From the Guidelines
Elevated bilirubin with low alkaline phosphatase is most likely indicative of Gilbert's syndrome, a benign condition that does not require treatment or lifestyle modifications. This condition is characterized by a deficiency in the enzyme responsible for conjugating bilirubin in the liver, leading to increased levels of unconjugated bilirubin in the blood 1. The low alkaline phosphatase levels in this scenario help to distinguish Gilbert's syndrome from other liver conditions, such as obstructive liver diseases, which typically present with elevated alkaline phosphatase levels 1. Some key points to consider in the evaluation of elevated bilirubin with low alkaline phosphatase include:
- The majority of measurable bilirubin should be conjugated, even in individuals with significant liver disease, and if the majority of the elevated bilirubin comprises the unconjugated fraction, the cause is virtually always Gilbert’s syndrome 1
- Albumin concentrations can be reduced in many clinical situations, including sepsis, systemic inflammatory disorders, nephrotic syndrome, malabsorption, and gastrointestinal protein loss, and should not be overinterpreted as a marker of liver disease severity 1
- Prothrombin time (PT) and INR are assessments of blood clotting that can be used to measure liver function, but can also be affected by vitamin K deficiency and other factors 1
- A reduction in platelets, or thrombocytopenia, is a common haematological abnormality found in patients with chronic liver disease, and can be caused by multiple factors, including decreased production, splenic sequestration, and increased destruction 1. In patients with symptoms beyond occasional mild jaundice, further evaluation, including liver function tests, complete blood count, and possibly imaging studies, may be recommended to rule out other liver conditions 1. However, in the absence of significant symptoms or other abnormal laboratory findings, Gilbert's syndrome can be diagnosed and patients can be reassured, as this condition is harmless and requires no treatment 1.
From the Research
Implication of Elevated Bilirubin and Low Alkaline Phosphatase
- Elevated bilirubin levels can imply hepatocellular disease or cholestasis, and an elevated conjugated bilirubin level is often associated with these conditions 2.
- Low alkaline phosphatase levels, in combination with elevated bilirubin, may be associated with better outcomes in patients with primary biliary cirrhosis, as seen in a study where lower levels of alkaline phosphatase were associated with longer transplant-free survival 3.
- The evaluation of abnormal liver chemistries, including bilirubin and alkaline phosphatase, should consider the pattern and magnitude of elevation, as well as the clinical context, to guide further testing and treatment 2, 4.
- 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, however, this information is not directly relevant to the implication of elevated bilirubin and low alkaline phosphatase 2.
- The presence of an elevated ALT has been associated with increased liver-related mortality, but this information is not directly relevant to the implication of elevated bilirubin and low alkaline phosphatase 2.
Patterns of Liver Injury
- Hepatocellular injury is defined as disproportionate elevation of AST and ALT levels compared with alkaline phosphatase levels, while cholestatic injury is defined as disproportionate elevation of alkaline phosphatase level as compared with AST and ALT levels 2.
- Elevated total serum bilirubin levels should be fractionated to direct and indirect bilirubin fractions, and an elevated serum conjugated bilirubin implies hepatocellular disease or biliary obstruction in most settings 2.
Clinical Evaluation
- The evaluation of hepatocellular injury includes testing for viral hepatitis A, B, and C, assessment for nonalcoholic fatty liver disease and alcoholic liver disease, screening for hereditary hemochromatosis, autoimmune hepatitis, Wilson's disease, and alpha-1 antitrypsin deficiency, however, this information is not directly relevant to the implication of elevated bilirubin and low alkaline phosphatase 2.
- A liver biopsy may be considered when serologic testing and imaging fails to elucidate a diagnosis, to stage a condition, or when multiple diagnoses are possible, however, this information is not directly relevant to the implication of elevated bilirubin and low alkaline phosphatase 2.