of atherosclerotic complications in the nephrotic syndrome. In addition to hyperlipidemia, many nephrotic patients have additional cardiovascular risk factors, including hypertension, smoking, and left ventricular hypertrophy. Initial evaluation of the nephrotic patient includes laboratory tests to define whether the patient has primary, idiopathic nephrotic syndrome or a secondary cause related to a systemic disease. Common screening tests include the fasting blood sugar and glycosylated hemoglobin tests for diabetes, an antinuclear antibody test for collagen vascular disease, and the serum complement, which screens for many immune complex-mediated diseases (Table 106-1). Once secondary causes have been excluded, treating the adult nephrotic patient often requires a renal biopsy to define the pattern of glomerular involvement. In many studies, patients with heavy proteinuria and the nephrotic syndrome have been a group highly likely to benefit from renal biopsy in terms of a change in specific diagnosis, prognosis, and therapy. Selected adult nephrotic patients such as the elderly have a slightly different spectrum of disease, but once again the renal biopsy is the best guide to treatment and prognosis (Tables 106-2 and 106-3). Minimal change disease, also known as nil disease and lipoid nephrosis, is the most common pattern of nephrotic syndrome in children and comprises from 10 to 15% of idiopathic nephrotic syndrome in adults. Patients typically present with periorbital and peripheral edema related to the proteinuria, which is usually well into the nephrotic range. Additional findings in adults are hypertension and microscopic hematuria, each in about 30% of patients. Many adult patients have mild to moderate azotemia, which may be related to hypoalbuminemia and intravascular volume depletion. The tubules may show lipid droplet accumulation from absorbed lipoproteins (hence the older term lipoid nephrosis). The course of minimal change nephrotic syndrome is often one of remissions and relapses and responses to additional treatment. In adults, the response rate is somewhat lower, with 75 to 85% of patients responding to regimens of daily (60 mg) or alternate-day (120 mg) prednisone therapy, tapered after 2 months of treatment. The time to clinical response may be slower in adults, and they should not be considered steroid-resistant until they have failed to respond to 16 weeks of treatment. Tapering of the steroid dose after remission should be gradual over 1 to 2 months. Both children and adults are likely to have a relapse of their minimal change disease once corticosteroids have been discontinued. Approximately 30% of adults experience relapse by 1 year, and in 50% it occurs by 5 years. Most clinicians treat the first relapse similarly to the initial episode of nephrotic syndrome. Patients who relapse a third time or who become corticosteroid dependent (unable to tolerate decrease in the prednisone dose beyond a certain level without proteinuria recurring) may be treated with a 2-month course of an alkylating agent. Cyclophosphamide at a dose of up to 2 mg/kg/day has been used successfully, as has chlorambucil. Electron micrograph shows widespread effacement of foot processes with microvillous transformation of the visceral epithelium. An alternative to an alkylating agent is low-dose cyclosporine (4 to 6 mg/kg/day for 4 months), but this carries the risk of nephrotoxicity and a higher relapse rate. This histologic diagnosis may be either idiopathic or secondary to a number of different causes. Although the nephrotic syndrome is present in two thirds of patients at presentation, proteinuria may vary from less than 1 to 30 g/day and is typically non-selective. Hypertension is found in 30 to 50%, and microscopic hematuria occurs in about one half of these patients. As renal function declines, repeat biopsy specimens show more glomeruli with segmental sclerosing lesions and increased numbers of globally sclerotic glomeruli. There have been few randomized, controlled trials, and newer studies with promising results remain uncontrolled. Recent studies using more intensive and more prolonged immunosuppressive regimens (6 to 12 months) with corticosteroids and cytotoxics have achieved up to a 40 to 60% remission rate of the nephrotic syndrome with preservation of long-term renal function. Low-dose cyclosporine (4 to 6 mg/kg/day for 4 to 6 months) has also been used with success even in patients who have been corticosteroid and cytotoxic unresponsive. Membranous nephropathy is the most common pattern of idiopathic nephrotic syndrome in 589 white Americans. It may also be associated with infections (lues, hepatitis B and C), with systemic lupus, with certain medications (gold salts), and with certain tumors (solid tumors and lymphomas). Despite the finding of complement in the glomerular immune deposits, serum complement levels are normal. Membranous nephropathy is the most common pattern of the nephrotic syndrome to be associated with a hypercoagulable state and renal vein thrombosis. The presence of sudden flank pain, deterioration of renal function, or symptoms of pulmonary disease in a patient with membranous nephropathy should prompt an investigation for renal vein thrombosis and pulmonary emboli. Both the slow progression and spontaneous remission rate have confounded clinical treatment trials. A number of older studies using corticosteroids to treat membranous nephropathy have given conflicting results. A more recent controlled trial of alternating monthly corticosteroids and monthly oral chlorambucil over 6 months has given a greater number of total remissions and better preservation of renal function. Recent controlled studies using only corticosteroids for 6 months have shown similar beneficial results. Although others believe that the good results in the treatment arms are not significantly better than the natural history of the disease, recent meta-analyses have found beneficial results from the use of cytotoxic agents in idiopathic membranous nephropathy. Finally, several uncontrolled studies suggest that patients with membranous nephropathy who are progressing to renal failure may benefit from cyclophosphamide plus corticosteroids with a reversal of progressive renal failure and remission of heavy proteinuria. On ultrastructural examination, there are numerous, closely apposed epimembranous electron-dense deposits separated by basement membrane spikes (uranyl acetate, lead citrate, Ч2500). By preventing degradation of the enzyme, there is increased activation and consumption of complement noted in dense deposit disease. This may be secondary to infiltrating inflammatory cells, proliferation of resident glomerular cells, or both. Both invading inflammatory neutrophils and monocytes, as well as resident cells, can damage the glomerulus through a number of mediators, including a host of oxidants, chemoattractants, proteases, cytokines, and growth factors. Some factors, such as transforming growth factor-beta, have been related to eventual glomerulosclerosis and chronic glomerular damage. The hypertension is caused by intravascular volume expansion, although renin levels may not be appropriately suppressed for the degree of volume expansion. Patients may note dark, smoky, or cola-colored urine in association with the active urinary sediment. In geographic areas where renal biopsies are commonly performed for milder urinary findings, a higher incidence of IgA has been noted. In the United States, some centers report this diagnosis in up to 20% of all primary glomerulopathies.

The mechanism of gallstone formation in these individuals is unclear; pigmented gallstones are most common anxiety symptoms mayo clinic 20mg cymbalta with visa. Diseases That Impair Mucosal Absorption Mucosal malabsorption can be caused by specific (usually congenital) brush border enzyme or nutrient transporter deficiencies or by generalized diseases that damage the small intestinal mucosa or result in surgical resection or bypass of small intestine anxiety pill names purchase 30mg cymbalta with mastercard. The nutrient(s) malabsorbed in these general malabsorptive diseases depend on the site of intestinal injury (proximal anxiety poems quality 60mg cymbalta, distal anxiety 4 weeks after quitting smoking discount cymbalta 60 mg, or diffuse) and the severity of damage. The main mechanism of malabsorption in these conditions is a decrease in surface area available for absorption. Some conditions (infection, celiac disease, tropical sprue, food allergies, and graft versus host disease) are characterized by intestinal inflammation and villus flattening; other conditions by ulceration (ulcerative jejunitis, nonsteroidal anti-inflammatory drugs), infiltration (amyloidosis), or ischemia (radiation enteritis, mesenteric ischemia). Acquired lactase deficiency is the most common cause of selective carbohydrate malabsorption. Most individuals, except those of northern European descent, begin to lose lactase activity by the age of 5 years. The prevalence of lactase deficiency is highest (85 to 100%) in Asians, African blacks, and Native Americans. In most individuals, lactase deficiency is due to decreased synthesis of the enzyme. In some, however, intracellular transport and glycosylation of lactase is defective. Adults with lactase deficiency typically complain of gas, bloating, and diarrhea after the ingestion of milk or dairy products but do not lose weight. Unabsorbed lactose is osmotically active, drawing water followed by ions into the intestinal lumen. On reaching the colon, bacteria metabolize lactose to short-chain fatty acids, carbon dioxide, and hydrogen gas. Short-chain fatty acids are transported with sodium into colonic epithelial cells, facilitating the reabsorption of fluid in the colon. If the colonic capacity for the reabsorption of short-chain fatty acids is exceeded, an osmotic diarrhea results (see Chapter 133). The diagnosis of lactase deficiency can be made by empirical treatment with a lactose-free diet, which results in resolution of symptoms, or by the hydrogen breath test after oral administration of lactose. A number of intestinal diseases cause secondary reversible lactase deficiency, such as viral gastroenteritis, celiac disease, giardiasis, and bacterial overgrowth. Enteropeptidase is a brush border protease that cleaves trypsinogen to trypsin, thereby triggering the cascade of pancreatic protease activation in the intestinal lumen. The rare congenital deficiency of enteropeptidase results in the inability to activate all pancreatic proteases and leads to severe protein malabsorption. It manifests in infancy as diarrhea, growth retardation, and hypoproteinemic edema. Formation and exocytosis of chylomicrons at the basolateral membrane of intestinal epithelial cells are necessary for the delivery of lipids to the systemic circulation. One of the proteins required for assembly and secretion of chylomicrons is the microsomal triglyceride transfer protein, which is mutated in individuals with abetalipoproteinemia. Children with this disorder suffer from fat malabsorption and, in particular, from the consequences of vitamin E deficiency (retinopathy and spinocerebellar degeneration). Biochemical tests show low plasma levels of apoprotein B, triglyceride, and cholesterol. Intestinal biopsy is diagnostic and characterized by engorgement of epithelial cells with lipid droplets. Calories are provided by treatment with a low-fat diet containing medium-chain triglycerides. Medium-chain fatty acids are easily absorbed and released directly into the portal circulation, thereby bypassing the defect of abetalipoproteinemia. Poor absorption of long-chain fatty acids can sometimes result in essential fatty acid deficiency. Celiac disease, also called celiac sprue, nontropical sprue, and gluten-sensitive enteropathy, is an inflammatory condition of the small intestine precipitated by the ingestion of wheat, rye, and barley in individuals with certain genetic predispositions. The prevalence of celiac disease in the United States, based on the number of individuals presenting with typical gastrointestinal symptoms, is estimated at 1:4500. However, recent screening studies for the antigliadin and antiendomysial antibodies that are associated with celiac disease suggest a much higher prevalence in Northern Ireland (1:122), as well as in Europe and the United States (about 1:250). High-risk groups for celiac disease include first-degree relatives and individuals with type I diabetes mellitus and autoimmune thyroid disease. Virtually 100% of individuals with dermatitis herpetiformis have gluten-sensitive enteropathy. Both environmental and genetic factors are important in the development of celiac disease. The alcohol-soluble protein fraction of wheat gluten, the gliadins, and similar prolamins in rye and barley trigger intestinal inflammation in susceptible individuals. Oat grains, which have prolamins rich in glutamine but not proline, appear to be less toxic. The specific peptide sequence or sequences responsible for triggering intestinal inflammation and the processes leading to villus flattening remain unknown. Approximately 15% of first-degree relatives of affected individuals are found to have celiac disease. The diagnosis of celiac disease is made by characteristic changes found on small intestinal biopsy and improving when a gluten-free diet is instituted. Mucosal flattening can be observed endoscopically as reduced duodenal folds or duodenal scalloping. Characteristic features found on intestinal biopsy include the absence of villi, crypt hyperplasia, increased intraepithelial lymphocytes, and infiltration of the lamina propria with plasma cells and lymphocytes. Serologic markers for celiac disease are useful in supporting the diagnosis, in screening first-degree relatives, and in following the response to a gluten-free diet. Antiendomysial IgA antibodies (antibodies against tissue transglutaminase) are highly sensitive (90%) and specific (90 to 100%) for active celiac disease in skilled laboratory testing. Antiendomysial and antigliadin IgA antibodies will be negative in the small percentage of individuals with selective IgA deficiency. Celiac disease usually manifests early in life at about 2 years of age, after wheat has been introduced into the diet, or later in the third or fourth decades of adult life. Individuals with significant mucosal involvement present with watery diarrhea, weight loss or growth retardation, and the clinical manifestations of vitamin and mineral deficiencies. All nutrients, most notably carbohydrate, fat, protein, electrolytes, fat-soluble vitamins, calcium, magnesium, iron, folate, and zinc, are malabsorbed. Cobalamin malabsorption is rare, as the disease most often affects the proximal small intestine more than the distal. Some individuals also have impaired pancreatic 720 Figure 134-3 Intestinal biopsy appearance of flattened villi and hyperplastic crypts. Diarrhea is due to a number of mechanisms, including a decreased surface area for water and electrolyte absorption, the osmotic effect of unabsorbed luminal nutrients, and the stimulation of intestinal fluid secretion by inflammatory mediators and unabsorbed fatty acids. A significant number of adults with celiac disease present with anemia or osteoporosis without gastrointestinal symptoms. These individuals likely have proximal disease that impairs iron, folate, and calcium absorption but an adequate surface area in the remaining intestine for absorption of other nutrients. Other extraintestinal manifestations of celiac disease include rash (dermatitis herpetiformis), neurologic disorders (myopathy, epilepsy), psychiatric disorders (depression, paranoia), and reproductive disorders (infertility, spontaneous abortion). Rice and corn grains are tolerated, and a moderate amount of oat grain (if not contaminated by wheat grain) may be tolerated as well. Early referral to a celiac support group is often helpful in maintaining dietary compliance. Owing to secondary lactase deficiency, a lactose-free diet should be recommended until symptoms improve. All individuals with celiac disease should be screened for vitamin and mineral deficiencies and have bone densitometry. Documented deficiencies of vitamins and minerals should be replenished (Table 134-6), and women of childbearing age should take folic acid supplements. Up to 90% of patients with celiac disease treated with a gluten-free diet experience symptomatic improvement within 2 weeks. The most common cause of a poor dietary response is continued ingestion of gluten.

Ethanol oxidation to acetaldehyde by alcohol dehydrogenase in the liver is the rate-limiting step and accounts for more than 90% of ethanol metabolism in vivo anxiety symptoms racing thoughts best cymbalta 40mg. Alcohol dehydrogenase has a high affinity for ethanol and accounts for essentially all ethanol oxidation at low to moderate doses anxiety jokes buy cymbalta 30 mg amex. When the blood alcohol concentration is high anxiety symptoms vibration cheap cymbalta 30mg overnight delivery, however anxiety xyrem cheap cymbalta 20mg overnight delivery, a microsomal ethanol-oxidizing system with a lower affinity for ethanol can also generate acetaldehyde (Fig. This oxidizing system can be induced by ethanol to accelerate drug metabolism in the liver (see Chapter 148). Barbiturates have a similar effect, which accounts for the metabolic cross-tolerance between these agents. Acetaldehyde is converted to acetate by aldehyde dehydrogenase, a metabolic event with important clinical ramifications. For example, in 50% of Japanese and other Asian people, a genetic variation in an aldehyde dehydrogenase isoenzyme results in reduced enzyme activity in vivo. Shortly after drinking alcohol, affected individuals have increased blood acetaldehyde levels and experience an alcohol-flush reaction characterized by vasodilatation with facial flushing, hot sensations, tachycardia, and hypotension. These unpleasant experiences appear to deter drinking; Japanese and Chinese people with this isoenzyme have a lower rate of alcoholism. Pharmacologic inhibition of aldehyde dehydrogenase can cause severe aversive symptoms after drinking alcohol and is the reason why disulfiram (Antabuse) has been used to discourage drinking. Disulfiram inhibits aldehyde dehydrogenase (and other sulfhydryl-containing enzymes), but it is not ordinarily toxic when taken therapeutically without ethanol. After drinking alcohol, however, patients on prophylactic disulfiram therapy have significant increases in blood acetaldehyde levels, and a more severe acetaldehyde syndrome develops. They can experience dysphoria, intense palpitations, sweating, thirst, throbbing headache, dyspnea, nausea and vomiting, weakness, vertigo, and syncope. Moreover, other drugs that likewise inhibit aldehyde dehydrogenase, such as metronidazole (Flagyl), may also make patients ill if they drink ethanol. Alcoholics often obtain 50% of their calories from ethanol, and serious nutritional deficiencies, particularly protein, thiamine, folate, and pyridoxine deficiency, develop in many (Table 16-1) (see Chapter 231). Moreover, as a consequence of ethanol metabolism, alcoholics are prone to hypoglycemia (Chapter 243), lactic acidosis (Chapter 102), hyperuricemia (Chapter 299), and hypertriglyceridemia (Chapter 206). Binge drinking, inadequate diet, and severe vomiting on a background of chronic alcohol consumption can lead to alcoholic ketoacidosis (see Chapter 102). The blood-brain barrier to ethanol is virtually non-existent, and shortly after drinking, the concentration Figure 16-1 Ethanol metabolism. In a non-alcoholic, intoxication occurs at blood alcohol levels of 50 to 150 mg/dL (Table 16-2), and legal intoxication ranges from 80 to 100 mg/dL in most states. Symptoms vary directly with the rate of drinking and are more severe when blood alcohol concentrations are rising than falling. Most individuals feel euphoric, lose social inhibitions, and manifest expansive, sometimes garrulous behavior; others may become gloomy, belligerent, or even explosively combative. Some people do not experience euphoria but become sleepy after moderate drinking; they rarely abuse alcohol. Neurologic signs of intoxication include impaired cognition, slurred speech, incoordination, mild truncal ataxia, and slow or irregular eye movements. Signs of increased sympathetic activity include mydriasis, tachycardia, and skin flushing. Cerebellar and vestibular function deteriorates at higher blood alcohol levels, and drunkenness is characterized by dysarthria, more severe ataxia, nystagmus, and diplopia. Patients may become lethargic with bradycardia, reduced blood pressure, and diminished respirations, sometimes complicated by vomiting and pulmonary aspiration. Other central nervous system depressants such as narcotics and sedative-hypnotics act synergistically with alcohol. Alcoholic blackouts sometimes complicate acute alcohol intoxication during the consumption of large amounts of ethanol. These episodes, which can occur in alcoholics or sporadic drinkers, are characterized by amnesia for several hours without impaired consciousness. The patient reports an inability to remember new events but has no difficulty with long-term memory or immediate recall. These symptoms resemble the syndrome of transient global amnesia (see Chapters 449 and 470). Ethanol can depress myocardial function at moderate doses, and binge drinking can cause arrhythmias, or the holiday heart syndrome (see Chapter 64). Relaxation of vascular smooth muscle causes vasodilation, which can lead to hypothermia, particularly in cold environments. A reduced response to ethanol, or tolerance, develops both acutely and chronically during drinking and is due to adaptive changes in the central nervous system, not ethanol metabolism. Acute tolerance occurs during a single episode of drinking and is characterized by greater intoxication at a given blood alcohol concentration when the level is rising than when falling (Mellanby effect). Chronic tolerance occurs in alcoholics and is characterized by greater resistance to the intoxicating effects of ethanol; they may appear to be sober at levels of 400 to 500 mg/dL, concentrations known to produce stupor, coma, or death in naive individuals. The highest blood alcohol level reported is 1510 mg/dL in an ambulatory chronic alcoholic who had stopped drinking 3 days earlier. Tolerance appears to be due to ethanol-induced changes in gene expression and intracellular signaling cascades involving neurotransmitter receptors, ion channels, and protein kinases. Up to half of male drinkers have alcohol-related problems such as blackouts, fighting, or a single alcohol-related arrest during their late teens or early twenties. Craving and uncontrolled drinking accompanied by tolerance and symptoms of withdrawal signal the development of alcoholism. Episodes of abstention and failed efforts to control drinking are common and highlight the relapsing and remitting course of the disease. Some alcoholics achieve long-term sobriety on their own; those who do not face increased mortality from trauma and medical complications. When drinking is abruptly reduced or discontinued, these adaptive neural mechanisms are left unrestrained by ethanol, and physical dependence is manifested by a hyperexcitable alcohol withdrawal syndrome. The alcohol withdrawal syndrome typically evolves in a recognizable temporal sequence (Fig. Tremor, the earliest, most common, and most apparent symptom, begins about 6 to 8 hours after the last drink, usually the morning after an overnight abstinence ("morning shakes"). Tremor is generalized, coarse, and rapid and often accompanied by irritability, nausea, and vomiting. The patient usually senses an inner tremulousness even when the tremor is not severe. Self-treatment is usually a morning drink to "quiet the nerves," followed by drinking for the rest of the day. If the alcoholic does not resume drinking, tremor intensifies by 24 to 36 hours and is exacerbated by motor activity or stress. The patient is increasingly anxious and easily startled by minor stimuli and complains of insomnia and anorexia. Increased sweating, facial flushing, mydriasis, tachycardia, and mild hypertension are noted. Most abnormalities subside in a few days, but increased arousal and anxiety may persist for 2 weeks. Disordered perceptions accompany tremor and sympathetic hyperactivity in approximately 25% of patients, become most pronounced at 24 to 36 hours, and clear in a few days. Often, vivid nightmares interfere with sleep; while awake, ordinary visual, auditory, and tactile experiences become distorted and misinterpreted. Isolated and prolonged auditory hallucinations may develop in alcoholics undergoing withdrawal (alcoholic hallucinosis) despite being alert, oriented, and without memory loss. Hallucinations may persist for weeks even though other signs of ethanol withdrawal have improved and the patient is less agitated and tremulous. In the absence of sympathetic hyperactivity, persistent auditory hallucinations may be confused with acute schizophrenia (see Chapter 450). However, alcoholic hallucinosis is closely associated with ethanol withdrawal and usually subsides in weeks to months. Generalized tonic-clonic seizures develop in about one third of alcoholics, most often within 12 to 24 hours after reducing or stopping drinking. Some propose that the first seizure in alcoholics may be a consequence of ethanol toxicity. However, ethanol dependence is followed by withdrawal seizures in animals, particularly in mice bred to have convulsions during withdrawal, thus suggesting a role for genetic vulnerability in humans. Ethanol withdrawal seizures usually follow chronic daily drinking but can also occur after 5 to 7 days of binge drinking.

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