From the Guidelines
The workup of direct bilirubinemia should begin with a thorough history and physical examination, followed by laboratory and imaging studies, with ultrasound of the liver and biliary system as the first-line imaging study to evaluate for biliary obstruction, as recommended by the American College of Radiology in 2019 1. The initial laboratory tests should include a complete liver panel (ALT, AST, alkaline phosphatase, GGT), complete blood count, coagulation studies (PT/INR), and hepatitis serologies.
- Key laboratory tests to identify the underlying cause of direct bilirubinemia include:
- Complete liver panel to assess liver function and identify potential liver damage
- Hepatitis serologies to rule out hepatitis as a cause of liver dysfunction
- Coagulation studies to assess the patient's coagulation status and risk of bleeding
- Imaging studies, such as ultrasound, can help evaluate for biliary obstruction, gallstones, or structural abnormalities, and guide further testing and treatment. If ultrasound is inconclusive, magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) may be necessary to further evaluate the biliary tree, as suggested by the European Association for the Study of the Liver in 2009 1. Additional testing may include autoimmune markers (ANA, anti-smooth muscle antibody, anti-mitochondrial antibody), ceruloplasmin levels to rule out Wilson's disease, alpha-1 antitrypsin levels, and iron studies, as recommended by the American Gastroenterological Association in 2002 1. In cases where the diagnosis remains unclear after non-invasive testing, a liver biopsy may be required to establish a definitive diagnosis and guide treatment. The workup should be tailored to the patient's age, as neonatal direct hyperbilirubinemia has different etiologies than adult cases, potentially requiring genetic testing for conditions like progressive familial intrahepatic cholestasis or Alagille syndrome, and should prioritize the patient's morbidity, mortality, and quality of life as the primary outcome.
From the Research
Evaluation of Direct Bilirubinemia
To work up direct bilirubinemia, the following steps can be taken:
- Assess abnormal liver chemistries, including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and bilirubin levels 2
- Fractionate total bilirubin elevation to direct and indirect bilirubin fractions to determine the cause of the elevation 2
- Evaluate for hepatocellular disease or biliary obstruction, as an elevated serum conjugated bilirubin implies one of these conditions in most settings 2
- Consider testing for viral hepatitis A, B, and C, nonalcoholic fatty liver disease, alcoholic liver disease, hereditary hemochromatosis, autoimmune hepatitis, Wilson's disease, and alpha-1 antitrypsin deficiency 2
- Assess for primary biliary cholangitis and primary sclerosing cholangitis if the alkaline phosphatase elevation is determined to be of hepatic origin 2
- Consider a liver biopsy if serologic testing and imaging fail to elucidate a diagnosis, to stage a condition, or when multiple diagnoses are possible 2
Laboratory Tests
The following laboratory tests can be used to evaluate direct bilirubinemia:
- Serum ALT and AST levels to assess for hepatocellular injury 2
- Alkaline phosphatase level to assess for cholestatic injury 2
- Total bilirubin level to assess for elevation 2
- Direct and indirect bilirubin fractions to determine the cause of the elevation 2
Clinical Considerations
The degree of elevation of ALT and/or AST can help guide the evaluation of direct bilirubinemia 2 A true healthy normal ALT level ranges from 29 to 33 IU/l for males, 19 to 25 IU/l for females, and levels above this should be assessed 2 A history of prescribed and over-the-counter medicines should be sought to rule out drug-induced liver injury 2