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InternalMed_Harrison. Measurement of perineal descent is relatively easy to gauge clinically by placing the patient in the left decubitus position and watching 274 the perineum to detect inadequate descent (<1.5 cm, a sign of pelvic floor dysfunction) or perineal ballooning during straining relative to bony landmarks (>4 cm, suggesting excessive perineal descent). A useful overall test of evacuation is the balloon expulsion test. A balloon-tipped urinary catheter is placed and inflated with 50 mL of water. Normally, a patient can expel it while seated on a toilet or in the left lateral decubitus position. In the lateral position, the weight needed to facilitate expulsion of the balloon is determined; normally, expulsion occurs with <200 g added or unaided within 2 min. Anorectal manometry, when used in the evaluation of patients with severe constipation, may find an excessively high resting (>80 mmHg) or squeeze anal sphincter tone, suggesting anismus (anal sphincter spasm). This test also identifies rare


InternalMed_Harrison

InternalMed_Harrison. of patients with severe constipation, may find an excessively high resting (>80 mmHg) or squeeze anal sphincter tone, suggesting anismus (anal sphincter spasm). This test also identifies rare syndromes, such as adult Hirschsprung’s disease, by the absence of the rectoanal inhibitory reflex. Defecography (a dynamic barium enema including lateral views obtained during barium expulsion or a magnetic resonance defecogram) reveals “soft abnormalities” in many patients; the most relevant findings are the measured changes in rectoanal angle, anatomic defects of the rectum such as internal mucosal prolapse, and enteroceles or rectoceles. Surgically remediable conditions are identified in only a few patients. These include severe, whole-thickness intussusception with complete outlet obstruction due to funnel-shaped plugging at the anal canal or an extremely large rectocele that fills preferentially during attempts at defecation instead of expulsion of the barium through the anus. In summary,


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InternalMed_Harrison. to funnel-shaped plugging at the anal canal or an extremely large rectocele that fills preferentially during attempts at defecation instead of expulsion of the barium through the anus. In summary, defecography requires an interested and experienced radiologist, and abnormalities are not pathognomonic for pelvic floor dysfunction. The most common cause of outlet obstruction is failure of the puborectalis muscle to relax; this is not identified by barium defecography, but can be demonstrated by magnetic resonance defecography, which provides more information about the structure and function of the pelvic floor, distal colorectum, and anal sphincters. Neurologic testing (electromyography) is more helpful in the evaluation of patients with incontinence than of those with symptoms suggesting obstructed defecation. The absence of neurologic signs in the lower extremities suggests that any documented denervation of the puborectalis results from pelvic (e.g., obstetric) injury or from


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InternalMed_Harrison. obstructed defecation. The absence of neurologic signs in the lower extremities suggests that any documented denervation of the puborectalis results from pelvic (e.g., obstetric) injury or from stretching of the pudendal nerve by chronic, long-standing straining. Constipation is common among patients with spinal cord injuries, neurologic diseases such as Parkinson’s disease, multiple sclerosis, and diabetic neuropathy. Spinal-evoked responses during electrical rectal stimulation or stimulation of external anal sphincter contraction by applying magnetic stimulation over the lumbosacral cord identify patients with limited sacral neuropathies with sufficient residual nerve conduction to attempt biofeedback training. In summary, a balloon expulsion test is an important screening test for anorectal dysfunction. Rarely, an anatomic evaluation of the rectum or anal sphincters and an assessment of pelvic floor relaxation are the tools for evaluating patients in whom obstructed defecation is


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InternalMed_Harrison. dysfunction. Rarely, an anatomic evaluation of the rectum or anal sphincters and an assessment of pelvic floor relaxation are the tools for evaluating patients in whom obstructed defecation is suspected and is associated with symptoms of rectal mucosal prolapse, pressure of the posterior wall of the vagina to facilitate defecation (suggestive of anterior rectocele), or prior pelvic surgery that may be complicated by enterocele.


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InternalMed_Harrison. After the cause of constipation is characterized, a treatment decision can be made. Slow-transit constipation requires aggressive medical or surgical treatment; anismus or pelvic floor dysfunction usually responds to biofeedback management (Fig. 40-4). The remaining ∼60% of patients with constipation has normal colonic transit and can be treated symptomatically. Patients with spinal cord injuries or other neurologic disorders require a dedicated bowel regimen that often includes rectal stimulation, enema therapy, and carefully timed laxative therapy. Patients with constipation are treated with bulk, osmotic, pro- kinetic, secretory, and stimulant laxatives including fiber, psyllium, milk of magnesia, lactulose, polyethylene glycol (colonic lavage


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases solution), lubiprostone, linaclotide, and bisacodyl, or, in some countries, prucalopride, a 5-HT4 agonist. If a 3-to 6-month trial of medical therapy fails, unassociated with obstructed defecation, the patients should be considered for laparoscopic colectomy with ileorectostomy; however, this should not be undertaken if there is continued evidence of an evacuation disorder or a generalized GI dysmotility. Referral to a specialized center for further tests of colonic motor function is warranted. The decision to resort to surgery is facilitated in the presence of megacolon and megarectum. The complications after surgery include small-bowel obstruction (11%) and fecal soiling, particularly at night during the first postoperative year. Frequency of defecation is 3–8 per day during the first year, dropping to 1–3 per day from the second year after surgery.


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InternalMed_Harrison. Patients who have a combined (evacuation and transit/motility) disorder should pursue pelvic floor retraining (biofeedback and muscle relaxation), psychological counseling, and dietetic advice first. If symptoms are intractable despite biofeedback and optimized medical therapy, colectomy and ileorectostomy could be considered as long as the evacuation disorder is resolved and optimized medical therapy is unsuccessful. In patients with pelvic floor dysfunction alone, biofeedback training has a 70–80% success rate, measured by the acquisition of comfortable stool habits. Attempts to manage pelvic floor dysfunction with operations (internal anal sphincter or puborectalis muscle division) or injections with botulinum toxin have achieved only mediocre success and have been largely abandoned. Russell G. Robertson, J. Larry Jameson


InternalMed_Harrison

InternalMed_Harrison. Involuntary weight loss (IWL) is frequently insidious and can have important implications, often serving as a harbinger of serious underlying disease. Clinically important weight loss is defined as the loss of 10 pounds (4.5 kg) or >5% of one’s body weight over a period of 6–12 months. IWL is encountered in up to 8% of all adult outpatients and 27% of frail persons age 65 years and older. There is no identifiable cause in up to one-quarter of patients despite extensive investigation. Conversely, up to half of people who claim to have lost weight have no documented evidence of weight loss. People with no known cause of weight loss generally have a better prognosis than do those with known causes, particularly when the source is neoplastic. Weight loss in older persons is associated with a variety of deleterious effects, including hip fracture, pressure ulcers, impaired immune function, and decreased functional status. Not surprisingly, significant weight loss is associated with


InternalMed_Harrison

InternalMed_Harrison. with a variety of deleterious effects, including hip fracture, pressure ulcers, impaired immune function, and decreased functional status. Not surprisingly, significant weight loss is associated with increased mortality, which can range from 9% to as high as 38% within 1 to 2.5 years in the absence of clinical awareness and attention.


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InternalMed_Harrison. (See also Chaps. 94e and 415e) Among healthy aging people, total body weight peaks in the sixth decade of life and generally remains stable until the ninth decade, after which it gradually falls. In contrast, lean body mass (fat-free mass) begins to decline at a rate of 0.3 kg per year in the third decade, and the rate of decline increases further beginning at age 60 in men and age 65 in women. These changes in lean body mass largely reflect the age-dependent decline in growth hormone secretion and, consequently, circulating levels of insulin-like growth factor type I (IGF-I) that occur with normal aging. Loss of sex steroids, at menopause in women and more gradually with aging in men, also contributes to these changes in body composition. In the healthy elderly, an increase in fat tissue balances the loss in lean body mass until very old age, when loss of both fat and skeletal muscle occurs. Age-dependent changes also occur at the cellular level. Telomeres shorten, and body cell


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InternalMed_Harrison. balances the loss in lean body mass until very old age, when loss of both fat and skeletal muscle occurs. Age-dependent changes also occur at the cellular level. Telomeres shorten, and body cell mass—the fat-free portion of cells— declines steadily with aging.


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InternalMed_Harrison. Between ages 20 and 80, mean energy intake is reduced by up to 1200 kcal/d in men and 800 kcal/d in women. Decreased hunger is a reflection of reduced physical activity and loss of lean body mass, producing lower demand for calories and food intake. Several important age-associated physiologic changes also predispose elderly persons to weight loss, such as declining chemosensory function (smell and taste), reduced efficiency of chewing, slowed gastric emptying, and alterations in the neuroendocrine axis, including changes in levels of leptin, cholecystokinin, neuropeptide Y, and other hormones and peptides. These changes are associated with early satiety and a decline in both appetite and the hedonistic appreciation of food. Collectively, they contribute to the “anorexia of aging.”


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InternalMed_Harrison. Most causes of IWL belong to one of four categories: (1) malignant neoplasms, (2) chronic inflammatory or infectious diseases, (3) metabolic disorders (e.g., hyperthyroidism and diabetes), or (4) psychiatric disorders (Table 56-1). Not infrequently, more than one of these causes can be responsible for IWL. In most series, IWL is caused by malignant disease in a quarter of patients and by organic disease in one-third, with the remainder due to psychiatric disease, medications, or uncertain causes. The most common malignant causes of IWL are gastrointestinal, hepatobiliary, hematologic, lung, breast, genitourinary, ovarian, and prostate. Half of all patients with cancer lose some body weight; CAuSES of invoLunTARy wEigHT LoSS


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InternalMed_Harrison. CAuSES of invoLunTARy wEigHT LoSS Disorders of the mouth and teeth one-third lose more than 5% of their original body weight, and up to 20% 275 of all cancer deaths are caused directly by cachexia (through immobility and/or cardiac/respiratory failure). The greatest incidence of weight loss is seen among patients with solid tumors. Malignancy that reveals itself through significant weight loss usually has a very poor prognosis. In addition to malignancies, gastrointestinal causes are among the most prominent causes of IWL. Peptic ulcer disease, inflammatory bowel disease, dysmotility syndromes, chronic pancreatitis, celiac disease, constipation, and atrophic gastritis are some of the more common entities. Oral and dental problems are easily overlooked and may manifest with halitosis, poor oral hygiene, xerostomia, inability to chew, reduced masticatory force, nonocclusion, temporomandibular joint syndrome, edentulousness, and pain due to caries or abscesses.


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InternalMed_Harrison. Tuberculosis, fungal diseases, parasites, subacute bacterial endocarditis, and HIV are well-documented causes of IWL. Cardiovascular and pulmonary diseases cause unintentional weight loss through increased metabolic demand and decreased appetite and caloric intake. Uremia produces nausea, anorexia, and vomiting. Connective tissue diseases may increase metabolic demand and disrupt nutritional balance. As the incidence of diabetes mellitus increases with aging, the associated glucosuria can contribute to weight loss. Hyperthyroidism in the elderly may have less prominent sympathomimetic features and may present as “apathetic hyperthyroidism” or T3 toxicosis (Chap. 405).


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InternalMed_Harrison. Neurologic injuries such as stroke, quadriplegia, and multiple sclerosis may lead to visceral and autonomic dysfunction that can impair caloric intake. Dysphagia from these neurologic insults is a common mechanism. Functional disability that compromises activities of daily living (ADLs) is a common cause of undernutrition in the elderly. Visual impairment from ophthalmic or central nervous system disorders such as a tremor can limit the ability of people to prepare and eat meals. IWL may be one of the earliest manifestations of Alzheimer’s dementia.


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InternalMed_Harrison. Isolation and depression are significant causes of IWL that may manifest as an inability to care for oneself, including nutritional needs. A cytokine-mediated inflammatory metabolic cascade can be both a cause of and a manifestation of depression. Bereavement can be a cause of IWL and, when present, is more pronounced in men. More intense forms of mental illness such as paranoid disorders may lead to delusions about food and cause weight loss. Alcoholism can be a significant source of weight loss and malnutrition. Elderly persons living in poverty may have to choose whether to purchase food or use the money for other expenses, including medications. Institutionalization is an independent risk factor, as up to 30–50% of nursing home patients have inadequate food intake. Medications can cause anorexia, nausea, vomiting, gastrointestinal distress, diarrhea, dry mouth, and changes in taste. This is particularly an issue in the elderly, many of whom take five or more medications.


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InternalMed_Harrison. The four major manifestations of IWL are (1) anorexia (loss of appetite), (2) sarcopenia (loss of muscle mass), (3) cachexia (a syndrome that combines weight loss, loss of muscle and adipose tissue, anorexia, and weakness), and (4) dehydration. The current obesity epidemic adds complexity, as excess adipose tissue can mask the development of sarcopenia and delay awareness of the development of cachexia. If it is not possible to measure weight directly, a change in clothing size, corroboration of weight loss by a relative or friend, and a numeric estimate of weight loss provided by the patient are suggestive of true weight loss.


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InternalMed_Harrison. Initial assessment includes a comprehensive history and physical, a complete blood count, tests of liver enzyme levels, C-reactive protein, erythrocyte sedimentation rate, renal function studies, thyroid function tests, chest radiography, and an abdominal ultrasound (Table 56-2). Age, sex, and risk factor–specific cancer screening tests, such as mammography and colonoscopy, should be performed (Chap. 100). Patients at risk should have HIV testing. All elderly patients with weight loss should undergo screening for dementia and depression by using instruments such as the PART 2 Cardinal Manifestations and Presentation of Diseases 10% weight loss in 180 d Comprehensive electrolyte and metabolic panel, including liver and renal function tests


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases 10% weight loss in 180 d Comprehensive electrolyte and metabolic panel, including liver and renal function tests Body mass index <21 Thyroid function tests 25% of food left uneaten after 7 d Erythrocyte sedimentation rate Change in fit of clothing C-reactive protein Change in appetite, smell, or taste Ferritin Abdominal pain, nausea, vomiting, HIV testing, if indicated diarrhea, constipation, dysphagia aMay be more specific to assess weight loss in the elderly.


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InternalMed_Harrison. Mini-Mental State Examination and the Geriatric Depression Scale, respectively (Chap. 11). The Mini Nutritional Assessment (www .mna-elderly.com) and the Nutrition Screening Initiative (http:// www.ncbi.nlm.nih.gov/pmc/articles/PMC1694757/) are also available for the nutritional assessment of elderly patients. Almost all patients with a malignancy and >90% of those with other organic diseases have at least one laboratory abnormality. In patients presenting with substantial IWL, major organic and malignant diseases are unlikely when a baseline evaluation is completely normal. Careful follow-up rather than undirected testing is advised since the prognosis of weight loss of undetermined cause is generally favorable.


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InternalMed_Harrison. The first priority in managing weight loss is to identify and treat the underlying causes systematically. Treatment of underlying metabolic, psychiatric, infectious, or other systemic disorders may be sufficient to restore weight and functional status gradually. Medications that cause nausea or anorexia should be withdrawn or changed, if possible. For those with unexplained IWL, oral nutritional supplements such as high-energy drinks sometimes reverse weight loss. Advising patients to consume supplements between meals rather than with a meal may help minimize appetite suppression and facilitate increased overall intake. Orexigenic, anabolic, and anticytokine agents are under investigation. In selected patients, the antidepressant mirtazapine results in a significant increase in body weight, body fat mass, and leptin concentration. Patients with wasting conditions who can comply with an appropriate exercise program gain muscle protein mass, strength, and endurance and may be more


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InternalMed_Harrison. weight, body fat mass, and leptin concentration. Patients with wasting conditions who can comply with an appropriate exercise program gain muscle protein mass, strength, and endurance and may be more capable of performing ADLs.


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InternalMed_Harrison. Gastrointestinal bleeding (GIB) accounts for ~150 hospitalizations per 100,000 population annually in the United States, with upper GIB (UGIB) ~1.5–2 times more common than lower GIB (LGIB) The incidence of GIB has decreased in recent decades, primarily due to a reduction in UGIB, and the mortality has also decreased to <5%. Patients today rarely die from exsanguination, but rather die due to decompensation of other underlying illnesses.


InternalMed_Harrison

InternalMed_Harrison. GIB presents as either overt or occult bleeding. Overt GIB is manifested by hematemesis, vomitus of red blood or “coffee-grounds” material; melena, black, tarry, foul-smelling stool; and/or hematochezia, passage of bright red or maroon blood from the rectum. Occult GIB may be identified in the absence of overt bleeding when patients present with symptoms of blood loss or anemia such as lightheadedness, syncope, angina, or dyspnea; or when routine diagnostic evaluation reveals iron deficiency anemia or a positive fecal occult blood test. GIB is also categorized by the site of bleeding as UGIB, LGIB, or obscure GIB if the source is unclear.


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InternalMed_Harrison. SOuRCES OF gASTROINTESTINAL BLEEDINg upper gastrointestinal Sources of Bleeding (Table 57-1) Peptic ulcers are the most common cause of UGIB, accounting for ∼50% of cases. Mallory-Weiss tears account for ~5–10% of cases. The proportion of patients bleeding from varices varies widely from ~5–40%, depending on the population. Hemorrhagic or erosive gastropathy (e.g., due to nonsteroidal anti-inflammatory drugs [NSAIDs] or alcohol) and erosive esophagitis often cause mild UGIB, but major bleeding is rare.


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InternalMed_Harrison. PEPTIC ULCERS Characteristics of an ulcer at endoscopy provide important prognostic information. One-third of patients with active bleeding or a nonbleeding visible vessel have further bleeding that requires urgent surgery if they are treated conservatively. These patients benefit from endoscopic therapy with bipolar electrocoagulation, heater probe, injection therapy (e.g., absolute alcohol, 1:10,000 epinephrine), and/or clips with reductions in bleeding, hospital stay, mortality, and costs. In contrast, patients with clean-based ulcers have rates of recurrent bleeding approaching zero. If stable with no other reason for hospitalization, such patients may be discharged home after endoscopy. Patients without clean-based ulcers usually remain in the hospital for 3 days because most episodes of recurrent bleeding occur within 3 days.


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InternalMed_Harrison. Randomized controlled trials document that high-dose, constant-infusion IV proton pump inhibitor (PPI) (80-mg bolus and 8-mg/h infusion), designed to sustain intragastric pH >6 and enhance clot stability, decreases further bleeding and mortality in patients with high-risk ulcers (active bleeding, nonbleeding visible vessel, adherent clot) when given after endoscopic therapy. Patients with lower-risk findings (flat pigmented spot or clean base) do not require endoscopic Sources of Bleeding Proportion of Patients, % Source: Data on hospitalizations from year 2000 onward from Am J Gastroenterol 98:1494, 2003; Gastrointest Endosc 57:AB147, 2003; 60;875, 2004; Eur J Gastroenterol Hepatol 16:177, 2004; 17:641, 2005; J Clin Gastroenterol 42:128, 2008; World J Gastroenterol 14:5046, 2008; Dig Dis Sci 54:333, 2009; Gut 60:1327, 2011; Endoscopy 44:998, 2012; J Clin Gastroenterol 48:113, 2014.


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InternalMed_Harrison. therapy and receive standard doses of oral PPI. Approximately one-third of patients with bleeding ulcers will rebleed within the next 1–2 years if no preventive strategies are employed. Prevention of recurrent bleeding focuses on the three main factors in ulcer pathogenesis, Helicobacter pylori, NSAIDs, and acid. Eradication of H. pylori in patients with bleeding ulcers decreases rates of rebleeding to <5%. If a bleeding ulcer develops in a patient taking NSAIDs, the NSAIDs should be discontinued. If NSAIDs must be given, a cyclooxygenase 2 (COX-2) selective inhibitor (coxib) plus a PPI should be used. PPI co-therapy alone or a coxib alone is associated with an annual rebleeding rate of ~10% in patients with a recent bleeding ulcer, whereas the combination of a coxib and PPI provides a further significant decrease in recurrent ulcer bleeding. Patients with established cardiovascular disease who develop bleeding ulcers while taking low-dose aspirin should restart aspirin as soon as


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InternalMed_Harrison. further significant decrease in recurrent ulcer bleeding. Patients with established cardiovascular disease who develop bleeding ulcers while taking low-dose aspirin should restart aspirin as soon as possible after their bleeding episode (1–7 days). A randomized trial showed that failure to restart aspirin was associated with no significant difference in rebleeding (5% vs. 10% at 30 days) but a significant increase in mortality at 30 days (9% vs. 1%) and 8 weeks (13% vs. 1%) compared with immediate reinstitution of aspirin. Patients with bleeding ulcers unrelated to H. pylori or NSAIDs should remain on PPI therapy indefinitely. Peptic ulcers are discussed in Chap. 348.


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InternalMed_Harrison. MALLORY-wEISS TEARS The classic history is vomiting, retching, or coughing preceding hematemesis, especially in an alcoholic patient. Bleeding from these tears, which are usually on the gastric side of the gastroesophageal junction, stops spontaneously in 80–90% of patients and recurs in only 0–10%. Endoscopic therapy is indicated for actively bleeding Mallory-Weiss tears. Angiographic therapy with embolization and operative therapy with oversewing of the tear are rarely required. Mallory-Weiss tears are discussed in Chap. 347.


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InternalMed_Harrison. ESOPHAgEAL VARICES Patients with variceal hemorrhage have poorer outcomes than patients with other sources of UGIB. Urgent endoscopy within 12 h is recommended in cirrhotics with UGIB, and if esophageal varices are present, endoscopic ligation is performed and an IV vasoactive medication (e.g., octreotide 50 μg bolus and 50 μg/h infusion) is given for 2–5 days. Combination endoscopic and medical therapy appears to be superior to either therapy alone in decreasing rebleeding. In patients with advanced liver disease (e.g., Child-Pugh class C with score 10–13), a transjugular intrahepatic portosystemic shunt (TIPS) should be strongly considered within the first 1–2 days of hospitalization because randomized trials show significant decreases in rebleeding and mortality compared with standard endoscopic and medical therapy. Over the long term, treatment with nonselective beta blockers plus endoscopic ligation is recommended because the combination of endoscopic and medical therapy is more


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InternalMed_Harrison. endoscopic and medical therapy. Over the long term, treatment with nonselective beta blockers plus endoscopic ligation is recommended because the combination of endoscopic and medical therapy is more effective than either alone in reduction of recurrent esophageal variceal bleeding.


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InternalMed_Harrison. In patients who have persistent or recurrent bleeding despite endoscopic and medical therapy, TIPS is recommended. Decompressive surgery (e.g., distal splenorenal shunt) may be considered instead of TIPS in patients with well-compensated cirrhosis. Portal hypertension is also responsible for bleeding from gastric varices, varices in the small and large intestine, and portal hypertensive gastropathy and enterocolopathy. Bleeding gastric varices due to cirrhosis are treated with endoscopic injection of tissue adhesive (e.g., n-butyl cyanoacrylate), if available; if not, TIPS is performed.


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InternalMed_Harrison. HEMORRHAgIC ANd EROSIVE gASTROPATHY (“gASTRITIS”) Hemorrhagic and erosive gastropathy, often labeled gastritis, refers to endoscopically visualized subepithelial hemorrhages and erosions. These are mucosal lesions and do not cause major bleeding due to the absence of arteries and veins in the mucosa. Erosions develop in various clinical settings, the most important of which are NSAID use, alcohol intake, and stress. Half of patients who chronically ingest NSAIDs have erosions, whereas up to 20% of actively drinking alcoholic patients with symptoms of UGIB have evidence of subepithelial hemorrhages or erosions.


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InternalMed_Harrison. Stress-related gastric mucosal injury occurs only in extremely sick patients, such as those who have experienced serious trauma, major surgery, burns covering more than one-third of the body surface area, 277 major intracranial disease, or severe medical illness (i.e., ventilator dependence, coagulopathy). Severe bleeding should not develop unless ulceration occurs. The mortality rate in these patients is quite high because of their serious underlying illnesses. The incidence of bleeding from stress-related gastric mucosal injury has decreased dramatically in recent years, most likely due to better care of critically ill patients. Pharmacologic prophylaxis for bleeding may be considered in the high-risk patients mentioned above. Meta-analyses of randomized trials indicate that PPIs are more effective than H2 receptor antagonists in reduction of overt and clinically important UGIB without differences in mortality or nosocomial pneumonia.


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InternalMed_Harrison. OTHER CAUSES Other less frequent causes of UGIB include erosive duodenitis, neoplasms, aortoenteric fistulas, vascular lesions (including hereditary hemorrhagic telangiectasias [Osler-Weber-Rendu] and gastric antral vascular ectasia [“watermelon stomach”]), Dieulafoy’s lesion (in which an aberrant vessel in the mucosa bleeds from a pinpoint mucosal defect), prolapse gastropathy (prolapse of proximal stomach into esophagus with retching, especially in alcoholics), and hemobilia or hemosuccus pancreaticus (bleeding from the bile duct or pancreatic duct).


InternalMed_Harrison

InternalMed_Harrison. Small-Intestinal Sources of Bleeding Small-intestinal sources of bleeding (bleeding from sites beyond the reach of the standard upper endoscope) are often difficult to diagnose and are responsible for the majority of cases of obscure GIB. Fortunately, small-intestinal bleeding is uncommon. The most common causes in adults are vascular ectasias, tumors (e.g., GI stromal tumor, carcinoid, adenocarcinoma, lymphoma, metastases), and NSAID-induced erosions and ulcers. Other less common causes in adults include Crohn’s disease, infection, ischemia, vasculitis, small-bowel varices, diverticula, Meckel’s diverticulum, duplication cysts, and intussusception. Meckel’s diverticulum is the most common cause of significant LGIB in children, decreasing in frequency as a cause of bleeding with age. In adults <40–50 years, small-bowel tumors often account for obscure GIB; in patients >50–60 years, vascular ectasias and NSAID-induced lesions are more commonly responsible.


InternalMed_Harrison

InternalMed_Harrison. Vascular ectasias should be treated with endoscopic therapy if possible. Although estrogen/progesterone compounds have been used for vascular ectasias, a large double-blind trial found no benefit in prevention of recurrent bleeding. Octreotide is also used, based on case series but no randomized trials. A randomized trial reported significant benefit of thalidomide and awaits further confirmation. Other isolated lesions, such as tumors, are generally treated with surgical resection.


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InternalMed_Harrison. Colonic Sources of Bleeding Hemorrhoids are probably the most common cause of LGIB; anal fissures also cause minor bleeding and pain. If these local anal processes, which rarely require hospitalization, are excluded, the most common causes of LGIB in adults are diverticula, vascular ectasias (especially in the proximal colon of patients >70 years), neoplasms (primarily adenocarcinoma), colitis (ischemic, infectious, idiopathic inflammatory bowel disease), and postpolypectomy bleeding. Less common causes include NSAID-induced ulcers or colitis, radiation proctopathy, solitary rectal ulcer syndrome, trauma, varices (most commonly rectal), lymphoid nodular hyperplasia, vasculitis, and aortocolic fistulas. In children and adolescents, the most common colonic causes of significant GIB are inflammatory bowel disease and juvenile polyps.


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InternalMed_Harrison. Diverticular bleeding is abrupt in onset, usually painless, sometimes massive, and often from the right colon; chronic or occult bleeding is not characteristic. Clinical reports suggest that bleeding colonic diverticula stop bleeding spontaneously in ~80% of patients and, on long-term follow-up, rebleed in ~15–25% of patients. Case series suggest endoscopic therapy may decrease recurrent bleeding in the uncommon case when colonoscopy identifies the specific bleeding diverticulum. When diverticular bleeding is found at angiography, transcatheter arterial embolization by superselective technique stops bleeding in a majority of patients. If bleeding persists or recurs, segmental surgical resection is indicated.


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InternalMed_Harrison. Bleeding from right colonic vascular ectasias in the elderly may be overt or occult; it tends to be chronic and only occasionally is hemodynamically significant. Endoscopic hemostatic therapy may be useful in the treatment of vascular ectasias, as well as discrete bleeding ulcers and postpolypectomy bleeding. Surgical therapy is generally required for major, persistent, or recurrent bleeding from the wide variety of colonic sources of GIB that cannot be treated medically, angiographically, or endoscopically. APPROACH TO THE PATIENT:


InternalMed_Harrison

InternalMed_Harrison. Measurement of the heart rate and blood pressure is the best way to initially assess a patient with GIB. Clinically significant bleeding leads to postural changes in heart rate or blood pressure, tachycardia, and, finally, recumbent hypotension. In contrast, the hemoglobin does not fall immediately with acute GIB, due to proportionate reductions in plasma and red cell volumes (i.e., “people bleed whole blood”). Thus, hemoglobin may be normal or only minimally decreased at the initial presentation of a severe bleeding episode. As extravascular fluid enters the vascular space to restore volume, the hemoglobin falls, but this process may take up to 72 h. Transfusion is recommended when the hemoglobin drops below 7 g/dL, based on a large randomized trial showing this restrictive transfusion strategy decreases rebleeding and death in acute UGIB compared with a transfusion threshold of 9 g/dL. Patients with slow, chronic GIB may have very low hemoglobin values despite normal blood pressure


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InternalMed_Harrison. decreases rebleeding and death in acute UGIB compared with a transfusion threshold of 9 g/dL. Patients with slow, chronic GIB may have very low hemoglobin values despite normal blood pressure and heart rate. With the development of iron-deficiency anemia, the mean corpuscular volume will be low and red blood cell distribution width will increase.


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InternalMed_Harrison. Hematemesis indicates an upper GI source of bleeding (above the ligament of Treitz). Melena indicates blood has been present in the GI tract for at least 14 h, and as long as 3–5 days. The more proximal the bleeding site, the more likely melena will occur. Hematochezia usually represents a lower GI source of bleeding, although an upper GI lesion may bleed so briskly that blood transits the bowel before melena develops. When hematochezia is the presenting symptom of UGIB, it is associated with hemodynamic instability and dropping hemoglobin. Bleeding lesions of the small bowel may present as melena or hematochezia. Other clues to UGIB include hyperactive bowel sounds and an elevated blood urea nitrogen (due to volume depletion and blood proteins absorbed in the small intestine). PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases A nonbloody nasogastric aspirate may be seen in up to ~18% of patients with UGIB, usually from a duodenal source. Even a bile-stained appearance does not exclude a bleeding postpyloric lesion because reports of bile in the aspirate are incorrect in ~50% of cases. Testing of aspirates that are not grossly bloody for occult blood is not useful. EVALuATION AND MANAgEMENT OF ugIB (FIg. 57-1)


InternalMed_Harrison

InternalMed_Harrison. At presentation, patients are generally stratified as higher or lower risk for further bleeding and death. Baseline characteristics predictive of rebleeding and death include hemodynamic compromise (tachycardia or hypotension), increasing age, and comorbidities. PPI infusion may be considered at presentation: it decreases high-risk ulcer stigmata (e.g., active bleeding) and need for endoscopic therapy but does not improve clinical outcomes such as further bleeding, surgery, or death. Treatment to improve endoscopic visualization with the promotility agent erythromycin, 250 mg intravenously ~30 min before endoscopy, also may be considered: it provides a small but significant increase in diagnostic yield and decrease in second endoscopies but is not documented to decrease further bleeding or death. Cirrhotic patients presenting with UGIB should be placed on antibiotics (e.g., quinolone, ceftriaxone) and started on a vasoactive medication (octreotide, terlipressin, somatostatin,


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InternalMed_Harrison. or death. Cirrhotic patients presenting with UGIB should be placed on antibiotics (e.g., quinolone, ceftriaxone) and started on a vasoactive medication (octreotide, terlipressin, somatostatin, vapreotide) upon presentation, even before endoscopy. Antibiotics decrease bacterial infections, rebleeding, and mortality in this population, and vasoactive medications appear to improve control of bleeding in the first 12 h after presentation.


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InternalMed_Harrison. Upper endoscopy should be performed within 24 h in most patients with UGIB. Patients at higher risk (e.g., hemodynamic instability, cirrhosis) may benefit from more urgent endoscopy within 12 h. Early endoscopy is also beneficial in low-risk patients for management decisions. Patients with major bleeding and high-risk endoscopic findings (e.g., varices, ulcers with active bleeding or a visible vessel) benefit from endoscopic hemostatic therapy, whereas patients with low-risk lesions (e.g., clean-based ulcers, nonbleeding Mallory-Weiss tears, erosive or hemorrhagic gastropathy) who have stable vital signs and hemoglobin and no other medical problems can be discharged home. EVALuATION AND MANAgEMENT OF LgIB (FIg. 57-2) Patients with hematochezia and hemodynamic instability should have upper endoscopy to rule out an upper GI source before evaluation of the lower GI tract.


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InternalMed_Harrison. Colonoscopy after an oral lavage solution is the procedure of choice in most patients admitted with LGIB unless bleeding is too massive, in which case angiography is recommended. Sigmoidoscopy is used primarily in patients <40 years old with minor bleeding. In patients with no source identified on colonoscopy, imaging studies may be employed. 99mTc-labeled red cell scan allows repeated imaging for up to 24 h and may identify the general location of bleeding. However, radionuclide scans should be interpreted with caution because results, especially from later images, are highly variable. Multidector computed tomography (CT) “angiography” is an increasingly used technique that is likely superior to nuclear scintigraphy. In active LGIB, angiography can detect the site of bleeding (extravasation of contrast into the gut) and permits treatment with embolization. Even after bleeding has stopped, angiography may identify lesions with abnormal vasculature, such as vascular ectasias or tumors.


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InternalMed_Harrison. Acute upper GI bleeding ICU for 1–2 days; ward for 2–3 days Ligation + IV vasoactive drug (e.g., octreotide) Esophageal varicesUlcer Mallory-Weiss tear Clean base Discharge No IV PPI or endoscopic therapy Active bleeding or visible vessel ICU for 1 day; ward for 2 days IV PPI therapy + endoscopic therapy Adherent clot Ward for 2–3 days IV PPI therapy +/– endoscopic therapy Flat, pigmented spot No IV PPI or endoscopic therapy Ward for 3 days Active bleeding No active bleeding No endoscopic therapy Discharge Endoscopic therapy Ward for 1–2 days FIguRE 57-1 Suggested algorithm for patients with acute upper gastrointestinal (GI) bleeding. Recommendations on level of care and time of discharge assume patient is stabilized without further bleeding or other concomitant medical problems. ICU, intensive care unit; PPI, proton pump inhibitor.


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InternalMed_Harrison. Hemodynamic instability Site identified; bleeding stops Angiography Obscure bleeding work-up Flexible sigmoidoscopy (colonoscopy if iron-deficiency anemia, familial colon cancer, or copious bleeding)* Bleeding persists Surgery Acute lower GI bleeding No hemodynamic instability Age ˜40 yrs Upper endoscopy^Age <40 yrs Colonoscopy Colonoscopy† Site identified; bleeding persists Site not identified; bleeding persists FIguRE 57-2 Suggested algorithm for patients with acute lower gastrointestinal (GI) bleeding. *Some suggest colonoscopy for any degree of rectal bleeding in patients <40 years as well. ^If upper GI endoscopy reveals definite source, no further evaluation is needed. †If massive bleeding does not allow time for colonic lavage, proceed to angiography.


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InternalMed_Harrison. Obscure GIB is defined as persistent or recurrent bleeding for which no source has been identified by routine endoscopic and contrast x-ray studies; it may be overt (melena, hematochezia) or occult (iron-deficiency anemia). Current guidelines suggest angiography as the initial test for massive obscure bleeding, and video capsule endoscopy, which allows examination of the entire small intestine, for all others. Push enteroscopy, usually performed with a pediatric colonoscope, to inspect the entire duodenum and proximal jejunum also may be considered as an initial evaluation. A systematic review of 14 trials comparing push enteroscopy to capsule revealed “clinically significant findings” in 26% and 56% of patients, respectively. However, in contrast to enteroscopy, lack of control of the capsule prevents its manipulation and full visualization of the intestine; in addition, tissue cannot be sampled and therapy cannot be applied.


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InternalMed_Harrison. If capsule endoscopy is positive, management is dictated by the finding. If capsule endoscopy is negative, current recommendations suggest patients may either be observed or, if their clinical course mandates (e.g., recurrent bleeding, need for transfusions or hospitalization), undergo further testing. “Deep” enteroscopy (e.g., double-balloon, single-balloon, and spiral enteroscopy) is commonly the next test undertaken in patients with clinically important obscure GIB because it allows the endoscopist to examine, obtain specimens from, and provide therapy to much or all of the small intestine. CT and magnetic resonance enterography also are used to examine the small intestine. Other imaging techniques sometimes used in evaluation of obscure GIB include 99mTc-labeled red blood cell scintigraphy, multidetector CT “angiography,” angiography, and 99mTc-pertechnetate scintigraphy for Meckel’s diverticulum (especially in young patients). If all tests are unrevealing, intraoperative


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InternalMed_Harrison. scintigraphy, multidetector CT “angiography,” angiography, and 99mTc-pertechnetate scintigraphy for Meckel’s diverticulum (especially in young patients). If all tests are unrevealing, intraoperative endoscopy is indicated in patients with severe recurrent or persistent bleeding requiring repeated transfusions.


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InternalMed_Harrison. Fecal occult blood testing is recommended only for colorectal cancer screening and may be used beginning at age 50 in average-risk adults and beginning at age 40 in adults with a first-degree relative with colorectal neoplasm at ≥60 years or two second-degree relatives with colorectal cancer. A positive test necessitates colonoscopy. If evaluation of the colon is negative, further workup is not recommended unless iron-deficiency anemia or GI symptoms are present. Savio John, Daniel S. Pratt


InternalMed_Harrison

InternalMed_Harrison. Jaundice, or icterus, is a yellowish discoloration of tissue resulting from the deposition of bilirubin. Tissue deposition of bilirubin occurs only in the presence of serum hyperbilirubinemia and is a sign of either liver disease or, less often, a hemolytic disorder. The degree of serum bilirubin elevation can be estimated by physical examination. Slight increases in serum bilirubin level are best detected by examining the sclerae, which have a particular affinity for bilirubin due to their high elastin content. The presence of scleral icterus indicates a serum bilirubin level of at least 51 μmol/L (3 mg/dL). The ability to detect scleral icterus is made more difficult if the examining room has fluorescent lighting. If the examiner suspects scleral icterus, a second site to examine is underneath the tongue. As serum bilirubin levels rise, the skin will eventually become yellow in light-skinned patients and even green if the process is long-standing; the green color is produced by


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InternalMed_Harrison. underneath the tongue. As serum bilirubin levels rise, the skin will eventually become yellow in light-skinned patients and even green if the process is long-standing; the green color is produced by oxidation of bilirubin to biliverdin.


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InternalMed_Harrison. The differential diagnosis for yellowing of the skin is limited. In addition to jaundice, it includes carotenoderma, the use of the drug quinacrine, and excessive exposure to phenols. Carotenoderma is the yellow color imparted to the skin of healthy individuals who ingest excessive amounts of vegetables and fruits that contain carotene, such as carrots, leafy vegetables, squash, peaches, and oranges. In jaundice the yellow coloration of the skin is uniformly distributed over the body, whereas in carotenoderma the pigment is concentrated on the palms, soles, forehead, and nasolabial folds. Carotenoderma can be distinguished from jaundice by the sparing of the sclerae. Quinacrine causes a yellow discoloration of the skin in 4–37% of patients treated with it.


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InternalMed_Harrison. Another sensitive indicator of increased serum bilirubin is darkening of the urine, which is due to the renal excretion of conjugated bilirubin. Patients often describe their urine as teaor cola-colored. Bilirubinuria indicates an elevation of the direct serum bilirubin fraction and, therefore, the presence of liver disease. Serum bilirubin levels increase when an imbalance exists between bilirubin production and clearance. A logical evaluation of the patient who is jaundiced requires an understanding of bilirubin production and metabolism. (See also Chap. 359) Bilirubin, a tetrapyrrole pigment, is a breakdown product of heme (ferroprotoporphyrin IX). About 70–80% of the 250– 300 mg of bilirubin produced each day is derived from the breakdown of hemoglobin in senescent red blood cells. The remainder comes from prematurely destroyed erythroid cells in bone marrow and from the turnover of hemoproteins such as myoglobin and cytochromes found in tissues throughout the body.


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InternalMed_Harrison. The formation of bilirubin occurs in reticuloendothelial cells, primarily in the spleen and liver. The first reaction, catalyzed by the microsomal enzyme heme oxygenase, oxidatively cleaves the α bridge of the porphyrin group and opens the heme ring. The end products of this reaction are biliverdin, carbon monoxide, and iron. The second reaction, catalyzed by the cytosolic enzyme biliverdin reductase, reduces the central methylene bridge of biliverdin and converts it to bilirubin. Bilirubin formed in the reticuloendothelial cells is virtually insoluble in water due to tight internal hydrogen bonding between the water-soluble moieties of bilirubin—i.e., the bonding of the proprionic acid carboxyl groups of one dipyrrolic half of the molecule with the imino and lactam groups of the opposite half. This configuration blocks solvent access to the polar residues of bilirubin and places the hydrophobic residues on the outside. To be transported in blood, bilirubin must be solubilized.


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InternalMed_Harrison. half. This configuration blocks solvent access to the polar residues of bilirubin and places the hydrophobic residues on the outside. To be transported in blood, bilirubin must be solubilized. Solubilization is accomplished by the reversible, noncovalent binding of bilirubin to albumin. Unconjugated bilirubin bound to albumin is transported to the liver. There, the bilirubin—but not the albumin—is taken up by hepatocytes via a process that at least partly involves carrier-mediated membrane transport. No specific bilirubin transporter has yet been identified (Chap. 359, Fig. 359-1).


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InternalMed_Harrison. After entering the hepatocyte, unconjugated bilirubin is bound in the cytosol to a number of proteins including proteins in the glutathione-S-transferase superfamily. These proteins serve both to reduce efflux of bilirubin back into the serum and to present the bilirubin for conjugation. In the endoplasmic reticulum, bilirubin is solubilized by conjugation to glucuronic acid, a process that disrupts the internal hydrogen bonds and yields bilirubin monoglucuronide and diglucuronide. The conjugation of glucuronic acid to bilirubin is catalyzed by bilirubin uridine diphosphate-glucuronosyl transferase (UDPGT). The now-hydrophilic bilirubin conjugates diffuse from the endoplasmic reticulum to the canalicular membrane, where bilirubin monoglucuronide and diglucuronide are actively transported into canalicular bile by an energy-dependent mechanism involving the multidrug resistance–associated protein 2 (MRP2).


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InternalMed_Harrison. The conjugated bilirubin excreted into bile drains into the duodenum and passes unchanged through the proximal small bowel. Conjugated bilirubin is not taken up by the intestinal mucosa. When the conjugated bilirubin reaches the distal ileum and colon, it is hydrolyzed to unconjugated bilirubin by bacterial β-glucuronidases. The unconjugated bilirubin is reduced by normal gut bacteria to form a group of colorless tetrapyrroles called urobilinogens. About 80–90% of these products are excreted in feces, either unchanged or oxidized to orange derivatives called urobilins. The remaining 10–20% of the urobilinogens are passively absorbed, enter the portal venous blood, and are re-excreted by the liver. A small fraction (usually <3 mg/dL) escapes hepatic uptake, filters across the renal glomerulus, and is excreted in urine.


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InternalMed_Harrison. The terms direct and indirect bilirubin—i.e., conjugated and unconjugated bilirubin, respectively—are based on the original van den Bergh reaction. This assay, or a variation of it, is still used in most clinical chemistry laboratories to determine the serum bilirubin level. In this assay, bilirubin is exposed to diazotized sulfanilic acid and splits into two relatively stable dipyrrylmethene azopigments that absorb PART 2 Cardinal Manifestations and Presentation of Diseases maximally at 540 nm, allowing photometric analysis. The direct fraction is that which reacts with diazotized sulfanilic acid in the absence of an accelerator substance such as alcohol. The direct fraction provides an approximation of the conjugated bilirubin level in serum. The total serum bilirubin is the amount that reacts after the addition of alcohol. The indirect fraction is the difference between the total and the direct bilirubin levels and provides an estimate of the unconjugated bilirubin in serum.


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InternalMed_Harrison. With the van den Bergh method, the normal serum bilirubin concentration usually is 17 μmol/L (<1 mg/dL). Up to 30%, or 5.1 μmol/L (0.3 mg/dL), of the total may be direct-reacting (conjugated) bilirubin. Total serum bilirubin concentrations are between 3.4 and 15.4 μmol/L (0.2 and 0.9 mg/dL) in 95% of a normal population.


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InternalMed_Harrison. Several new techniques, although less convenient to perform, have added considerably to our understanding of bilirubin metabolism. First, studies using these methods demonstrate that, in normal persons or those with Gilbert’s syndrome, almost 100% of the serum bilirubin is unconjugated; <3% is monoconjugated bilirubin. Second, in jaundiced patients with hepatobiliary disease, the total serum bilirubin concentration measured by these new, more accurate methods is lower than the values found with diazo methods. This finding suggests that there are diazo-positive compounds distinct from bilirubin in the serum of patients with hepatobiliary disease. Third, these studies indicate that, in jaundiced patients with hepatobiliary disease, monoglucuronides of bilirubin predominate over diglucuronides. Fourth, part of the direct-reacting bilirubin fraction includes conjugated bilirubin that is covalently linked to albumin. This albumin-linked bilirubin fraction (delta fraction, or biliprotein)


InternalMed_Harrison

InternalMed_Harrison. Fourth, part of the direct-reacting bilirubin fraction includes conjugated bilirubin that is covalently linked to albumin. This albumin-linked bilirubin fraction (delta fraction, or biliprotein) represents an important fraction of total serum bilirubin in patients with cholestasis and hepatobiliary disorders. The delta fraction (delta bilirubin) is formed in serum when hepatic excretion of bilirubin glucuronides is impaired and the glucuronides accumulate in serum. By virtue of its tight binding to albumin, the clearance rate of delta bilirubin from serum approximates the half-life of albumin (12–14 days) rather than the short half-life of bilirubin (about 4 h).


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InternalMed_Harrison. The prolonged half-life of albumin-bound conjugated bilirubin accounts for two previously unexplained enigmas in jaundiced patients with liver disease: (1) that some patients with conjugated hyperbilirubinemia do not exhibit bilirubinuria during the recovery phase of their disease because the bilirubin is covalently bound to albumin and therefore not filtered by the renal glomeruli, and (2) that the elevated serum bilirubin level declines more slowly than expected in some patients who otherwise appear to be recovering satisfactorily. Late in the recovery phase of hepatobiliary disorders, all the conjugated bilirubin may be in the albumin-linked form.


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InternalMed_Harrison. Unconjugated bilirubin is always bound to albumin in the serum, is not filtered by the kidney, and is not found in the urine. Conjugated bilirubin is filtered at the glomerulus, and the majority is reabsorbed by the proximal tubules; a small fraction is excreted in the urine. Any bilirubin found in the urine is conjugated bilirubin. The presence of bilirubinuria implies the presence of liver disease. A urine dipstick test (Ictotest) gives the same information as fractionation of the serum bilirubin and is very accurate. A false-negative result is possible in patients with prolonged cholestasis due to the predominance of delta bilirubin, which is covalently bound to albumin and therefore not filtered by the renal glomeruli. APPROACH TO THE PATIENT:


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InternalMed_Harrison. APPROACH TO THE PATIENT: The goal of this chapter is not to provide an encyclopedic review of all of the conditions that can cause jaundice. Rather, the chapter is intended to offer a framework that helps a physician to evaluate the patient with jaundice in a logical way (Fig. 58-1). History (focus on medication/drug exposure) Physical examination Lab tests: Bilirubin with fractionation, ALT, AST, alkaline phosphatase, prothrombin time, and albumin


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InternalMed_Harrison. Isolated elevation of the bilirubin Indirect hyperbilirubinemia (direct < 15%) See Table 58-1 Direct hyperbilirubinemia (direct > 15%) See Table 58-1 Drugs Rifampicin Probenecid Inherited disorders Dubin-Johnson syndrome Rotor syndrome 1. Viral serologies Hepatitis A IgM Hepatitis B surface antigen and core antibody (IgM) Hepatitis C RNA 2. Toxicology screen Acetaminophen level 3. Ceruloplasmin (if patient < 40 years of age) 4. ANA, SMA, SPEP Inherited disorders Gilbert's syndrome Crigler-Najjar syndromes Hemolytic disorders Ineffective erythropoiesis Bilirubin and other liver tests elevated Hepatocellular pattern: ALT/AST elevated out of proportion to alkaline phosphatase See Table 58-2 Cholestatic pattern: Alkaline phosphatase out of proportion ALT/AST See Table 58-3 Dilated ducts Extrahepatic cholestasis CT/MRCP/ERCP Liver biopsy Liver biopsy MRCP/Liver biopsy Results negativeResults negative Additional virologic testing CMV DNA, EBV capsid antigen Hepatitis D antibody (if


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InternalMed_Harrison. Extrahepatic cholestasis CT/MRCP/ERCP Liver biopsy Liver biopsy MRCP/Liver biopsy Results negativeResults negative Additional virologic testing CMV DNA, EBV capsid antigen Hepatitis D antibody (if indicated) Hepatitis E IgM (if indicated) Results negative AMA positive Serologic testing AMA Hepatitis serologies Hepatitis A, CMV, EBV Review drugs (see Table 58-3) Ultrasound Ducts not dilated Intrahepatic cholestasis


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InternalMed_Harrison. FIguRE 58-1 Evaluation of the patient with jaundice. ALT, alanine aminotransferase; AMA, antimitochondrial antibody; ANA, antinuclear antibody; AST, aspartate aminotransferase; CMV, cytomegalovirus; EBV, Epstein-Barr virus; LKM, liver-kidney microsomal antibody; MRCP, magnetic resonance cholangiopancreatography; SMA, smooth-muscle antibody; SPEP, serum protein electrophoresis. Simply stated, the initial step is to perform appropriate blood tests in order to determine whether the patient has an isolated elevation of serum bilirubin. If so, is the bilirubin elevation due to an increased unconjugated or conjugated fraction? If the hyperbilirubinemia is accompanied by other liver test abnormalities, is the disorder hepatocellular or cholestatic? If cholestatic, is it intraor extrahepatic? All of these questions can be answered with a thoughtful history, physical examination, and interpretation of laboratory and radiologic tests and procedures.


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InternalMed_Harrison. The bilirubin present in serum represents a balance between input from the production of bilirubin and hepatic/biliary removal of the pigment. Hyperbilirubinemia may result from (1) overproduction of bilirubin; (2) impaired uptake, conjugation, or excretion of bilirubin; or (3) regurgitation of unconjugated or conjugated bilirubin from damaged hepatocytes or bile ducts. An increase in unconjugated bilirubin in serum results from overproduction, impaired uptake, or conjugation of bilirubin. An increase in conjugated bilirubin is due to decreased excretion into the bile ductules or backward leakage of the pigment. The initial steps in evaluating the patient with jaundice are to determine (1) whether the hyperbilirubinemia is predominantly conjugated or unconjugated in nature and (2) whether other biochemical liver tests are abnormal.


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InternalMed_Harrison. The thoughtful interpretation of limited data permits a rational evaluation of the patient (Fig. 58-1). The following discussion will focus solely on the evaluation of the adult patient with jaundice. ISOLATED ELEVATION OF SERuM BILIRuBIN unconjugated Hyperbilirubinemia The differential diagnosis of isolated unconjugated hyperbilirubinemia is limited (Table 58-1). The critical determination is whether the patient is suffering from a hemolytic process resulting in an overproduction of bilirubin (hemolytic disorders and ineffective erythropoiesis) or from impaired hepatic uptake/conjugation of bilirubin (drug effect or genetic disorders).


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InternalMed_Harrison. Hemolytic disorders that cause excessive heme production may be either inherited or acquired. Inherited disorders include spherocytosis, sickle cell anemia, thalassemia, and deficiency of red cell enzymes such as pyruvate kinase and glucose-6-phosphate dehydrogenase. In these conditions, the serum bilirubin level rarely exceeds 86 μmol/L (5 mg/dL). Higher levels may occur when there is coexistent renal or hepatocellular dysfunction or in acute hemolysis, such as a sickle cell crisis. In evaluating jaundice in patients with chronic hemolysis, it is important to remember the high incidence of pigmented (calcium bilirubinate) gallstones found in these CAuSES of iSoLATED HyPERBiLiRuBinEMiA PART 2 Cardinal Manifestations and Presentation of Diseases I. Indirect hyperbilirubinemia A. Hemolytic disorders 1. Inherited a. Spherocytosis, elliptocytosis, glucose-6-phosphate dehydrogenase and pyruvate kinase deficiencies b. 2. Acquired a. b. c. d. e. B. 1.


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InternalMed_Harrison. A. Hemolytic disorders 1. Inherited a. Spherocytosis, elliptocytosis, glucose-6-phosphate dehydrogenase and pyruvate kinase deficiencies b. 2. Acquired a. b. c. d. e. B. 1. Cobalamin, folate, and severe iron deficiencies 2. C. Increased bilirubin production 1. 2. Resorption of hematoma D. Drugs 1. 2. 3. E. Inherited conditions 1. 2. II. A. B. patients, which increases the likelihood of choledocholithiasis as an alternative explanation for hyperbilirubinemia. lytic anemia (e.g., hemolytic-uremic syndrome), paroxysmal noc turnal hemoglobinuria, spur cell anemia, immune hemolysis, and parasitic infections (e.g., malaria and babesiosis). Ineffective erythro poiesis occurs in cobalamin, folate, and iron deficiencies. Resorption increased hemoglobin release and overproduction of bilirubin. In the absence of hemolysis, the physician should consider a problem with the hepatic uptake or conjugation of bilirubin.


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InternalMed_Harrison. In the absence of hemolysis, the physician should consider a problem with the hepatic uptake or conjugation of bilirubin. Certain drugs, including rifampin and probenecid, may cause of bilirubin. Impaired bilirubin conjugation occurs in three genetic conditions: Crigler-Najjar syndrome types I and II and Gilbert’s syndrome. Crigler-Najjar type I is an exceptionally rare condition >342 μmol/L [>20 mg/dL]) and neurologic impairment due to kernicterus, frequently leading to death in infancy or childhood. These patients have a complete absence of bilirubin UDPGT activ ity, usually due to mutations in the critical 3′ domain of the UDPGT gene; are totally unable to conjugate bilirubin; and hence cannot excrete it. Crigler-Najjar type II is somewhat more common than type I. Patients live into adulthood with serum bilirubin levels of 103–428 μmol/L (6–25 mg/dL). In these patients, mutations in the bilirubin


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InternalMed_Harrison. Crigler-Najjar type II is somewhat more common than type I. Patients live into adulthood with serum bilirubin levels of 103–428 μmol/L (6–25 mg/dL). In these patients, mutations in the bilirubin UDPGT gene cause the reduction—but not the complete eradica tion—of the enzyme’s activity. Bilirubin UDPGT activity can be induced by the administration of phenobarbital, which can reduce serum bilirubin levels in these patients. Despite marked jaundice, these patients usually survive into adulthood, although they may be susceptible to kernicterus under the stress of intercurrent illness or surgery.


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InternalMed_Harrison. Gilbert’s syndrome is also marked by the impaired conjugation of bilirubin (to approximately one-third of normal) due to reduced bilirubin UDPGT activity. Patients with Gilbert’s syndrome have mild unconjugated hyperbilirubinemia, with serum levels almost always <103 μmol/L (6 mg/dL). The serum levels may fluctuate, and jaundice is often identified only during periods of fasting. The molecular defect in Gilbert’s syndrome is linked to a reduction in transcription of the bilirubin UDPGT gene due to mutations in the promoter and, rarely, in the coding region. Unlike both Crigler-Najjar syndromes, Gilbert’s syndrome is very common. The reported incidence is 3–7% of the population, with males predominating over females by a ratio of 2–7:1.


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InternalMed_Harrison. Conjugated Hyperbilirubinemia Elevated conjugated hyperbilirubinemia is found in two rare inherited conditions: Dubin-Johnson syndrome and Rotor syndrome (Table 58-1). Patients with either condition present with asymptomatic jaundice. The defect in Dubin-Johnson syndrome is the presence of mutations in the gene for MRP2. These patients have altered excretion of bilirubin into the bile ducts. Rotor syndrome may represent a deficiency of the major hepatic drug uptake transporters OATP1B1 and OATP1B3. Differentiating between these syndromes is possible but is clinically unnecessary due to their benign nature.


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InternalMed_Harrison. The remainder of this chapter will focus on the evaluation of patients with conjugated hyperbilirubinemia in the setting of other liver test abnormalities. This group of patients can be divided into those with a primary hepatocellular process and those with intraor extrahepatic cholestasis. This distinction, which is based on the history and physical examination as well as the pattern of liver test abnormalities, guides the clinician’s evaluation (Fig. 58-1).


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InternalMed_Harrison. History A complete medical history is perhaps the single most important part of the evaluation of the patient with unexplained jaundice. Important considerations include the use of or exposure to any chemical or medication, whether physician-prescribed, overthe-counter, complementary, or alternative medicines (e.g., herbal and vitamin preparations) or other drugs such as anabolic steroids. The patient should be carefully questioned about possible parenteral exposures, including transfusions, intravenous and intranasal drug use, tattooing, and sexual activity. Other important points include recent travel history; exposure to people with jaundice; exposure to possibly contaminated foods; occupational exposure to hepatotoxins; alcohol consumption; the duration of jaundice; and the presence of any accompanying signs and symptoms, such as arthralgias, myalgias, rash, anorexia, weight loss, abdominal pain, fever, pruritus, and changes in the urine and stool. While none of the latter


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InternalMed_Harrison. of any accompanying signs and symptoms, such as arthralgias, myalgias, rash, anorexia, weight loss, abdominal pain, fever, pruritus, and changes in the urine and stool. While none of the latter manifestations is specific for any one condition, any of them can suggest a particular diagnosis. A history of arthralgias and myalgias predating jaundice suggests hepatitis, either viral or drug-related. Jaundice associated with the sudden onset of severe right-upper-quadrant pain and shaking chills suggests choledocholithiasis and ascending cholangitis.


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InternalMed_Harrison. Physical Examination The general assessment should include evaluation of the patient’s nutritional status. Temporal and proximal muscle wasting suggests long-standing disease such as pancreatic cancer or cirrhosis. Stigmata of chronic liver disease, including spider nevi, palmar erythema, gynecomastia, caput medusae, Dupuytren’s contractures, parotid gland enlargement, and testicular atrophy, are commonly seen in advanced alcoholic (Laennec’s) cirrhosis and occasionally in other types of cirrhosis. An enlarged left supraclavicular node (Virchow’s node) or a periumbilical nodule (Sister Mary Joseph’s nodule) suggests an abdominal malignancy. Jugular venous distention, a sign of right-sided heart failure, suggests hepatic congestion. Right pleural effusion in the absence of clinically apparent ascites may be seen in advanced cirrhosis.


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InternalMed_Harrison. Jugular venous distention, a sign of right-sided heart failure, suggests hepatic congestion. Right pleural effusion in the absence of clinically apparent ascites may be seen in advanced cirrhosis. The abdominal examination should focus on the size and consistency of the liver, on whether the spleen is palpable and hence enlarged, and on whether ascites is present. Patients with cirrhosis may have an enlarged left lobe of the liver, which is felt below the xiphoid, and an enlarged spleen. A grossly enlarged nodular liver or an obvious abdominal mass suggests malignancy. An enlarged tender liver could signify viral or alcoholic hepatitis; an infiltrative process such as amyloidosis; or, less often, an acutely congested liver secondary to right-sided heart failure. Severe right-upper-quadrant tenderness with respiratory arrest on inspiration (Murphy’s sign) suggests cholecystitis. Ascites in the presence of jaundice suggests either cirrhosis or malignancy with peritoneal spread.


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InternalMed_Harrison. Laboratory Tests A battery of tests are helpful in the initial evaluation of a patient with unexplained jaundice. These include total and direct serum bilirubin measurement with fractionation; determination of serum aminotransferase, alkaline phosphatase, and albumin concentrations; and prothrombin time tests. Enzyme tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase [ALP]) are helpful in differentiating between a hepatocellular process and a cholestatic process (Table 358-1; Fig. 58-1)—a critical step in determining what additional workup is indicated. Patients with a hepatocellular process generally have a rise in the aminotransferases that is disproportionate to that in ALP, whereas patients with a cholestatic process have a rise in ALP that is disproportionate to that of the aminotransferases. The serum bilirubin can be prominently elevated in both hepatocellular and cholestatic conditions and therefore is not necessarily helpful in


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InternalMed_Harrison. is disproportionate to that of the aminotransferases. The serum bilirubin can be prominently elevated in both hepatocellular and cholestatic conditions and therefore is not necessarily helpful in differentiating between the two.


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InternalMed_Harrison. In addition to enzyme tests, all jaundiced patients should have additional blood tests—specifically, an albumin level and a prothrombin time—to assess liver function. A low albumin level suggests a chronic process such as cirrhosis or cancer. A normal albumin level is suggestive of a more acute process such as viral hepatitis or choledocholithiasis. An elevated prothrombin time indicates either vitamin K deficiency due to prolonged jaundice and malabsorption of vitamin K or significant hepatocellular dysfunction. The failure of the prothrombin time to correct with parenteral administration of vitamin K indicates severe hepatocellular injury. The results of the bilirubin, enzyme, albumin, and prothrombin time tests will usually indicate whether a jaundiced patient has a hepatocellular or a cholestatic disease and offer some indication of the duration and severity of the disease. The causes and evaluations of hepatocellular and cholestatic diseases are quite different.


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InternalMed_Harrison. Hepatocellular Conditions Hepatocellular diseases that can cause jaundice include viral hepatitis, drug or environmental toxicity, alcohol, and end-stage cirrhosis from any cause (Table 58-2). Wilson’s disease occurs primarily in young adults. Autoimmune hepatitis is typically seen in young to middle-aged women but may affect men and women of any age. Alcoholic hepatitis can be differentiated from viral and toxin-related hepatitis by the pattern of the aminotransferases: patients with alcoholic hepatitis typically have an AST-to-ALT ratio of at least 2:1, and the AST level rarely exceeds 300 U/L. Patients with acute viral hepatitis and toxin-related injury severe enough to produce jaundice typically have aminotransferase levels >500 U/L, with the ALT greater than or equal to the AST. While ALT and AST values <8 times normal may be seen in either hepatocellular or cholestatic liver disease, values 25 times normal or higher are seen primarily in acute hepatocellular diseases. Patients


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InternalMed_Harrison. ALT and AST values <8 times normal may be seen in either hepatocellular or cholestatic liver disease, values 25 times normal or higher are seen primarily in acute hepatocellular diseases. Patients with jaundice from cirrhosis can have normal or only slightly elevated aminotransferase levels.


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InternalMed_Harrison. When the clinician determines that a patient has a hepatocellular disease, appropriate testing for acute viral hepatitis includes Hepatitis A, B, C, D, and E Predictable, dose-dependent (e.g., acetaminophen) Unpredictable, idiosyncratic (e.g., isoniazid) Wild mushrooms—Amanita phalloides, A. verna a hepatitis A IgM antibody assay, a hepatitis B surface antigen and core IgM antibody assay, a hepatitis C viral RNA test, and, depend ing on the circumstances, a hepatitis E IgM antibody assay. Because it can take many weeks for hepatitis C antibody to become detect able, its assay is an unreliable test if acute hepatitis C is suspected. Studies for hepatitis D and E viruses, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) may also be indicated. Ceruloplasmin is the initial screening test for Wilson’s disease. Testing for autoim measurement of specific immunoglobulins.


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InternalMed_Harrison. Drug-induced hepatocellular injury can be classified as either predictable or unpredictable. Predictable drug reactions are dose- dependent and affect all patients who ingest a toxic dose of the drug in question. The classic example is acetaminophen hepatotoxicity. Unpredictable or idiosyncratic drug reactions are not dose-depen dent and occur in a minority of patients. A great number of drugs can cause idiosyncratic hepatic injury. Environmental toxins are also an important cause of hepatocellular injury. Examples include industrial chemicals such as vinyl chloride, herbal preparations containing pyrrolizidine alkaloids (Jamaica bush tea) or Kava Kava, and the mushrooms Amanita phalloides and A. verna, which con tain highly hepatotoxic amatoxins.


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InternalMed_Harrison. Cholestatic Conditions When the pattern of the liver tests suggests a cholestatic disorder, the next step is to determine whether it is intra or extrahepatic cholestasis (Fig. 58-1). Distinguishing intrahepatic from extrahepatic cholestasis may be difficult. History, physical examination, and laboratory tests often are not helpful. The next appropriate test is an ultrasound. The ultrasound is inexpensive, does not expose the patient to ionizing radiation, and can detect dilation of the intraand extrahepatic biliary tree with a high degree of sensitivity and specificity. The absence of biliary dilation suggests intrahepatic cholestasis, while its presence indicates extrahepatic cholestasis. False-negative results occur in patients with partial obstruction of the common bile duct or in patients with cirrhosis or primary sclerosing cholangitis (PSC), in which scarring prevents the intrahepatic ducts from dilating.


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InternalMed_Harrison. sis, it rarely identifies the site or cause of obstruction. The distal common bile duct is a particularly difficult area to visual ize by ultrasound because of overlying bowel gas. Appropriate next tests include CT, magnetic resonance cholangiopancreatog raphy (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), and endoscopic ultrasound (EUS). CT scanning and


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InternalMed_Harrison. MRCP are better than ultrasonography for assessing the head of the pancreas and for identifying choledocholithiasis in the distal common bile duct, particularly when the ducts are not dilated. ERCP is the “gold standard” for identifying choledocholithiasis. Beyond its diagnostic capabilities, ERCP allows therapeutic interventions, including the removal of common bile duct stones and the placement of stents. MRCP has replaced ERCP as the initial diagnostic test in cases where the need for intervention is thought to be small. EUS displays sensitivity and specificity comparable to that of MRCP in the detection of bile duct obstruction. EUS also allows biopsy of suspected malignant lesions, but is invasive and requires sedation.


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InternalMed_Harrison. In patients with apparent intrahepatic cholestasis, the diagnosis is often made by serologic testing in combination with percutaneous liver biopsy. The list of possible causes of intrahepatic cholestasis is long and varied (Table 58-3). A number of conditions that typically cause a hepatocellular pattern of injury can also present as a cholestatic variant. Both hepatitis B and C viruses can cause cholestatic hepatitis (fibrosing cholestatic hepatitis). This disease variant has been reported in patients who have undergone solid organ transplantation. Hepatitis A and E, alcoholic hepatitis, and EBV or CMV infections may also present as cholestatic liver disease.


InternalMed_Harrison

InternalMed_Harrison. Drugs may cause intrahepatic cholestasis that is usually reversible after discontinuation of the offending agent, although it may take many months for cholestasis to resolve. Drugs most commonly associated with cholestasis are the anabolic and contraceptive steroids. Cholestatic hepatitis has been reported with chlorpromazine, imipramine, tolbutamide, sulindac, cimetidine, and erythromycin estolate. It also occurs in patients taking trimethoprim; sulfamethoxazole; and penicillin-based antibiotics such as ampicillin, dicloxacillin, and clavulanic acid. Rarely, cholestasis may be chronic and associated with progressive fibrosis despite early discontinuation of the offending drug. Chronic cholestasis has been associated with chlorpromazine and prochlorperazine.


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InternalMed_Harrison. Primary biliary cirrhosis is an autoimmune disease predominantly affecting middle-aged women and characterized by progressive destruction of interlobular bile ducts. The diagnosis is made by the detection of antimitochondrial antibody, which is found in 95% of patients. Primary sclerosing cholangitis is characterized by the destruction and fibrosis of larger bile ducts. The diagnosis of PSC is made with cholangiography (either MRCP or ERCP), which demonstrates the pathognomonic segmental strictures. Approximately 75% of patients with PSC have inflammatory bowel disease.


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InternalMed_Harrison. The vanishing bile duct syndrome and adult bile ductopenia are rare conditions in which a decreased number of bile ducts are seen in liver biopsy specimens. The histologic picture is similar to that in primary biliary cirrhosis. This picture is seen in patients who develop chronic rejection after liver transplantation and in those who develop graft-versus-host disease after bone marrow transplantation. Vanishing bile duct syndrome also occurs in rare cases of sarcoidosis, in patients taking certain drugs (including chlorpromazine), and idiopathically.


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InternalMed_Harrison. There are also familial forms of intrahepatic cholestasis. The familial intrahepatic cholestatic syndromes include progressive familial intrahepatic cholestasis (PFIC) types 1–3 and benign recurrent cholestasis (BRC). PFIC1 and BRC are autosomal recessive diseases that result from mutations in the ATP8B1 gene that encodes a protein belonging to the subfamily of P-type ATPases; the exact function of this protein remains poorly defined. While PFIC1 is a progressive condition that manifests in childhood, BRC presents later and is marked by recurrent episodes of jaundice and pruritus; the episodes are self-limited but can be debilitating. PFIC2 is caused by mutations in the ABCB11 gene, which encodes the bile salt export pump, and PFIC3 is caused by mutations in the multidrugresistant P-glycoprotein 3. Cholestasis of pregnancy occurs in the second and third trimesters and resolves after delivery. Its cause is unknown, but the condition is probably inherited, and cholestasis can be


InternalMed_Harrison

InternalMed_Harrison. P-glycoprotein 3. Cholestasis of pregnancy occurs in the second and third trimesters and resolves after delivery. Its cause is unknown, but the condition is probably inherited, and cholestasis can be triggered by estrogen administration.


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases I. Intrahepatic A. Viral hepatitis 1. 2. Hepatitis A, Epstein-Barr virus infection, cytomegalovirus infection B. Alcoholic hepatitis C. Drug toxicity 1. 2. Cholestatic hepatitis—chlorpromazine, erythromycin estolate 3. D. Primary biliary cirrhosis E. Primary sclerosing cholangitis F. Vanishing bile duct syndrome 1. Chronic rejection of liver transplants 2. 3. G. Congestive hepatopathy and ischemic hepatitis H. Inherited conditions 1. 2. I. Cholestasis of pregnancy J. Total parenteral nutrition K. Nonhepatobiliary sepsis L. Benign postoperative cholestasis M. Paraneoplastic syndrome N. Veno-occlusive disease O. Graft-versus-host disease P. Infiltrative disease 1. 2. 3. Q. Infections 1. 2. II. A. 1. 2. 3. 4. 5. Malignant involvement of the porta hepatis lymph nodes B. Benign 1. 2. 3. 4. 5. 6. 7.


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InternalMed_Harrison. Other causes of intrahepatic cholestasis include total parenteral nutrition (TPN); nonhepatobiliary sepsis; benign postoperative cholestasis; and a paraneoplastic syndrome associated with a number of different malignancies, including Hodgkin’s disease, medullary thyroid cancer, renal cell cancer, renal sarcoma, T cell lymphoma, prostate cancer, and several gastrointestinal malignancies. The term Stauffer’s syndrome has been used for intrahepatic cholestasis specifically associated with renal cell cancer. In patients developing cholestasis in the intensive care unit, the major considerations should be sepsis, ischemic hepatitis (“shock liver”), and TPN jaundice. Jaundice occurring after bone marrow transplantation is most likely due to veno-occlusive disease or graft-versus-host disease. In addition to hemolysis, sickle cell disease may cause intrahepatic and extrahepatic cholestasis. Jaundice is a late finding in heart failure caused by hepatic congestion and hepatocellular hypoxia.


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InternalMed_Harrison. In addition to hemolysis, sickle cell disease may cause intrahepatic and extrahepatic cholestasis. Jaundice is a late finding in heart failure caused by hepatic congestion and hepatocellular hypoxia. Ischemic hepatitis is a distinct entity of acute hypoperfusion characterized by an acute and dramatic elevation in the serum aminotransferases followed by a gradual peak in serum bilirubin.


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InternalMed_Harrison. Jaundice with associated liver dysfunction can be seen in severe cases of Plasmodium falciparum malaria. The jaundice in these cases is due to a combination of indirect hyperbilirubinemia from hemolysis and both cholestatic and hepatocellular jaundice. Weil’s disease, a severe presentation of leptospirosis, is marked by jaundice with renal failure, fever, headache, and muscle pain.


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InternalMed_Harrison. Causes of extrahepatic cholestasis can be split into malignant and benign (Table 58-3). Malignant causes include pancreatic, gallbladder, and ampullary cancers as well as cholangiocarcinoma. This last malignancy is most commonly associated with PSC and is exceptionally difficult to diagnose because its appearance is often identical to that of PSC. Pancreatic and gallbladder tumors as well as cholangiocarcinoma are rarely resectable and have poor prognoses. Ampullary carcinoma has the highest surgical cure rate of all the tumors that present as painless jaundice. Hilar lymphadenopathy due to metastases from other cancers may cause obstruction of the extrahepatic biliary tree.


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InternalMed_Harrison. Choledocholithiasis is the most common cause of extrahepatic cholestasis. The clinical presentation can range from mild right-upper-quadrant discomfort with only minimal elevations of enzyme test values to ascending cholangitis with jaundice, sepsis, and circulatory collapse. PSC may occur with clinically important strictures limited to the extrahepatic biliary tree. IgG4-associated cholangitis is marked by stricturing of the biliary tree. It is critical that the clinician differentiate this condition from PSC as it is responsive to glucocorticoid therapy. In rare instances, chronic pancreatitis causes strictures of the distal common bile duct, where it passes through the head of the pancreas. AIDS cholangiopathy is a condition that is usually due to infection of the bile duct epithelium with CMV or cryptosporidia and has a cholangiographic appearance similar to that of PSC. The affected patients usually present with greatly elevated serum alkaline phosphatase levels (mean, 800 IU/L),


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InternalMed_Harrison. CMV or cryptosporidia and has a cholangiographic appearance similar to that of PSC. The affected patients usually present with greatly elevated serum alkaline phosphatase levels (mean, 800 IU/L), but the bilirubin level is often near normal. These patients do not typically present with jaundice.


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InternalMed_Harrison. gLOBAL CONSIDERATIONS While extrahepatic biliary obstruction and drugs are common causes of new-onset jaundice in developed countries, infections remain the leading cause in developing countries. Liver involvement and jaundice are observed with numerous infections, particularly malaria, babesiosis, severe leptospirosis, infections due to Mycobacterium tuberculosis and the Mycobacterium avium complex, typhoid fever, viral hepatitis secondary to infection with hepatitis viruses A–E, EBV and CMV infections, late phases of yellow fever, dengue hemorrhagic fever, schistosomiasis, fascioliasis, clonorchiasis, opisthorchiasis, ascariasis, echinococcosis, hepatosplenic candidiasis, disseminated histoplasmosis, cryptococcosis, coccidioimycosis, ehrlichiosis, chronic Q fever, yersiniosis, brucellosis, syphilis, and lep rosy. Bacterial infections that do not necessarily involve the liver and bile ducts may also lead to jaundice, as in cholestasis of sepsis.


InternalMed_Harrison

InternalMed_Harrison. This chapter is a revised version of chapters that have appeared in prior editions of Harrison’s in which Marshall M. Kaplan was a co-author together with Daniel Pratt. Kathleen E. Corey, Lawrence S. Friedman Abdominal swelling is a manifestation of numerous diseases. Patients may complain of bloating or abdominal fullness and may note increasing abdominal girth on the basis of increased clothing or belt size. Abdominal discomfort is often reported, but pain is less frequent. When abdominal pain does accompany swelling, it is frequently the result of an intraabdominal infection, peritonitis, or pancreatitis. Patients with abdominal distention from ascites (fluid in the abdomen) may report the new onset of an inguinal or umbilical hernia. Dyspnea may result from pressure against the diaphragm and the inability to expand the lungs fully.


InternalMed_Harrison

InternalMed_Harrison. The causes of abdominal swelling can be remembered conveniently as the six Fs: flatus, fat, fluid, fetus, feces, or a “fatal growth” (often a neoplasm).


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InternalMed_Harrison. Flatus Abdominal swelling may be the result of increased intestinal gas. The normal small intestine contains approximately 200 mL of gas made up of nitrogen, oxygen, carbon dioxide, hydrogen, and methane. Nitrogen and oxygen are consumed (swallowed), whereas carbon dioxide, hydrogen, and methane are produced intraluminally by bacterial fermentation. Increased intestinal gas can occur in a number of conditions. Aerophagia, the swallowing of air, can result in increased amounts of oxygen and nitrogen in the small intestine and lead to abdominal swelling. Aerophagia typically results from gulping food; chewing gum; smoking; or as a response to anxiety, which can lead to repetitive belching. In some cases, increased intestinal gas is the consequence of bacterial metabolism of excess fermentable substances such as lactose and other oligosaccharides, which can lead to production of hydrogen, carbon dioxide, or methane. In many cases, the precise cause of abdominal distention cannot be


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InternalMed_Harrison. substances such as lactose and other oligosaccharides, which can lead to production of hydrogen, carbon dioxide, or methane. In many cases, the precise cause of abdominal distention cannot be determined. In some persons, particularly those with irritable bowel syndrome and bloating, the subjective sense of abdominal pressure is attributable to impaired intestinal transit of gas rather than increased gas volume. Abdominal distention—an objective increase in girth—is the result of a lack of coordination between diaphragmatic contraction and anterior abdominal wall relaxation, a response in some cases to an increase in intraabdominal volume loads. Occasionally, increased lumbar lordosis accounts for apparent abdominal distention.


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InternalMed_Harrison. Fat Weight gain with an increase in abdominal fat can result in an increase in abdominal girth and can be perceived as abdominal swelling. Abdominal fat may be caused by an imbalance between caloric intake and energy expenditure associated with a poor diet and sedentary lifestyle; it also can be a manifestation of certain diseases, such as Cushing’s syndrome. Excess abdominal fat has been associated with an increased risk of insulin resistance and cardiovascular disease. Fluid The accumulation of fluid within the abdominal cavity (ascites) often results in abdominal distention and is discussed in detail below. Fetus Pregnancy results in increased abdominal girth. Typically, an increase in abdominal size is first noted at 12–14 weeks of gestation, when the uterus moves from the pelvis into the abdomen. Abdominal distention may be seen before this point as a result of fluid retention and relaxation of the abdominal muscles.


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InternalMed_Harrison. Feces In the setting of severe constipation or intestinal obstruction, increased stool in the colon leads to increased abdominal girth. These conditions are often accompanied by abdominal discomfort or pain, nausea, and vomiting and can be diagnosed by imaging studies. Fatal growth An abdominal mass can result in abdominal swelling. Enlargement of the intraabdominal organs, specifically the liver (hepatomegaly) or spleen (splenomegaly), or an abdominal aortic aneurysm 286 can result in abdominal distention. Bladder distention also may result in abdominal swelling. In addition, malignancies, abscesses, or cysts can grow to sizes that lead to increased abdominal girth. APPROACH TO THE PATIENT: PART 2 Cardinal Manifestations and Presentation of Diseases


InternalMed_Harrison

InternalMed_Harrison. APPROACH TO THE PATIENT: PART 2 Cardinal Manifestations and Presentation of Diseases Determining the etiology of abdominal swelling begins with history-taking and a physical examination. Patients should be questioned regarding symptoms suggestive of malignancy, including weight loss, night sweats, and anorexia. Inability to pass stool or flatus together with nausea or vomiting suggests bowel obstruction, severe constipation, or an ileus (lack of peristalsis). Increased eructation and flatus may point toward aerophagia or increased intestinal production of gas. Patients should be questioned about risk factors for or symptoms of chronic liver disease, including excessive alcohol use and jaundice, which suggest ascites. Patients should also be asked about other symptoms of medical conditions, including heart failure and tuberculosis, which may cause ascites.


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InternalMed_Harrison. Physical examination should include an assessment for signs of systemic disease. The presence of lymphadenopathy, especially supraclavicular lymphadenopathy (Virchow’s node), suggests metastatic abdominal malignancy. Care should be taken during the cardiac examination to evaluate for elevation of jugular venous pressure (JVP); Kussmaul’s sign (elevation of the JVP during inspiration); a pericardial knock, which may be seen in heart failure or constrictive pericarditis; or a murmur of tricuspid regurgitation. Spider angiomas, palmar erythema, dilated superficial veins around the umbilicus (caput medusae), and gynecomastia suggest chronic liver disease.


InternalMed_Harrison

InternalMed_Harrison. The abdominal examination should begin with inspection for the presence of uneven distention or an obvious mass. Auscultation should follow. The absence of bowel sounds or the presence of high-pitched localized bowel sounds points toward an ileus or intestinal obstruction. An umbilical venous hum may suggest the presence of portal hypertension, and a harsh bruit over the liver is heard rarely in patients with hepatocellular carcinoma or alcoholic hepatitis. Abdominal swelling caused by intestinal gas can be differentiated from swelling caused by fluid or a solid mass by percussion; an abdomen filled with gas is tympanic, whereas an abdomen containing a mass or fluid is dull to percussion. The absence of abdominal dullness, however, does not exclude ascites, because a minimum of 1500 mL of ascitic fluid is required for detection on physical examination. Finally, the abdomen should be palpated to assess for tenderness, a mass, enlargement of the spleen or liver, or presence of a nodular


InternalMed_Harrison

InternalMed_Harrison. ascitic fluid is required for detection on physical examination. Finally, the abdomen should be palpated to assess for tenderness, a mass, enlargement of the spleen or liver, or presence of a nodular liver suggesting cirrhosis or tumor. Light palpation of the liver may detect pulsations suggesting retrograde vascular flow from the heart in patients with right-sided heart failure, particularly tricuspid regurgitation.


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InternalMed_Harrison. Abdominal x-rays can be used to detect dilated loops of bowel sug gesting intestinal obstruction or ileus. Abdominal ultrasonography can detect as little as 100 mL of ascitic fluid, hepatosplenomegaly, a nodular liver, or a mass. Ultrasonography is often inadequate to detect retroperitoneal lymphadenopathy or a pancreatic lesion because of overlying bowel gas. If malignancy or pancreatic disease is suspected,


InternalMed_Harrison

InternalMed_Harrison. CT can be performed. CT may also detect changes associated with advanced cirrhosis and portal hypertension (Fig. 59-1). Laboratory evaluation should include liver biochemical testing, serum albumin level measurement, and prothrombin time determina tion (international normalized ratio) to assess hepatic function as well as a complete blood count to evaluate for the presence of cytopenias that may result from portal hypertension or of leukocytosis, anemia, and thrombocytosis that may result from systemic infection. Serum amylase and lipase levels should be checked to evaluate the patient for acute pancreatitis. Urinary protein quantitation is indicated when nephrotic syndrome, which may cause ascites, is suspected. FIguRE 59-1 CT of a patient with a cirrhotic, nodular liver (white arrow), splenomegaly (yellow arrow), and ascites (arrowheads).


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InternalMed_Harrison. FIguRE 59-1 CT of a patient with a cirrhotic, nodular liver (white arrow), splenomegaly (yellow arrow), and ascites (arrowheads). In selected cases, the hepatic venous pressure gradient (pressure across the liver between the portal and hepatic veins) can be measured via cannulation of the hepatic vein to confirm that ascites is caused by cirrhosis (Chap. 365). In some cases, a liver biopsy may be necessary to confirm cirrhosis.


InternalMed_Harrison

InternalMed_Harrison. Ascites in patients with cirrhosis is the result of portal hypertension and renal salt and water retention. Similar mechanisms contribute to ascites formation in heart failure. Portal hypertension signifies elevation of the pressure within the portal vein. According to Ohm’s law, pressure is the product of resistance and flow. Increased hepatic resistance occurs by several mechanisms. First, the development of hepatic fibrosis, which defines cirrhosis, disrupts the normal architecture of the hepatic sinusoids and impedes normal blood flow through the liver. Second, activation of hepatic stellate cells, which mediate fibrogenesis, leads to smooth-muscle contraction and fibrosis. Finally, cirrhosis is associated with a decrease in endothelial nitric oxide synthetase (eNOS) production, which results in decreased nitric oxide production and increased intrahepatic vasoconstriction.


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InternalMed_Harrison. The development of cirrhosis is also associated with increased systemic circulating levels of nitric oxide (contrary to the decrease seen intrahepatically) as well as increased levels of vascular endothelial growth factor and tumor necrosis factor that result in splanchnic arterial vasodilation. Vasodilation of the splanchnic circulation results in pooling of blood and a decrease in the effective circulating volume, which is perceived by the kidneys as hypovolemia. Compensatory vasoconstriction via release of antidiuretic hormone ensues; the consequences are free water retention and activation of the sympathetic nervous system and the renin angiotensin aldosterone system, which lead in turn to renal sodium and water retention.


InternalMed_Harrison

InternalMed_Harrison. Ascites in the absence of cirrhosis generally results from peritoneal carcinomatosis, peritoneal infection, or pancreatic disease. Peritoneal carcinomatosis can result from primary peritoneal malignancies such as mesothelioma or sarcoma, abdominal malignancies such as gastric or colonic adenocarcinoma, or metastatic disease from breast or lung carcinoma or melanoma (Fig. 59-2). The tumor cells lining the peritoneum produce a protein-rich fluid that contributes to the development of ascites. Fluid from the extracellular space is drawn into the peritoneum, further contributing to the development of ascites. Tuberculous peritonitis causes ascites via a similar mechanism; tubercles deposited on the peritoneum exude a proteinaceous fluid. Pancreatic ascites results from leakage of pancreatic enzymes into the peritoneum. FIguRE 59-2 CT of a patient with peritoneal carcinomatosis (white arrow) and ascites (yellow arrow).