What does an elevation of both direct (conjugated) bilirubin and indirect (unconjugated) bilirubin indicate?

From the Guidelines

Elevated direct and indirect bilirubin levels indicate a complex liver dysfunction, suggesting both an obstruction of bile flow and an impairment in the liver's ability to process bilirubin, which may be due to conditions like hepatitis, cirrhosis, or genetic disorders, and warrants prompt medical evaluation. When direct (conjugated) bilirubin is elevated, it suggests that bile flow from the liver is obstructed, commonly due to conditions like gallstones, liver disease, or certain medications affecting the liver, as stated in the guidelines on the management of abnormal liver blood tests 1. Elevated indirect (unconjugated) bilirubin typically points to excessive red blood cell destruction (hemolysis), genetic conditions like Gilbert's syndrome, or impaired liver uptake of bilirubin, with the majority of measurable bilirubin being conjugated, even in individuals with significant liver disease, except in the neonatal period 1. Some key points to consider in the evaluation of abnormal liver blood tests include:

• The pattern and degree of elevation of bilirubin levels help physicians determine the underlying cause and appropriate treatment approach.
• The measurement of γ-glutamyltransferase can indicate whether the ALP is of hepatic or non-hepatic origin 1.
• In neonates and infants, referral to a paediatrician for urgent assessment of possible liver disease is essential if the conjugated bilirubin is >25 μmol/L 1.
• A reduction in platelets, termed thrombocytopenia, is the most common haematological abnormality found in patients with chronic liver disease and is an indicator of advanced disease 1. The american gastroenterological association medical position statement: evaluation of liver chemistry tests 1 provides guidelines for the interpretation and evaluation of abnormal serum liver chemistries, including the use of computerized tomography or abdominal magnetic resonance imaging, and liver biopsy in certain cases. However, the most recent and highest quality study, the guidelines on the management of abnormal liver blood tests 1, published in 2018, should be prioritized in the evaluation and management of patients with elevated direct and indirect bilirubin levels.

From the Research

Elevated Direct and Indirect Bilirubin

Elevated plasma bilirubin levels can be secondary to alterations in any stage of its metabolism, including:

• Excess bilirubin production (i.e., pathologic hemolysis) 2
• Impaired liver uptake, with elevation of indirect bilirubin 2
• Impaired conjugation, prompted by a defect in the UDP-glucuronosyltransferase 2
• Bile clearance defect, with elevation of direct bilirubin secondary to defects in clearance proteins, or inability of the bile to reach the small bowel through bile ducts 2

Causes of Elevated Bilirubin

Some possible causes of elevated bilirubin include:

• Liver lesion of any cause, which reduces hepatocyte cell number and may impair the uptake of indirect bilirubin from plasma and diminish direct bilirubin transport and clearance through the bile ducts 2
• Bile duct obstruction, which can cause an elevation of direct bilirubin 3
• Common bile duct stones, which can cause an elevation of bilirubin 4

Diagnostic Methods

Various analytical methods are available for measuring bilirubin and its metabolites in serum, urine, and feces, including:

• Diazo transfer reaction, currently the gold-standard 2
• High-performance liquid chromatography (HPLC) 2
• Oxidative, enzymatic, and chemical methods 2
• Direct spectrophotometry 2
• Transcutaneous methods 2
• Ultrasound imaging of the liver and bile ducts 5, 4
• Endoscopic ultrasound (EUS) 6