Clinical Approach to the Patient With Abnormal Liver Test Results. ALT =alanine aminotransferase; AST =aspartate aminotransferase;

Transcription

1 Concise Review o rlmary..._.. Physicians Clinical Approach to the Patient With Abnormal Liver Test Results PATRICK S. KAMATH, M.D. Abnormal results of standard biochemical liver tests occur frequently; however, the prevalence of clinically significant liver disease is only about 1% in all patients screened. Thus, development of a rational and costeffective approach to these patients is important. Liver diseases are generally classified as hepatocellular, cholestatic, and infiltrative. Cholestatic liver disease is further categorized as intrahepatic and extrahepatic. Hepatocellular disease is characterized by transaminase increases greater than 5 times the upper limit of normal, with alkaline phosphatase levels usually increased less than 2 to 3 times the upper limit of normal. Cholestatic disease is characterized by an increase in the alkaline phosphatase level that is 3 to 5 times greater than the upper limit of normal, with only a mild increase of transaminases. The exception to this is cholestasis with cholangitis when the trans- aminases can be more substantially increased. In infiltrative diseases of the liver such as lymphoma or granulomatous hepatitis, the alkaline phosphatase level is increased disproportionately to that of the bilirubin. Specific etiologic diagnoses cannot usually be based on routine biochemical liver test results, and thus more specialized serum tests are necessary. A liver biopsy is often needed for a precise diagnosis in patients with long-term increases in liver test results. Ultrasonography is the best initial imaging technique for the liver, and if biliary dilatation is noted, endoscopic retrograde cholangiopancreatography is recommended. (Mayo Clin Proc 1996; 71: ) ALT =alanine aminotransferase; AST =aspartate aminotransferase; GGT = y-glutamyltransferase; NASH = nonalcoholic steatohepatitis; PBC =primary biliary cirrhosis "Liver function tests" provide indirect evidence of hepatobiliary disease. The standard biochemistry panel offered by most laboratories includes aspartate aminotransferase (AST), alkaline phosphatase, bilirubin, and albumin. These tests do not measure liver function but rather indicate hepatobiliary disease and are best referred to as "livertests." True liver function tests are not widely used and include galactose clearance and aminopyrineclearance tests. Abnormal test results occur in as many as one-third of patients screened, but the incidence of clinically significant unsuspected liver disease is approximately 1%. CLINICAL ASSESSMENT OF THE PATIENT Symptoms of anorexia, nausea, vomiting, and low-grade fever indicate hepatocellular necrosis, as in viral hepatitis. Symptoms of deep jaundice, pruritus, clay-colored stools, and dark-colored urine suggest cholestasis or inadequate bile flow. Cholestasis is either intrahepatic, related to a defect in secretion of bile at the hepatocyte level, or extrahepatic, related to structural obstruction in the biliary tree. Biliary From the Division of Gastroenterology and Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota. Address reprint requests to Dr. P. S. Kamath, Division of Gastroenterology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN colic, especially when associated with fever and chills, indicates that the cause of cholestasis is most likely to be in the extrahepatic biliary tree and related to gallstones or a tumor. Symptoms, however, are not specific enough to make an accurate diagnosis of liver disease. In fact, fatigue may be the only symptom of chronic liver disease. Elicitation of the family history is important. In a patient with indirect hyperbilirubinemia, a family history of this condition might indicate hemolysis or Gilbert's syndrome, whereas direct hyperbilirubinemia suggests Dubin-Johnson syndrome. A family history of severe liver disease may indicate Wilson's disease, hemochromatosis, or (XI,antitrypsin deficiency. Other important factors include sexual history, travel, volume and duration of alcohol use, drug use and intake of vitamin A, history of blood transfusion or needle stick injury, and consumption of raw oysters (hepatitis A). The physician must ask about extrahepatic illnesses like cardiac disease; inflammatory bowel disease; other conditions of hemochromatosis such as diabetes, skin pigmentation, cardiac disease, arthritis, and hypogonadism; and thyroid disease. Patients with hematologic diseases can have hepatic venous thrombosis, which manifests as onset of acute pain in the right upper quadrant of the abdomen, ascites, hepatomegaly, and abnormal liver test results. Mayo Clin Proc 1996; 71: Mayo Foundation for Medical Education and Research

2 1090 ABNORMAL LIVER TEST RESULTS Physical findings such as jaundice, palmar erythema, spider nevi, parotid enlargement, ascites, and encephalopathy are indices of chronic liver disease. Physical findings are more important in confirming the presence of liver disease than in determining a specific diagnosis; however, some exceptions exist. A palpable gallbladder implies extrahepatic cholestasis. A bruit over the liver might suggest an arterial aneurysm or tricuspid regurgitation. KayserFleischer rings indicate Wilson's disease, and a positive Murphy's sign indicates acute cholecystitis. Once liver disease is suspected, results of the liver tests are analyzed in an attempt to obtain a more specific diagnosis. INTERPRETATION OF ABNORMAL LIVER TEST RESULTS Bilirubin.-The total bilirubin level is usually less than l.l mg/dl, and approximately 70% is indirect (unconjugated). If more than 80% of the total bilirubin is indirect, the entity is termed "unconjugated hyperbilirubinemia" and suggests hemolysis or Gilbert's syndrome. In hemolysis and Gilbert's syndrome, the total bilirubin level is usually less than 6.0 mg/dl. If more than 50% of the total bilirubin is direct bilirubin, the state is termed "conjugated hyperbilirubinemia" and indicates either hepatocellular dysfunction or cholestasis. In common bile duct obstruction due to gallstones, it is unusual for the bilirubin level to increase to more than 15 mg/dl because obstruction is usually incomplete; it is usually less than 6.0 mg/dl. Because bilirubin is predominantly conjugated and hence water soluble, in extrahepatic cholestasis, bilirubin is excreted easily by the kidney. Thus, bilirubin excretion keeps pace with bilirubin production. Consequently, when the bilirubin level is higher than 25 to 30 mg/dl, extrahepatic cholestasis is an unlikely diagnosis. Transaminases.-The transaminases are enzymes involved in the transfer of amino groups of aspartate and alanine to ketoglutaric acid. The AST enzyme (formerly designated serum glutamic-oxaloacetic transaminase) is present in cardiac, skeletal, kidney, and brain tissue, as well as in the liver. In contrast, alanine aminotransferase (ALT [formerly known as serum glutamate pyruvate transaminase]) is present almost exclusively in the liver and is a better index of liver cell injury. An AST increase in the absence of an ALT increase is reflective of cardiac or muscle disease. A rare cause of increased AST is when AST exists as a macroenzyme (macro-ast). In this condition, the AST is complexed with an immunoglobulin and thus is not cleared from the blood. Macro-AST does not indicate serious liver disease. It is a condition analogous to macroamylasemia, which causes an increased amylase in the absence of acute pancreatitis. The AST can be falsely low after dialysis. The ratio of AST to ALT is sometimes a useful marker to diagnose specific liver diseases. AST is distributed both in Mayo Clin Proc, November 1996, Vol 71 cytosol and in mitochondria, but the normal serum activity of AST is predominantly related to cytosol. ALT is distributed mainly in the cytosol. In alcoholic hepatitis, the damage is primarily to the mitochondria, and thus the AST increase is higher than that of the ALT. Patients with alcoholic liver disease have pyridoxine deficiency, and ALT is more sensitive to pyridoxine deficiency than is AST; therefore, ALT levels tend to be lower. In viral hepatitis, the ALT is higher than the AST. In alcoholic hepatitis, the AST:AL T ratio is greater than 2.0, and the AST increase is not more than 250 U/L. The ratio of AST to ALT is less useful in chronic liver disease because hepatitis B virus-related cirrhosis and other causes of cirrhosis can also increase the AST:ALT ratio to more than 1.0. The pattern of AST and ALT increases provides some indication of the underlying cause of liver disease. In choledocholithiasis, an AST increase is the earliest abnormality detected and is usually not more than fivefold. In the presence of cholangitis, the increase can be up to lo-fold. Typically, in choledocholithiasis, the AST increase is transient and returns to normal within 72 hours. In viral and drug-induced hepatitis, the transaminase levels steadily increase and peak in the low thousands range within 7 to 14 days. In uncomplicated viral hepatitis, the transaminases return to normal in about 6 weeks. In ischemic hepatitis, which typically occurs in patients with cardiac failure and hypotension, the transaminases abruptly increase within 24 hours and may even be higher than 10,000 IU/L; they rapidly return to normal within a week. Transaminase increases greater than 10,000 IU/L are also noted with an overdose of acetaminophen and in herpes simplex hepatitis. In a patient with increased transaminases, a decrease usually indicates improvement; however, in a patient with acute liver disease, a rapid decrease may mean profound worsening of the patient's condition. Many medications cause increases in AST. The most common ones are acetaminophen; nonsteroidal anti-inflammatory drugs; angiotensin-converting enzyme inhibitors; nicotinic acid; antibacterial agents such as isoniazid, sulfonamides, and erythromycin; and antifungal agents such as griseofulvin and fluconazole. Finally, conditions such as nonalcoholic steatohepatitis (NASH) and both hyperthyroidism and hypothyroidism can cause increased transaminases. NASH is associated with various conditions such as diabetes mellitus and obesity, a jejunoileal bypass, drugs such as amiodarone, and total parenteral nutrition; however, NASH can be present without an obvious association. Alkaline Phosphatase.-Alkaline phosphatase refers to a family of enzymes that catalyze hydrolysis of phosphate esters at an alkaline ph. Alkaline phosphatase is present in bone, placenta, intestine, and kidney, as well as in liver

3 Mayo Clin Proc, November 1996, Vol 71 tissue; however, more than 80% of circulating alkaline phosphatase is in the liver and bone. During pregnancy, the alkaline phosphatase is concentrated predominantly in the placenta. Liver alkaline phosphatase is synthesized by the bile duct epithelial cells. The response to obstruction of bile ducts is increased synthesis and release of alkaline phosphatase. This outcome can result even if the obstruction is in a few small bile ducts and is insufficient to cause an increase in bilirubin. If, on fractionation, the alkaline phosphatase is found to be of hepatic origin, it indicates cholestasis at some level: diffusely within the liver (intrahepatic cholestasis), extrahepatic (gallstones or tumors), localized within the liver (hepatocellular carcinoma), or patchy involvement within the liver (granulomatous disease). Levels of alkaline phosphatase are also increased in hyperthyroidism, cardiac failure, lymphoma, and hypernephroma. If a laboratory does not have the capability to measure the liver fraction of alkaline phosphatase, measurement of y-glutamyltransferase (GGT) is recommended. This is the only recommended use of routine GGT testing in evaluation of liver disease. An increased GGT in the presence of an increased alkaline phosphatase level indicates that the alkaline phosphatase is most likely of hepatic origin. When the alkaline phosphatase level is increased disproportionately to the bilirubin levelthat is, bilirubin of less than 1.0 mg/dl and alkaline phosphatase greater than 1,000 U/L-suggested diagnoses are granulomatous or infiltrative diseases of the liver, including sarcoidosis, fungal infections, tuberculosis, and lymphoma. In patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis, the initial finding is also an increased alkaline phosphatase but normal bilirubin level. Recognizing the common pitfalls associated with interpretation of alkaline phosphatase levels is important. The test must be performed in fasting patients. Patients with blood group 0 and B who are secretors can have increased alkaline phosphatase after eating a fatty meal because of the release of the intestinal enzyme. In children, the alkaline phosphatase level is increased up to 3 times the upper limit of normal, and in pregnant patients, it can be increased up to 2 times that of normal. The alkaline phosphatase level may be low in patients with hypothyroidism, in some patients with Wilson's disease and hemolysis, and in those with congenital hypophosphatasia. Causes of intrahepatic cholestasis include PBC and drugs such as erythromycin, chlorpromazine, estrogens, and methyltestosterone; drugs are the most common cause. Typical causes of extrahepatic cholestasis are common bile duct gallstones or strictures and pancreatic cancer resulting in biliary obstruction. Albumin.-Plasma protein albumin is exclusively synthesized by the liver and has a circulating half-life of approximately 3 weeks. The normal serum albumin level is ABNORMAL LIVER TEST RESULTS 1091 higher than 3.5 g/dl. A decrease in albumin usually indicates liver disease of more than 3 weeks' duration; however, in any severe illness, albumin can be decreased. Furthermore, in rapidly progressing liver disease, the albumin is used rapidly; thus, albumin levels may be low, even if the duration of liver disease is less than 3 weeks. Prothrombin Time.-The vitamin K-dependent clotting factors are factors II (prothrombin), VII, IX, and X. The prothrombin time may be prolonged if vitamin K is not absorbed (due to cholestasis) or in the presence ofhepatocellular disease. If the prolonged prothrombin time is due to cholestasis, a more than 30% correction is noted in the prothrombin time 24 hours after parenteral administration of vitamin K. In the absence of liver disease, the prothrombin time is prolonged in patients with a dietary vitamin K deficiency and steatorrhea. In fact, the most common cause of a prolonged prothrombin time in patients in intensive-care units is dietary vitamin K deficiency, not liver disease. In patients with liver disease, a good correlation exists between the degree of prolongation of the prothrombin time and prognosis. The prothrombin time can be prolonged in patients with severe liver disease of only 24 hours' duration. It is a far more sensitive index of liver synthetic function than is albumin. Other Tests.-In the presence of autoimmune disease, immunoglobulin levels are higher than 3.0 g/dl., and in PBC, the IgM is increased. An antinuclear antibody greater than 1:160, especially in a homogeneous pattern, and smooth muscle antibody positivity indicate autoimmune liver disease. Antimitochondrial antibody is noted in almost 90% of patients with PBC. Low serum copper and ceruloplasmin levels indicate the presence of Wilson's disease, although ceruloplasmin, being a nonspecific acute phase reactant, may be normal in patients with acute Wilson's disease. A low uric acid concentration also suggests Wilson's disease because patients with this finding often have renal tubular acidosis and lose uric acid in urine. Transferrin saturation of more than 60% in men and more than 50% in women suggests hemochromatosis, and if the ferritin level is higher than 1,000 ug/l, the patient most likely has hemochromatosis. In patients with ai-antitrypsin deficiency, lung disease is noted when ai-antitrypsin levels are lower than 20 mg/dl. In the pathogenesis of liver disease, the absolute level of a l antitrypsin does not seem to be as important; of more importance is the phenotype. Normal persons have the MM phenotype (PiMM), whereas patients with ai-antitrypsin deficiency have the PiZZ phenotype. Serologic markers are essential for the diagnosis of viral hepatitis. A detailed discussion on interpretation of viral serology has been published. In brief, for the diagnosis of acute hepatitis A infection, the IgM hepatitis A virus antibody should be positive. The IgM hepatitis B core antibody

4 1092 ABNORMAL LIVER TEST RESULTS Mayo Clio Proc, November 1996, Vol 71 is positive in acute hepatitis B, and the hepatitis C virus is positive in hepatitis C-related liver disease. APPROACH TO THE PATIENT WITH ABNORMAL LIVER TEST RESULTS A thorough history, physical examination, and biochemical liver tests are sufficient for making an accurate diagnosis of the type of liver disease in at least 80% of patients. The first step is to confirm that the abnormal liver test result actually reflects liver disease. A good "rule of thumb" is to confirm each abnormal liver test result with another test. For example, an AST increase must be confirmed by an ALT increase, an alkaline phosphatase increase must be confirmed either by fractionation or by a GGT increase, and a low albumin level must be confirmed by a prolonged prothrombin time. Several nonhepatic factors cause abnormal results of liver tests. A low albumin level is predominantly due to gastrointestinal loss but can also occur with the nephrotic syndrome, malnutrition, and cardiac failure. The clinical setting is useful for distinguishing these conditions from liver disease. An (Xl-antitrypsin clearance confirms gastrointestinal losses of protein, and a 24-hour urine collection verifies urinary protein loss associated with the nephrotic syndrome. The alkaline phosphatase level can be increased in bone disease, during pregnancy, or in malignant disease, and a useful test for distinguishing these conditions from hepatic causes is electrophoresis of the alkaline phosphatase. AST can be increased in myocardial infarction, in muscle disease, and rarely as macro-ast. In myocardial infarction, the MB fraction of creatine kinase is increased, and in muscle disease, the MM fraction of creatine kinase is increased. The bilirubin level can be increased in hemolysis and in systemic sepsis. In the presence of hemolysis, the reticulocyte count is increased, and the peripheral smear is usually abnormal. Hyperbilirubinemia due to sepsis is diagnosed on the basis of the clinical setting. In fact, the highest values of bilirubinemia (substantially higher than 50 mg/dl) have been noted in sepsis. The prothrombin time can be increased due to nutritional deficiency of vitamin K, with anticoagulants, or in the presence of steatorrhea. Parenteral administration of vitamin K promptly corrects the prothrombin time in patients with steatorrhea and in those with dietary vitamin K deficiency. The second step in making an accurate diagnosis is to categorize the liver disease as hepatocellular, intrahepatic cholestasis, or extrahepatic cholestasis. Of importance, consider common conditions first. A transaminase increase is most commonly related to drugs, NASH, hepatitis C, or alcohol use. An alkaline phosphatase increase of hepatic origin may be related to drugs or a nonhepatic disease such as cardiac failure or hyperthyroidism. The approach to classification of patients with jaundice is presented in Table 1. Table I.-Clinical Approach to the Patient With Jaundice Symptoms Diagnostic factors Physical findings Liver tests Bilirubin Total Direct Alanine aminotransferase Alkaline phosphatase Prothrombin time Corrected by vitamin K Ultrasonography of liver Biliary dilatation Endoscopic retrograde cholangiopancreatography *May or may not be present. Hemolytic May be asymptomatic or back ache, joint pain Splenomegaly <6 mg/dl, <20% Normal Normal Normal No Not necessary Type ofjaundice Intrahepatic Extrahepatic Hepatocellular cholestatic cholestatic Nausea, vomiting, Deep jaundice, Deep jaundice, fever, anorexia dark-colored urine, dark-colored urine, light-colored stools, light-colored stools, pruritus pruritus, cholangitis, biliary colic Tender hepatomegaly, Tender hepatomegaly Hepatomegaly, splenomegaly* palpable gallbladder Variable Variable, may be <30mg/dL >30 mg/dl >50% >50% >50% >5-fold increase 2- to 5-fold increase <2- to 3-fold increase; >3- to 5-fold increase with cholangitis <2- to 3-fold increase >3- to 5-fold increase >3- to 5-fold increase Prolonged Prolonged Prolonged No Variable Yes No No Yes Not necessary Usually not necessary Usually necessary

5 Mayo eli" Proc, November 1996, Vol 71 ABNORMAL LIVER TEST RESULTS 1093 The third step is to make a specific diagnosis. Viral hepatitis is diagnosed on the basis of viral serology; a liver biopsy is rarely necessary. A biopsy may be done, however, in patients with chronic viral hepatitis to help determine the stage of liver disease and prognosis. Drug-induced hepatitis is diagnosed on the basis of the clinical setting. Eosinophil counts may be increased, but this finding is unusual. A liver biopsy is not diagnostic. <xt-antitrypsin deficiency is diagnosed on the basis of the phenotype (PjZZ), whereas autoimmune hepatitis is diagnosed on the basis of long-term increases in liver test results (usually more than 6 months) in the presence of a positive antinuclear antibody and antismooth muscle antibody. A liver biopsy is usually necessary for confirmation of the diagnosis of chronic autoimmune hepatitis and <XI-antitrypsin deficiency but is not essential. In Wilson's disease, the ceruloplasmin level is low, whereas the urinary copper level is high; in hemochromatosis, transferrin saturation is high, and the ferritin is increased. A liver biopsy is essential for the diagnosis of both Wilson's disease and hemochromatosis. In Wilson's disease, the hepatic copper level is more than 250 /-lg/g dry weight of liver, and in hemochromatosis, the iron index is increased. The hepatic iron index is the ratio of the liver concentration of iron to the age of the patient: hepatic iron (/-lg/g dry weight) 56 x age of patient A value greater than 2.0 is diagnostic of genetic hemochromatosis. In NASH, the transaminases are usually increased threefold to fivefold, and the alkaline phosphatase is increased about twofold. On ultrasound examination, the liver has a fatty echo texture, and a liver biopsy, although not always necessary, is diagnostic. Common cholestatic conditions are PBC, primary sclerosing cholangitis, and extrahepatic cholestasis related to gallstones or tumors obstructing the common bile duct. For the diagnosis of PBC, an antimitochondrial antibody should be positive. In primary sclerosing cholangitis, findings on endoscopic retrograde cholangiopancreatography are abnormal. A liver biopsy is essential to stage both PBC and primary sclerosing cholangitis. Extrahepatic cholestasis is diagnosed by ultrasonography or computed tomography of the liver and is confirmed by endoscopic retrograde cholangiopancreatography. A liver biopsy is unnecessary. For the diagnosis of hepatocellular carcinomas and infiltrative diseases of the liver, a biopsy is essential. A somewhat more difficult problem is the diagnostic approach to a patient with isolated increases in AST or alkaline phosphatase (Fig. I and 2, respectively). The aggressiveness of the approach and the need to refer the patient to a subspecialist depend substantially on the clinical situation and the degree of reassurance that the patient needs. The approaches outlined in this review are only guidelines. AST elevated AlT elevation--ffiq}- Other causes of AST elevation IVesl ALT > 3-5 x -lliq}----- Patient symptomatic or 1 Bilirubin/alkaline phosphatase elevated or No 3 e s ALT elevation > 6 months Investigate for liver d i s e a s e Viral serology ANA AMA Copper Ceruloplasmin Ferritin Alpha-1-antitrypsin Liver ultrasound Consider liver biopsy Fig. 1. Approach to patient with elevated aspartate aminotransferase (ASn. ALT = alanine aminotransferase; AMA = antimitochondrial antibody; ANA = antinuclear antibody.

6 1094 ABNORMAL LIVER TEST RESULTS Mayo elin Proe, November 1996, Vol 71 Alkaline phosphatase elevated Liver fraction or GGT elevated IVesl Alk phos > 2 x NoI I Non-hepatic causes NolI Alk phost > 6 months Recheck! Patient syrptomatic 3-6 months 'Vesl LSiliary dilatation on. liver ultrasound,/ \. IVesl INol!! Consider ERCP Ivesl I AMA Consider liver biopsy Fig. 2. Approach to patient with elevated alkaline phosphatase (Alk phos). AMA = antimitochondrial antibody; ERCP =endoscopic retrograde cholangiopancreatography; GGT =y-glutamyltransferase. BIBLIOGRAPHY 1. Litin SC, O'Brien JF, Pruett S, Forsman RW, Burritt MF, Bartholomew LG, et al. Macroenzyme as a cause of unexplained elevation of aspartate aminotransferase. Mayo Clin Proc 1987; 62: Moseley RH. Approach to the patient with abnormal liver chemistries. In: Yamada T, editor. Textbook of Gastroenterology. Vol 1. Philadelphia: Lippincott, 1991: Reichling JJ, Kaplan MM. Clinical use of serum enzymes in liver disease. Dig Dis Sci 1988; 33: Stolz A, Kaplowitz N. Biochemical tests for liver disease. In: Zakim D, Boyer TD, editors. Hepatology: A Textbook of Liver Disease. Vol!. 2nd ed. Philadelphia: Saunders, 1990: Summers KM, Halliday JW, Powell LW. Identification of homozygous hemochromatosis subjects by measurement of hepatic iron index. Hepatology 1990; 12: Zetterman R. Differential diagnosis of patients presenting with jaundice. Gastrointest Dis Today 1995; 4:1-10 Questions About Patients With Abnormal Liver Test Results (See article, pages 1089 to 1094) 1. A 36-year-old man seeks medical attention because of anorexia, nausea, and vomiting of 5 days' duration. He has a low-grade fever and pain in the right upper quadrant of the abdomen. Pertinent history includes consumption of raw oysters during a recent vacation and long-standing alcohol abuse. Because of recurrent back pain, he has been taking acetaminophen (Tylenol), less than 1 g/day. Liver tests yielded the following results: bilirubin, 4.8 mg/dl; alanine aminotransferase, 950 UIL; aspartate aminotransferase, 700 UIL; and alkaline' phosphatase, 480 UIL (normal, less than 251 UIL). Which one of the following is the most likely diagnosis? a. Viral A hepatitis b. Viral E hepatitis c. Alcoholic hepatitis d. Acetaminophen-induced hepatitis e. Alcohol- and acetaminophen-induced hepatitis

7 Mayo Clin Proc, November 1996, Vol 71 ABNORMAL LIVER TEST RESULTS A 39-year-old obese woman has an episode of acute pain in the right upper quadrant of the abdomen, fever, and jaundice. Ultrasonography shows gallstones and some dilatation of the extrahepatic and intrahepatic biliary system. Choledocholithiasis is diagnosed. The earliest abnormal ity in common duct obstruction due to a gallstone is likely to be an increase in which olle of the following? a. Bilirubin b. Alkaline phosphatase c. Amylase d. Aspartate aminotransferase e. Lipase 3. A 48-year-old man with arthriti s and hilar lymphadenopathy is being examined because of a low-grade fever. Results of liver tests are as follow s: bilirubin, 0.8 mg/dl ; alkaline phosphatase, 2,200 UIL; and aspartate aminotransferase, 48 UIL. Which olle of the following studie s would most likely be diagnostic? a. Computed tomography of the liver b. Ultrasonography of the liver c. Endoscopic retrograde cholangiopancreatography d. Liver biopsy e. Magnetic resonance imaging of the liver 4. A 70-year-old woman is admitted to the intensive-care unit to undergo ventilator therapy for chronic obstructive pulmonary disease. After admission, bronchopneumonia is detected, and ceftazidime therapy is initiated. The patient is also receiving intravenously administered crystalloids and has a systolic blood pressure of 85 mm Hg. Results of laboratory tests include leukocyte count, 16 X L; bilirubin, 0.8 mg/dl; aspartate aminotransferase, 45 UIL; alkaline phosphatase, 230 UIL; and prothrombin time, 1.6 intemational normalized ratio. Which olle of the following is the most likely cause for the prolonged prothrombin time? a. Sepsis b. Ceftaz idime c. Vitamin K deficiency d. Early liver failure e. Ischemic hepatitis 5. A 72-year-old man with alcoholic cardiomyopathy is admitted for management of cardiac failure. Medications include furosemide, digoxin, and captopril, which was initiated only 2 weeks previously. On admission of the patient, bilirubin is 3.0 mg/dl, alkaline phosphatase is 600 UIL, and aspartate aminotransferase (AST) is 9,200 UIL. Use of captopril and furosemide are discontinued, and 3 days later results of liver tests are as follows : bilirubin, 3.8 mg/dl ; alkaline phosphatase, 720 UIL; and AST, 400 UIL. Which one of the following is the most likely diagnosis? a. Viral hepatitis b. Alcoholic hepatitis c. Captopril-induced hepatiti s d. Furosemide-induced hepatitis e. Ischemic hepatitis Correct answers: I. G, 2. d, 3. d, 4. c, 5. e