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Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia

Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia
Literature review current through: Jan 2024.
This topic last updated: Sep 12, 2023.

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".)

TERMINOLOGY — For clinical purposes, serum bilirubin is fractionated to classify hyperbilirubinemia into one of two major categories (table 1) (see "Classification and causes of jaundice or asymptomatic hyperbilirubinemia"):

Unconjugated hyperbilirubinemia – Unconjugated hyperbilirubinemia is characterized by 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.

Conjugated hyperbilirubinemia – In patients with conjugated hyperbilirubinemia, both unconjugated and conjugated (direct) bilirubin are elevated. This may be due to hepatocellular disease, impaired canalicular excretion of bilirubin, or biliary obstruction.

EVALUATION — The diagnostic approach to the jaundiced patient begins with a careful history, physical examination, and initial laboratory studies [1]. 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. However, patients with these conditions are not asymptomatic. Expedient diagnosis and appropriate therapy can be life-saving in these settings.

History — Multiple clues to the etiology of a patient's hyperbilirubinemia can be obtained from the history information and should include the following (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.

Significant alcohol consumption (>210 grams of alcohol (15 drinks) per week in males, >140 grams of alcohol (10 drinks) per week in females.

Hepatitis risk factors (eg, travel to endemic areas, blood transfusions prior to 1992, intravenous drug use).

History of abdominal operations, including gallbladder surgery.

History of inherited disorders, including liver diseases and hemolytic disorders.

HIV status.

Occupational or recreational exposure to toxic substances.

Associated symptoms that should be elicited include:

Development/worsening of jaundice during times of stress is suggestive of Gilbert syndrome. (See "Gilbert syndrome".)

Fever, particularly when associated with chills or right upper quadrant pain and/or a history of prior biliary surgery, is suggestive of acute cholangitis.

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.

Physical examination — The physical examination may reveal a Courvoisier sign (a palpable gallbladder, caused by obstruction distal to 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 cholangitis [2]. (See "Approach to the patient with abnormal liver biochemical and function tests", section on 'Physical examination'.)

Initial laboratory tests and interpretation — Initial laboratory tests include measurements of the following:

Serum total and unconjugated bilirubin

Alkaline phosphatase

Aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT])

Prothrombin time/international normalized ratio (INR)

Albumin

Assessment of patterns of elevation — Subsequent testing is guided by the predominant pattern of liver injury. Major patterns of injury and their characteristics include the following:

Cholestatic injury pattern  

Disproportionate elevation in the alkaline phosphatase compared with the serum aminotransferases (eg, R value* ≤2)

Serum bilirubin may be elevated

Tests of synthetic function (eg, albumin, prothrombin time) may be abnormal

Hepatocellular injury pattern  

Disproportionate elevation (relative to the upper limit of normal [ULN]) in the serum aminotransferases (ALT and AST) compared with the alkaline phosphatase (eg, R value* ≥5)

Serum bilirubin may be elevated

Tests of synthetic function (eg, albumin, prothrombin time) may be abnormal

Isolated hyperbilirubinemia

Elevated bilirubin level (total or direct) with normal serum aminotransferases and alkaline phosphatase

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.

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).

Subsequent testing based on pattern of liver injury — Subsequent studies are guided based on findings from the history, physical examination, and initial laboratory tests. (See 'Initial laboratory tests and interpretation' above.)

Patients with hyperbilirubinemia and a cholestatic injury pattern — Elevation of the serum alkaline phosphatase out of proportion to the serum aminotransferases suggests biliary obstruction or intrahepatic cholestasis (algorithm 1). (See "Approach to the patient with abnormal liver biochemical and function tests", section on 'Elevated alkaline phosphatase'.)

Hepatic imaging for extrahepatic cholestasis — Testing in patients with elevated bilirubin and alkaline phosphatase of hepatic origin typically starts with right upper quadrant ultrasonography to assess the hepatic parenchyma and bile ducts [3].

The presence of biliary ductal dilatation on imaging suggests extrahepatic cholestasis. If ultrasonography shows biliary ductal dilatation without an apparent cause, advanced imaging with either magnetic resonance cholangiopancreatography (MRCP) or endoscopic ultrasound (EUS) is obtained to confirm biliary ductal dilatation and determine the etiology. Endoscopic retrograde cholangiopancreatography (ERCP) is reserved for therapy to remove stones or stenting a stricture. (See "Choledocholithiasis: Clinical manifestations, diagnosis, and management", section on 'Additional imaging (MRCP or EUS)' and "Overview of endoscopic retrograde cholangiopancreatography (ERCP) in adults".)

The absence of biliary ductal dilatation suggests intrahepatic cholestasis. (See 'Evaluation for intrahepatic cholestasis' below.)

Evaluation for intrahepatic cholestasis — In many cases, a possible cause of intrahepatic cholestasis can be identified based on the patient's history. If a likely source is identified, additional testing may not be required.

Discontinue culprit medications – Any medications or supplements associated with cholestasis should be discontinued.

Laboratory tests – There are numerous possible causes of intrahepatic cholestasis, including primary biliary cholangitis, primary sclerosing cholangitis, viral hepatitis, intrahepatic cholestasis of pregnancy, benign postoperative cholestasis, and infiltrative disease. The testing should be informed by the patient's history and risk factors. Typically, the evaluation starts with testing for primary biliary cholangitis along with any other conditions for which the patient is at increased risk due to history or possible exposure (eg, testing for primary sclerosing cholangitis in a patient with ulcerative colitis, obtaining serum bile acids in a woman who is pregnant).

Primary biliary cholangitis: Antimitochondrial antibody

Primary sclerosing cholangitis: MRCP

Hepatitis A virus: Immunoglobulin M (IgM) antihepatitis A

Hepatitis B virus: Hepatitis B surface antigen, IgM antihepatitis core antigen, antibody to hepatitis B surface antigen

Hepatitis C virus: Antihepatitis C antibody, hepatitis C viral RNA

Hepatitis E virus: Hepatitis E virus antibodies

Cytomegalovirus (CMV): Anti-CMV antibodies, CMV antigen

Epstein-Barr virus: Heterophile antibody

Intrahepatic cholestasis of pregnancy: Serum pregnancy test, serum bile acids

Patients with unexplained cholestasis despite serologic evaluation and imaging, should be referred to a hepatologist for further evaluation and consideration of a liver biopsy to rule out infiltrative disease.

Patients with isolated hyperbilirubinemia — If the alkaline phosphatase and aminotransferases are normal, hyperbilirubinemia is likely not due to hepatic injury or biliary tract disease. Further evaluation is based on the type of hyperbilirubinemia [4]. (See 'Terminology' above.)

Isolated unconjugated hyperbilirubinemia — The initial evaluation of a patient with isolated unconjugated hyperbilirubinemia includes an assessment for hemolytic anemia and discontinuation of medications (eg, rifampin and probenecid) that impair hepatic uptake of bilirubin (algorithm 2). In a patient with a history consistent with Gilbert syndrome (persistent unconjugated hyperbilirubinemia <4 mg/dL, no evidence of hemolysis and normal plasma aminotransferases and alkaline phosphatase concentrations with development of jaundice during times of stress), additional testing is not required. However, patients with unconjugated bilirubin levels ≥4 mg/dL or abnormal aminotransferases should be referred to a hepatologist for further evaluation and consideration of a liver biopsy. (See "Diagnosis of hemolytic anemia in adults" and "Gilbert syndrome" and "Crigler-Najjar syndrome".)

Isolated conjugated hyperbilirubinemia — Conjugated hyperbilirubinemia without other routine liver test abnormalities 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. Differentiating between these syndromes is possible but clinically unnecessary due to their benign nature. (See "Inherited disorders associated with conjugated hyperbilirubinemia".)

Patients with hyperbilirubinemia and a hepatocellular injury pattern — A predominant elevation of serum aminotransferase activity suggests that jaundice is caused by intrinsic hepatocellular disease (table 2). The evaluation is based on the degree and pattern of aminotransferase elevation and is discussed in detail separately. (See "Approach to the patient with abnormal liver biochemical and function tests", section on 'Laboratory tests'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Abnormal liver biochemical tests".)

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 education: Jaundice in adults (The Basics)")

SUMMARY AND RECOMMENDATIONS

Classification of hyperbilirubinemia – For clinical purposes, serum bilirubin is fractionated to classify hyperbilirubinemia into one of two major categories: unconjugated (indirect) hyperbilirubinemia and conjugated (direct) hyperbilirubinemia. Unconjugated hyperbilirubinemia is characterized by 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. In patients with conjugated hyperbilirubinemia, both unconjugated and conjugated (direct) bilirubin are elevated. This may be due to hepatocellular disease, impaired canalicular excretion of bilirubin, or biliary obstruction. (See 'Terminology' above.)

Historical clues – Multiple clues to the etiology of hyperbilirubinemia can be obtained from the history (see 'History' above):

Use of medications, herbal medications, dietary supplements, and recreational drugs

Significant alcohol consumption (>210 grams of alcohol (15 drinks) per week in males, >140 grams of alcohol (10 drinks) per week in females

Hepatitis risk factors (eg, travel to endemic areas, blood transfusions prior to 1992, intravenous drug use)

History of abdominal operations, including gallbladder surgery

History of inherited disorders, including liver diseases and hemolytic disorders

HIV status

Occupational or recreational exposure to toxic substances

Associated symptoms (eg, fever, right upper quadrant pain, myalgias)

Laboratory evaluation – Initial laboratory tests include measurements of serum total and unconjugated bilirubin, alkaline phosphatase, aminotransferases (aspartate aminotransferase and alanine aminotransferase), prothrombin time/international normalized ratio, and albumin. Subsequent testing is guided by the predominant pattern of liver injury. (See 'Initial laboratory tests and interpretation' above.)

Additional testing to determine etiology of hyperbilirubinemia based on pattern of liver tests

Conjugated hyperbilirubinemia and elevated alkaline phosphatase – Elevation of the serum alkaline phosphatase out of proportion to the serum aminotransferases suggests biliary obstruction or intrahepatic cholestasis. Testing in patients with elevated bilirubin and alkaline phosphatase of hepatic origin typically starts with right upper quadrant ultrasonography to assess the hepatic parenchyma and bile ducts (algorithm 1). The absence of biliary ductal dilatation suggests intrahepatic cholestasis. (See 'Patients with hyperbilirubinemia and a cholestatic injury pattern' above.)

Conjugated hyperbilirubinemia and hepatocellular injury – A predominant elevation of serum aminotransferase activity suggests that jaundice is caused by intrinsic hepatocellular disease (table 2). The evaluation is based on the degree and pattern of aminotransferase elevation and is discussed in detail separately. (See "Approach to the patient with abnormal liver biochemical and function tests", section on 'Elevated serum aminotransferases'.)

Isolated unconjugated hyperbilirubinemia – The evaluation of unconjugated hyperbilirubinemia typically involves evaluation for hemolytic anemia, drugs that impair hepatic uptake of bilirubin, and Gilbert syndrome (algorithm 2). However, patients with unconjugated bilirubin levels ≥4 mg/dL or abnormal aminotransferases should be referred to a hepatologist for further evaluation and consideration of a liver biopsy. (See 'Isolated unconjugated hyperbilirubinemia' above.)

Isolated conjugated hyperbilirubinemia – Conjugated hyperbilirubinemia without other routine liver test abnormalities 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.)

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