What are the causes of elevated total bilirubin (t bili)?

From the Guidelines

Elevated total bilirubin (t bili) is most commonly caused by unconjugated hyperbilirubinemia, which can result from haemolysis, impaired conjugation, or genetic conditions like Gilbert's syndrome, as seen in up to 10% of the population 1. The causes of elevated total bilirubin can be broadly categorized into two main types: unconjugated and conjugated hyperbilirubinemia. Unconjugated hyperbilirubinemia is usually due to haemolysis or impaired conjugation, whereas conjugated hyperbilirubinemia is typically due to parenchymal liver disease or obstruction of the biliary system 1. Some of the key causes of elevated total bilirubin include:

• Haemolysis, which can lead to an increased breakdown of red blood cells and a subsequent rise in unconjugated bilirubin
• Impaired conjugation, which can be caused by genetic conditions like Gilbert's syndrome or liver disease
• Parenchymal liver disease, which can affect the liver's ability to conjugate and excrete bilirubin
• Obstruction of the biliary system, which can prevent the flow of conjugated bilirubin into the intestine
• Genetic conditions like Gilbert's syndrome, which can affect the enzyme responsible for conjugating bilirubin 1. It is essential to note that 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, in the absence of haemolysis 1. In cases where the conjugated bilirubin is elevated, further evaluation is necessary to determine the underlying cause, which may include liver disease, biliary obstruction, or other conditions 1. In summary, elevated total bilirubin can result from a variety of causes, and a thorough evaluation, including laboratory tests and imaging studies, is necessary to determine the underlying cause and guide treatment 1.

From the Research

Causes of Elevated Total Bilirubin (t bili)

• Elevated total bilirubin levels can be caused by an increase in serum bilirubin, largely as a result of breakdown of red blood cells 2
• Jaundice, which is an indication of hyperbilirubinemia, can be caused by derangements in bilirubin metabolism, and is typically apparent when serum bilirubin levels exceed 3 mg/dL 3
• The liver's inability to properly metabolize or excrete bilirubin can also lead to elevated total bilirubin levels 4
• Clinical and genetic risk factors associated with neonatal severe hyperbilirubinemia include ABO/Rh incompatibility hemolysis, extravascular hemorrhage, weight loss, exclusive breastmilk feeding, and the homozygous mutant of UGT1A1 211G>A 5

Underlying Disease States

• Elevated total bilirubin levels almost always indicate the presence of an underlying disease state 4
• High levels of conjugated bilirubin in a term baby can indicate biliary atresia 2
• Alcoholic liver disease, biliary strictures, choledocholithiasis, drug-induced liver injury, hemolysis, or hepatitis can also cause elevated total bilirubin levels 3

Diagnostic Evaluation

• Evaluation of patients with jaundice starts with a careful history and physical examination, followed by directed imaging of the biliary tree and liver 4, 3
• Laboratory evaluation should include assays for bilirubin (total and fractionated), a complete blood cell count, aspartate transaminase, alanine transaminase, gamma-glutamyltransferase, alkaline phosphatase, albumin, prothrombin time, and international normalized ratio 3
• Measuring fractionated bilirubin allows for determination of whether the hyperbilirubinemia is conjugated or unconjugated 3