Sample Chapter CHAPTER 16: Liver, Biliary Tract, & Pancreas Disorders BUY NOW mhprofessional.com 728129654 – ©2021 McGraw Hill LLC. All Rights Reserved. CMDT 2022 677 Liver, Biliary Tract, & Pancreas Disorders Lawrence S. Friedman, MD 16 JAUNDICE & EVALUATION OF ABNORMAL hepatic uptake of bilirubin due to certain drugs; or impaired LIVER BIOCHEMICAL TESTS conjugation of bilirubin by glucuronide, as in Gilbert syn- drome, due to mild decreases in uridine diphosphate (UDP) glucuronyl transferase, or Crigler-Najjar syndrome, ESSENTIALS OF DIAGNOSIS caused by moderate decreases (type II) or absence (type I) of UDP glucuronyl transferase. Hemolysis alone rarely elevates the serum bilirubin level to more than 7 mg/dL » Jaundice results from accumulation of bilirubin in (119.7 mcmol/L). Predominantly conjugated hyperbiliru- body tissues; the cause may be hepatic or binemia may result from impaired excretion of bilirubin nonhepatic. from the liver due to hepatocellular disease, drugs, sepsis, » Hyperbilirubinemia may be due to abnormalities or hereditary hepatocanalicular transport defects (such as in the formation, transport, metabolism, or excre- Dubin-Johnson syndrome, progressive familial intrahe- tion of bilirubin. patic cholestasis syndromes, and intrahepatic cholestasis of » Persistent mild elevations of the aminotransferase pregnancy) or from extrahepatic biliary obstruction. Fea- levels are common in clinical practice and caused tures of some hyperbilirubinemic syndromes are summa- most often by nonalcoholic fatty liver disease rized in Table 16–2. The term “cholestasis” denotes (NAFLD). retention of bile in the liver, and the term “cholestatic jaundice” is often used when conjugated hyperbilirubine- » Evaluation of obstructive jaundice begins with ultrasonography and is usually followed by mia results from impaired bile formation or flow. Media- cholangiography. tors of pruritus due to cholestasis have been identified to be lysophosphatidic acid and autotaxin, the enzyme that forms lysophosphatidic acid. Clinical Findings » General Considerations » Jaundice (icterus) results from the accumulation of A. Unconjugated Hyperbilirubinemia bilirubin—a product of heme metabolism—in body tissues. Stool and urine color are normal, and there is mild jaun- Hyperbilirubinemia may be due to abnormalities in the dice and indirect (unconjugated) hyperbilirubinemia with formation, transport, metabolism, or excretion of bilirubin. no bilirubin in the urine. Splenomegaly occurs in all hemo- Total serum bilirubin is normally 0.2–1.2 mg/dL (3.42– lytic disorders except in sickle cell disease. 20.52 mcmol/L). Mean levels are higher in men than women, higher in Whites and Hispanics than Blacks, and B. Conjugated Hyperbilirubinemia correlate with an increased risk of symptomatic gallstone disease and inversely with the risk of stroke, respiratory Cholestasis is often accompanied by pruritus, light-colored disease, cardiovascular disease, and mortality, presumably stools, and jaundice, although the patient may be asymp- because of antioxidant and intestinal anti-inflammatory tomatic. Malaise, anorexia, low-grade fever, and right effects. Jaundice may not be recognizable until serum bili- upper quadrant discomfort are frequent with hepatocellu- rubin levels are about 3 mg/dL (51.3 mcmol/L). lar disease. Dark urine, jaundice, and, in women, amenor- Jaundice may be caused by predominantly unconju- rhea occur. An enlarged tender liver, spider telangiectasias, gated or conjugated bilirubin in the serum (Table 16–1). palmar erythema, ascites, gynecomastia, sparse body hair, Unconjugated hyperbilirubinemia may result from over- fetor hepaticus, and asterixis may be present, depending on production of bilirubin because of hemolysis; impaired the cause, severity, and chronicity of liver dysfunction. BUY NOW CMDT22_Ch16_p0677-p0740.indd 677 29/06/21 8:39 PM mhprofessional.com 728129654 – ©2021 McGraw Hill LLC. All Rights Reserved. 678 CMDT 2022 CHAPTER 16 Table 16–1. Classification of jaundice. Type of Hyperbilirubinemia Location and Cause Unconjugated hyperbilirubinemia Increased bilirubin production (eg, hemolytic anemias, hemolytic reactions, hematoma, pulmonary (predominantly indirect bilirubin) infarction) Impaired bilirubin uptake and storage (eg, posthepatitis hyperbilirubinemia, Gilbert syndrome, Crigler-Najjar syndrome, drug reactions) Conjugated hyperbilirubinemia Hereditary Cholestatic Syndromes (see also Table 16–2) (predominantly direct bilirubin) Faulty excretion of bilirubin conjugates (eg, Dubin-Johnson syndrome, Rotor syndrome) or mutation in genes coding for bile salt transport proteins (eg, progressive familial intrahepatic cholestasis syndromes, benign recurrent intrahepatic cholestasis, and some cases of intrahepatic cholestasis of pregnancy) Hepatocellular Dysfunction Biliary epithelial and hepatocyte damage (eg, hepatitis, hepatic cirrhosis) Intrahepatic cholestasis (eg, certain drugs, biliary cirrhosis, sepsis, postoperative jaundice) Hepatocellular damage or intrahepatic cholestasis resulting from miscellaneous causes (eg, spiro- chetal infections, infectious mononucleosis, cholangitis, sarcoidosis, lymphomas, hyperthyroidism, industrial toxins) Biliary Obstruction Choledocholithiasis, biliary atresia, carcinoma of biliary duct, sclerosing cholangitis, IgG4-related cholangitis, ischemic cholangiopathy, choledochal cyst, external pressure on bile duct, pancreati- tis, pancreatic neoplasms Ig, immunoglobulin. C. Biliary Obstruction expectancy. Truncal fat and early-onset paternal obesity are risk factors for increased ALT levels. Levels are mildly elevated There may be right upper quadrant pain, weight loss (sug- in more than 25% of persons with untreated celiac disease and gesting carcinoma), jaundice, pruritus, dark urine, and in type 1 diabetic patients with so-called glycogenic hepatopa- light-colored stools. Symptoms and signs may be intermit- thy and often rise transiently in healthy persons who begin tent if caused by a stone, carcinoma of the ampulla, or taking 4 g of acetaminophen per day or experience rapid cholangiocarcinoma. Pain may be absent early in pancre- weight gain on a fast-food diet. Levels may rise strikingly but atic cancer. Occult blood in the stools suggests cancer of transiently in patients with acute biliary obstruction from the ampulla. A palpable gallbladder (Courvoisier sign) is choledocholithiasis. NAFLD is by far the most common cause characteristic, but neither specific nor sensitive, of a pan- of persistent mildly to moderately elevated aminotransferase creatic head tumor. Fever and chills are more common in levels. Elevated ALT and AST levels, often greater than benign obstruction with associated cholangitis. 1000 units/L (20 mckat/L), are the hallmark of hepatocellular Diagnostic Studies necrosis or inflammation. Modest elevations are frequent in » systemic infections, including coronavirus disease 2019 (See Tables 16–3 and 16–4.) (COVID-19). The differential diagnosis of any liver test eleva- tion always includes toxicity caused by drugs, herbal and A. Laboratory Findings dietary supplements, and toxins. Elevated alkaline phosphatase levels are seen in cho- Elevated serum alanine and aspartate aminotransferase lestasis or infiltrative liver disease (such as tumor, granulo- (ALT and AST) levels reflect hepatocellular injury. Normal matous disease, or amyloidosis). Isolated alkaline reference values for ALT and AST are lower than generally phosphatase elevations of hepatic rather than bone, intesti- reported when persons with risk factors for fatty liver are nal, or placental origin are confirmed by concomitant ele- excluded. The upper limit of normal for ALT is vation of gamma-glutamyl transpeptidase or 5′-nucleotidase 29–33 units/L in men and 19–25 units/L in women. Levels levels. Serum gamma-glutamyl transpeptidase levels decrease with age and correlate with body mass index and appear to correlate with the risk of mortality and disability mortality from liver disease and inversely with caffeine in the general population. consumption and physical activity. There is controversy about whether a persistently elevated ALT level is associ- B. Imaging ated with a low or high vitamin D level and, in the general population, with mortality from coronary artery disease, Demonstration of dilated bile ducts by ultrasonography or cancer, diabetes mellitus, and all causes; elevated AST lev- CT indicates biliary obstruction (90–95% sensitivity). els have been reported to be associated with shorter life Ultrasonography, CT, and MRI may also demonstrate CMDT22_Ch16_p0677-p0740.indd 678 29/06/21BUY 8:39 PM NOW mhprofessional.com 728129654 – ©2021 McGraw Hill LLC. All Rights Reserved. LIVER, BILIARY TRACT, & PANCREAS DISORDERS CMDT 2022 679 Table 16–2. Hyperbilirubinemic disorders. Type of Nature of Defect Hyperbilirubinemia Clinical and Pathologic Characteristics Gilbert syndrome1 Reduced activity of Unconjugated Benign, asymptomatic hereditary jaundice. Hyperbilirubinemia uridine diphosphate (indirect) bilirubin increased by 24- to 36-hour fast. No treatment required. Asso- glucuronyl transferase ciated with reduced mortality from cardiovascular disease. Dubin-Johnson Reduced excretory Conjugated (direct) Benign, asymptomatic hereditary jaundice. Gallbladder does syndrome2 function of bilirubin not visualize on oral cholecystography. Liver darkly pig- hepatocytes mented on gross examination. Biopsy shows centrilobular brown pigment. Prognosis excellent. Rotor syndrome3 Reduced hepatic reuptake Conjugated (direct)