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Official reprint from UpToDate www.uptodate.com 2013 UpToDate

Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia Authors Namita Roy-Chowdhury, PhD Jayanta Roy-Chowdhury, MD, MRCP Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2013. | This topic last updated: Jun 19, 2013. INTRODUCTION Jaundice and asymptomatic hyperbilirubinemia are common clinical problems that can be caused by a variety of disorders, including bilirubin overproduction, impaired bilirubin conjugation, biliary obstruction, and hepatic inflammation. (See "Classification and causes of jaundice or asymptomatic hyperbilirubinemia".) This topic will provide an overview of the diagnostic approach to adults with jaundice or asymptomatic hyperbilirubinemia. The causes of jaundice and asymptomatic hyperbilirubinemia, detailed discussions of the specific testing used, and the evaluation of patients with other liver test abnormalities are discussed elsewhere. (See "Classification and causes of jaundice or asymptomatic hyperbilirubinemia" and "Approach to the patient with abnormal liver biochemical and function tests".) CAUSES OF HYPERBILIRUBINEMIA For clinical purposes, serum bilirubin is fractionated to classify hyperbilirubinemia into one of two major categories (table 1) (see "Clinical aspects of serum bilirubin determination"): Plasma elevation of predominantly unconjugated (indirect) bilirubin. This may be due to the overproduction of bilirubin, impaired bilirubin uptake by the liver, or abnormalities of bilirubin conjugation (algorithm 1). Plasma elevation of both unconjugated and conjugated (direct) bilirubin. This may be due to hepatocellular disease, impaired canalicular excretion of bilirubin, or biliary obstruction (algorithm 2). This is often referred to as conjugated hyperbilirubinemia, even though both fractions of bilirubin are elevated. Once the hyperbilirubinemia has been classified, the differential diagnosis can be narrowed. (See "Classification and causes of jaundice or asymptomatic hyperbilirubinemia".) Unconjugated hyperbilirubinemia may be caused by (table 1): Hemolysis Extravasation of blood into tissue Dyserythropoiesis Stress situations (eg, sepsis) leading to increased production of bilirubin Impaired hepatic bilirubin uptake Impaired bilirubin conjugation Conjugated hyperbilirubinemia may be caused by (table 1 and table 2): Biliary obstruction (eg, gallstones, pancreatic or biliary malignancy, AIDS cholangiopathy, parasites) Viral hepatitis Alcoholic hepatitis Nonalcoholic steatohepatitis Section Editor Sanjiv Chopra, MD Deputy Editor Anne C Travis, MD, MSc, FACG

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Primary biliary cirrhosis Drugs and toxins Ischemic hepatopathy Liver infiltration Inherited disorders (eg, Dubin-Johnson syndrome, Rotor syndrome, progressive familial intrahepatic cholestasis) Total parenteral nutrition Postoperative jaundice Intrahepatic cholestasis of pregnancy End-stage liver disease Organ transplantation (eg, bone marrow, liver) The frequency with which the different causes occur varies with age and the population being studied. One report, for example, evaluated the principal diagnoses obtained in 702 adults presenting with jaundice to 24 Dutch hospitals over a two-year period [1]. Pancreatic or biliary carcinoma accounted for 20 percent, gallstones for 13 percent, and alcoholic cirrhosis for 10 percent. In some cases, two or more factors contribute to the development of jaundice. This is particularly true in the following settings: sickle cell anemia, organ transplantation or surgery in general, total parenteral nutrition, and AIDS. When evaluating these patients, it is necessary to take into account the underlying illness, the type of therapy administered (eg, drugs, surgery), and the possible associated complications. DIAGNOSTIC EVALUATION The diagnostic approach to the jaundiced patient begins with a careful history, physical examination, and initial laboratory studies. A differential diagnosis is formulated based on those results and additional testing is performed to narrow the diagnostic possibilities. Although the evaluation is usually not urgent, jaundice can reflect a medical emergency in a few situations. These include massive hemolysis (eg, due to Clostridium perfringens sepsis or falciparum malaria), ascending cholangitis, and fulminant hepatic failure. Expedient diagnosis and appropriate therapy can be life-saving in these settings. History and physical examination Multiple clues to the etiology of a patients hyperbilirubinemia can be obtained from the history, which should seek the following information (see "Approach to the patient with abnormal liver biochemical and function tests", section on 'History'): Use of medications, herbal medications, dietary supplements, and recreational drugs Use of alcohol Hepatitis risk factors (eg, travel, possible parenteral exposures) History of abdominal operations, including gallbladder surgery History of inherited disorders, including liver diseases and hemolytic disorders HIV status Exposure to toxic substances Associated symptoms Associated symptoms often help narrow the differential diagnosis. As examples: A history of fever, particularly when associated with chills or right upper quadrant pain and/or a history of prior biliary surgery, is suggestive of acute cholangitis. Symptoms such as anorexia, malaise, and myalgias may suggest viral hepatitis. Right upper quadrant pain suggests extrahepatic biliary obstruction. Acholic stool (also termed clay colored stool) refers to stool without the yellow-brown color, which is normally derived mainly from the bilirubin breakdown products, urobilin and stercobilin. Although rare, it can also be seen in the acute cholestatic phase of viral hepatitis and in prolonged near-complete common bile duct obstruction from cancer of the pancreatic head or the duodenal ampulla. The physical examination may reveal a Courvoisier sign (a palpable gallbladder, caused by obstruction distal to

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the takeoff of the cystic duct by malignancy) or signs of chronic liver failure/portal hypertension such as ascites, splenomegaly, spider angiomata, and gynecomastia. Certain findings suggest specific diseases, such as hyperpigmentation in hemochromatosis, Kayser-Fleischer rings in Wilson disease, and xanthomas in primary biliary cirrhosis. (See "Approach to the patient with abnormal liver biochemical and function tests", section on 'Physical examination'.) Initial laboratory tests Initial laboratory tests include measurements of serum total and unconjugated bilirubin, alkaline phosphatase, aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), prothrombin time/international normalized ratio (INR), and albumin. The presence or absence of abnormalities and the type of abnormalities should help to distinguish the various causes of jaundice. (See "Approach to the patient with abnormal liver biochemical and function tests", section on 'Laboratory tests'.) However, while liver tests provide a broad guideline for the initial distinction between the different causes of jaundice, exceptions do occur. As an example, viral hepatitis, which normally presents primarily with an elevation of serum aminotransferases, may present as a predominantly cholestatic syndrome with marked pruritus. Normal alkaline phosphatase and aminotransferases If the alkaline phosphatase and aminotransferases are normal, the jaundice is likely not due to hepatic injury or biliary tract disease. In such patients, hemolysis or inherited disorders of bilirubin metabolism may be responsible for the hyperbilirubinemia. The inherited disorders associated with isolated unconjugated hyperbilirubinemia are Gilbert's and Crigler-Najjar syndromes; the disorders associated with isolated conjugated hyperbilirubinemia are Rotor and Dubin-Johnson syndromes. (See "Approach to the diagnosis of hemolytic anemia in the adult" and "Gilbert's syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction" and "Crigler-Najjar syndrome".) Predominant alkaline phosphatase elevation Elevation of the serum alkaline phosphatase out of proportion to the serum aminotransferases suggests biliary obstruction or intrahepatic cholestasis. Increased serum alkaline phosphatase is also found in granulomatous liver diseases, such as tuberculosis or sarcoidosis. These conditions may or may not be associated with jaundice. (See "Approach to the patient with abnormal liver biochemical and function tests", section on 'Elevated alkaline phosphatase'.) An elevation in the serum alkaline phosphatase concentration can also be derived from extrahepatic tissues, particularly bone. Extrahepatic disorders do not cause jaundice except in rare cases, such as bone tumors metastasizing to the liver. If necessary, the serum activities of the canalicular enzymes gamma-glutamyl transpeptidase (GGT) and 5'-nucleotidase can be measured to confirm the hepatic origin of alkaline phosphatase (algorithm 3). (See "Enzymatic measures of cholestasis (eg, alkaline phosphatase, 5-nucleotidase, gamma-glutamyl transpeptidase)".) Predominant aminotransferase elevation A predominant elevation of serum aminotransferase activity suggests that jaundice is caused by intrinsic hepatocellular disease (table 2). The pattern of the elevation may help identify a specific cause. (See "Approach to the patient with abnormal liver biochemical and function tests", section on 'Laboratory tests'.) As an example, alcoholic hepatitis is associated with a disproportionate elevation of the AST compared with the ALT. The AST elevation is usually less than eight times the upper limit of normal, and the ALT elevation is typically less than five times the upper limit of normal. The AST to ALT ratio is usually greater than 2.0, a value rarely seen in other forms of liver disease. (See "Clinical manifestations and diagnosis of alcoholic fatty liver disease and alcoholic cirrhosis", section on 'Liver test abnormalities'.) Elevated INR An elevated INR that corrects with vitamin K administration suggests impaired intestinal absorption of fat-soluble vitamins and is compatible with obstructive jaundice. On the other hand, an elevated INR that does not correct with vitamin K suggests moderate to severe hepatocellular disease with impaired synthetic function (particularly if unexplained hypoalbuminemia is also present). Subsequent evaluation Subsequent studies are guided based on findings from the history, physical examination, and initial laboratory tests. Unconjugated hyperbilirubinemia The evaluation of unconjugated hyperbilirubinemia typically involves evaluation for hemolytic anemia, drugs that impair hepatic uptake of bilirubin, and Gilbert's syndrome (algorithm 1). In a patient with a history consistent with Gilbert's syndrome (eg, the development of jaundice during times of

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stress) additional testing is not required. If this initial evaluation is negative and the unconjugated hyperbilirubinemia persists, other causes should be sought (eg, Crigler-Najjar syndrome). (See "Approach to the patient with abnormal liver biochemical and function tests", section on 'Unconjugated (indirect) hyperbilirubinemia'.) Conjugated hyperbilirubinemia In patients with conjugated hyperbilirubinemia, the evaluation will be based on whether the abnormalities are likely due to biliary obstruction, intrahepatic cholestasis, hepatocellular injury, or an inherited condition (based on the presence of isolated conjugated hyperbilirubinemia) (algorithm 2). Suspected biliary obstruction or intrahepatic cholestasis If there is evidence of biliary obstruction or intrahepatic cholestasis (eg, elevated conjugated bilirubin and alkaline phosphatase), the first step in the evaluation is hepatic imaging (eg, ultrasound, magnetic resonance cholangiopancreatography [MRCP], endoscopic retrograde cholangiopancreatography [ERCP]) to look for evidence of intra- or extrahepatic bile duct dilation [2]. If imaging is negative, the evaluation typically will also include obtaining an antimitochondrial antibody to evaluate for primary biliary cirrhosis. (See "Approach to the patient with abnormal liver biochemical and function tests", section on 'Evaluation of elevated alkaline phosphatase'.) In most instances, abdominal ultrasound (and less often spiral computed tomography [CT] scan) is the first imaging test obtained in patients with suspected biliary obstruction with unknown etiology [2]. (See "Approach to the patient with abnormal liver biochemical and function tests", section on 'Evaluation of elevated alkaline phosphatase'.) However, in some cases, other imaging studies may be more appropriate as initial tests: In the patient with a low probability of obstruction, abdominal CT should be performed and, in the absence of evidence of obstruction, further evaluation should be directed towards causes of hepatocellular disease. If, on the other hand, dilated biliary ducts are visualized, direct imaging of the biliary tree (eg, with ERCP) should be performed. In the patient with a high expectation of extrahepatic obstruction, endoscopic ultrasound (EUS) or ERCP can be the initial screening procedure, since a negative US would not preclude the subsequent performance of ERCP. One study performed percutaneous transhepatic cholangiography (PTC) in 107 patients with clinically suspected bile duct abnormalities but nondilated intrahepatic ducts on CT or ultrasound [3]. The cholangiogram was diagnostic in 72 patients (67 percent) and 31 (43 percent) showed poor emptying, stones, or strictures. Because of a high rate of complications, the authors to suggest that ERCP was preferable to PTC in patients with nondilated ducts. In the patient with evidence of obstruction but little clue as to the distinction between intrahepatic and extrahepatic disease, a screening ultrasound may provide information useful in determining the optimal use of EUS or ERCP versus intrahepatic cholangiography. Decision analysis studies suggest that EUS may be preferred in this setting when there is an intermediate probability of obstruction [4]. The imaging tests used in the evaluation of biliary obstruction are discussed in detail elsewhere. (See "Approach to the patient with suspected choledocholithiasis", section on 'Imaging tests' and "Ultrasonography of the hepatobiliary tract" and "Computed tomography of the hepatobiliary tract" and "Magnetic resonance cholangiopancreatography" and "Overview of indications for and complications of ERCP and endoscopic biliary sphincterotomy" and "Endoscopic ultrasound in patients with suspected choledocholithiasis" and "Percutaneous transhepatic cholangiography".) Suspected hepatocellular injury If there is evidence of hepatocellular injury (eg, a predominant elevation of serum aminotransferases), serologic testing should be performed to evaluate for causes of hepatocellular dysfunction. (See 'Predominant aminotransferase elevation' above and "Approach to the patient with abnormal liver biochemical and function tests", section on 'Elevated serum aminotransferases' and "Diagnostic approach to the patient with cirrhosis", section on 'Determining the cause of cirrhosis'.) Testing should include: Serologic tests for viral hepatitis

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Measurement of antimitochondrial antibodies (for primary biliary cirrhosis) Measurement of antinuclear anti-smooth muscle and liver-kidney microsomal antibodies (for autoimmune hepatitis) Serum levels of iron, transferrin, and ferritin (for hemochromatosis) Thyroid function tests Antibody screening for celiac disease Additional testing may also include (based on the clinical scenario): Serum levels of ceruloplasmin (for Wilson disease) Measurement of alpha-1 antitrypsin activity (for alpha-1 antitrypsin deficiency) Testing for adrenal insufficiency In some cases, liver biopsy may be required to confirm the diagnosis. Isolated conjugated hyperbilirubinemia Isolated conjugated hyperbilirubinemia is found in two rare inherited conditions: Dubin-Johnson syndrome and Rotor syndrome. Dubin-Johnson syndrome and Rotor syndrome should be suspected in patients with mild hyperbilirubinemia (with a conjugated fraction of approximately 50 percent) in the absence of other abnormalities of standard liver biochemical tests. Normal levels of serum alkaline phosphatase and GGT help to distinguish these conditions from disorders associated with biliary obstruction. Differentiating between these syndromes is possible but clinically unnecessary due to their benign nature. (See "Inherited disorders associated with conjugated hyperbilirubinemia".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient information: Jaundice in adults (The Basics)") SUMMARY AND RECOMMENDATIONS For clinical purposes, serum bilirubin is fractionated to classify hyperbilirubinemia into one of two major categories: unconjugated (indirect) hyperbilirubinemia and conjugated (direct) hyperbilirubinemia (table 1). This classification, along with findings from the history, physical examination, and initial laboratory testing is used to narrow the diagnostic possibilities and guide the subsequent evaluation. (See 'Causes of hyperbilirubinemia' above.) Multiple clues to the etiology of hyperbilirubinemia can be obtained from the history, which should seek the following information (see 'History and physical examination' above): Use of medications or recreational drugs (see "Drugs and the liver: Patterns of drug-induced liver injury") Use of dietary supplements or herbal medications (see "Hepatotoxicity due to herbal medications and dietary supplements") Use of alcohol (see "Screening for unhealthy use of alcohol and other drugs") Hepatitis risk factors (eg, travel, parenteral exposure) History of abdominal operations, including gallbladder surgery History of inherited disorders including liver diseases and hemolytic disorders

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HIV status Exposure to toxic substances Initial laboratory tests include measurements of serum total and unconjugated bilirubin, alkaline phosphatase, aminotransferases (aspartate aminotransferase and alanine aminotransferase), prothrombin time/international normalized ratio (INR), and albumin. The presence or absence of abnormalities and the type of abnormalities help distinguish the various causes of jaundice (algorithm 1 and algorithm 2). If the alkaline phosphatase and aminotransferases are normal, the jaundice is likely not due to hepatic injury or biliary tract disease. In such patients, hemolysis or inherited disorders of bilirubin metabolism may be responsible for the hyperbilirubinemia. (See 'Normal alkaline phosphatase and aminotransferases' above.) Elevation of the serum alkaline phosphatase out of proportion to the serum aminotransferases suggests biliary obstruction or intrahepatic cholestasis. (See 'Predominant alkaline phosphatase elevation' above.) A predominant elevation of serum aminotransferase activity suggests that jaundice is caused by intrinsic hepatocellular disease (table 2). (See 'Predominant aminotransferase elevation' above.) An elevated INR that corrects with vitamin K administration suggests impaired intestinal absorption of fat-soluble vitamins and is compatible with obstructive jaundice. On the other hand, an elevated INR that does not correct with vitamin K suggests moderate to severe hepatocellular disease with impaired synthetic function (particularly if unexplained hypoalbuminemia is also present). (See 'Elevated INR' above.) The evaluation of unconjugated hyperbilirubinemia typically involves evaluation for hemolytic anemia, drugs that impair hepatic uptake of bilirubin, and Gilbert's syndrome (algorithm 1). (See 'Unconjugated hyperbilirubinemia' above.) If there is evidence of biliary obstruction or intrahepatic cholestasis (eg, elevated conjugated bilirubin and alkaline phosphatase), the first step in the evaluation is hepatic imaging (eg, ultrasound, magnetic resonance cholangiopancreatography [MRCP], endoscopic retrograde cholangiopancreatography [ERCP]) to look for evidence of intra- or extrahepatic bile duct dilation. If imaging is negative, the evaluation typically will also include obtaining an antimitochondrial antibody to evaluate for primary biliary cirrhosis. (See 'Suspected biliary obstruction or intrahepatic cholestasis' above.) If there is evidence of hepatocellular injury (eg, a predominant elevation of serum aminotransferases), serologic testing should be performed to evaluate for causes of hepatocellular dysfunction, such as viral hepatitis, alcoholic liver disease, and metabolic liver disease (table 2 and table 3). (See 'Suspected hepatocellular injury' above.) Isolated conjugated hyperbilirubinemia is found in two rare inherited conditions: Dubin-Johnson syndrome and Rotor syndrome. Normal levels of serum alkaline phosphatase and gamma-glutamyl transpeptidase help distinguish these conditions from disorders associated with biliary obstruction. (See 'Isolated conjugated hyperbilirubinemia' above.)

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Reisman Y, Gips CH, Lavelle SM, Wilson JH. Clinical presentation of (subclinical) jaundice--the Euricterus project in The Netherlands. United Dutch Hospitals and Euricterus Project Management Group. Hepatogastroenterology 1996; 43:1190. 2. Saini S. Imaging of the hepatobiliary tract. N Engl J Med 1997; 336:1889.

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3. Teplick SK, Flick P, Brandon JC. Transhepatic cholangiography in patients with suspected biliary disease and nondilated intrahepatic bile ducts. Gastrointest Radiol 1991; 16:193. 4. Sahai AV, Mauldin PD, Marsi V, et al. Bile duct stones and laparoscopic cholecystectomy: a decision analysis to assess the roles of intraoperative cholangiography, EUS, and ERCP. Gastrointest Endosc 1999; 49:334. Topic 3620 Version 7.0

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GRAPHICS
Classification of jaundice according to type of bile pigment and mechanism
Unconjugated hyperbilirubinemia
Increased bilirubin production* Extravascular hemolysis Extravasation of blood into tissues Intravascular hemolysis Dyserythropoiesis Impaired hepatic bilirubin uptake Heart failure Portosystemic shunts Some patients with Gilbert's syndrome Certain drugs - rifampin, probenecid, flavaspadic acid, bunamiodyl Impaired bilirubin conjugation Crigler-Najjar syndrome types I and II Gilbert's syndrome Neonates Hyperthyroidism Ethinyl estradiol Liver diseases - chronic hepatitis, advanced cirrhosis, Wilson disease

Conjugated hyperbilirubinemia
Extrahepatic cholestasis (biliary obstruction) Choledocholithiasis Intrinsic and extrinsic tumors - eg, cholangiocarcinoma Primary sclerosing cholangitis AIDS cholangiopathy Acute and chronic pancreatitis Strictures after invasive procedures Certain parasitic infections - eg, Ascaris lumbricoides, liver flukes Intrahepatic cholestasis Viral hepatitis Alcoholic hepatitis Nonalcoholic steatohepatitis Chronic hepatitis Primary biliary cirrhosis Drugs and toxins - eg, alkylated steroids, chlorpromazine, herbal medications (eg, Jamaican bush tea), arsenic Sepsis and hypoperfusion states Infiltrative diseases - eg, amyloidosis, lymphoma, sarcoidosis, tuberculosis Total parenteral nutrition Postoperative cholestasis Following organ transplantation Hepatic crisis in sickle cell disease Pregnancy End-stage liver disease

AIDS: acquired immunodeficiency syndrome. * Serum bilirubin concentration usually less than 4 mg/dL (68 mmol/L) in the absence of underlying liver disease. The hyperbilirubinemia induced by drugs usually resolves within 48 hours after the drug is discontinued.

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Classification of jaundice due to mainly unconjugated hyperbilirubinemia

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Classification of jaundice due to both conjugated and unconjugated hyperbilirubinemia

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Differential diagnosis of hepatocellular jaundice

Neoplasms
Hepatocellular carcinoma Cholangio carcinoma Metastases (bronchogenic, GI-tract, breast, GU-tract) Lymphoma Hemangioendothelioma Hepatoblastoma

Infections
Viral Hepatitis viruses Herpes viruses "Hemorrhagic" viruses: yellow fever, Ebola, Marburg, Lassa Adenoviruses, enteroviruses, etc Bacterial Tuberculosis, leptospirosis, syphilis, pyogenic abscess, brucella, rickettsia, tropheryma whippelii, rochalimea Parasitic Helminths: ascaris, fasciola, clonorchis, schistosomiasis, echinococcosis Protozoa: amebiasis, plasmodia, babesiosis, toxoplasmosis, leishmaniasis Fungal Candida, blastomyces, coccidioides, histoplasma, cryptococcus

Metabolic/hereditary
Wilson's disease Alpha-1-antitrypsin deficiency Hemochromatosis Porphyrias Congenital hepatic fibrosis Fibropolycystic disease

Systemic
Acute ischemia Severe heart failure Tricuspid insufficiency Constrictive pericarditis Budd-Chiari syndrome Venoocclusive disease Telangiectasias Sarcoidosis Amyloidosis

Toxic/immunologic
Medications (allergic, idiosyncratic) Alcohol Chlorinated hydrocarbons (carbon tetrachloride, chloroform) Amanita phalloides toxin Aflatoxin B1 Vitamin A Pyrrolizidine alkaloids Arsenic Phosphorous Autoimmune Hepatitis Primary biliary cirrhosis Primary sclerosing cholangitis Overlap syndrome Autoimmune cholangiopathy Nonalcoholic steatohepatitis

Miscellaneous
Secondary biliary cirrhosis Cryptogenic cirrhosis

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Evaluation of elevated serum alkaline phosphatase

AMA: antimitochondrial antibodies; ERCP: endoscopic retrograde cholangiopancreatography; MRCP: magnetic resonance cholangiopancreatography; ULN: upper limit of normal.

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Common causes of abnormal liver blood tests

Disease
Alcoholic liver disease

Tests and findings

History of alcohol abuse AST/ALT >2 with both being less than 500 IU/mL if alcoholic hepatitis is present

Chronic hepatitis C

ELISA assay for anti-HCV PCR for HCV RNA if confirmatory test is necessary

Primary biliary cirrhosis Primary sclerosing cholangitis

Antimitochondrial antibodies as an isolated finding

Strong association with inflammatory bowel disease Contrastcholangiography to establish the diagnosis Antinuclear and antismoothmuscle antibodies and ANCA; these are not diagnostic

Autoimmune hepatitis

Hypergammaglobulinemia Antinuclear and antismooth muscle antibodies and ANCA in type 1; anti-LKM-1 in type 2

Chronic hepatitis B

HBsAg and HBeAg and, in some cases, HBV DNA by hybridization or bDNA assay Family history of cirrhosis Transferrin saturation and plasma ferritin should be performed but may be elevated by liver disease itself Diagnosis established by liver biopsy and calculation of hepatic iron index or by genetic testing

Hereditary hemochromatosis

Wilson disease

Family or personal history of cirrhosis at a young age Serumceruloplasmin reduced in 95 percent of patients Liver biopsy showsincreased copper content which may also be seen in cholestatic liver diseases

Alpha-1-antitrypsin deficiency Nonalcoholic fatty liver disease

Family or personal history of cirrhosis at a young age Serum AAT; phenotyping if low or borderline values History of diabetes mellitus or metabolic syndrome Diagnosis maybe suspected by abnormal liver biochemical tests and hepatic imagingshowing fatty infiltration and is confirmed by liver biopsy

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