From the Guidelines
Elevated total hyperbilirubinemia is primarily caused by an imbalance in the production, uptake, conjugation, or excretion of bilirubin, with common causes including hemolytic disorders, liver diseases, genetic conditions, biliary obstruction, and certain medications, as noted in the guidelines on the management of abnormal liver blood tests 1. The causes of elevated total hyperbilirubinemia can be broadly categorized into pre-hepatic, hepatic, and post-hepatic causes. Pre-hepatic causes include increased production of bilirubin, such as in hemolytic disorders like sickle cell disease, thalassemia, and autoimmune hemolytic anemia. Hepatic causes involve decreased liver uptake or impaired conjugation of bilirubin, which can be seen in liver diseases such as hepatitis, cirrhosis, and alcoholic liver disease, as well as genetic conditions like Gilbert's syndrome, Crigler-Najjar syndrome, and Dubin-Johnson syndrome. Post-hepatic causes are related to reduced excretion of bilirubin, often due to biliary obstruction from gallstones, tumors, or strictures.
Some key points to consider in the evaluation of elevated total hyperbilirubinemia include:
- The majority of measurable bilirubin should be conjugated, even in individuals with significant liver disease, except in the neonatal period or in cases of hemolysis or impaired conjugation 1.
- Gilbert's syndrome is a common cause of isolated elevated bilirubin concentration, characterized by impaired conjugation due to reduced activity of the enzyme glucuronyltransferase, and typically does not require treatment other than reassurance 1.
- In neonates, physiologic jaundice is common, but pathological jaundice, indicated by high or prolonged levels of total bilirubin, requires prompt evaluation and treatment to prevent kernicterus 1.
- Certain medications and conditions, such as sepsis and severe infections, can also contribute to hyperbilirubinemia through various mechanisms, including hemolysis and liver dysfunction.
Management of elevated total hyperbilirubinemia should focus on identifying and treating the underlying cause, which may involve laboratory tests to differentiate between pre-hepatic, hepatic, and post-hepatic causes, and prompt intervention to prevent complications, especially in neonates and individuals with significant liver disease 1.
From the Research
Causes of Elevated Total Hyperbilirubinemia
Elevated total hyperbilirubinemia can be caused by various factors, including:
- Derangements in bilirubin metabolism 2
- Liver disease, such as alcoholic liver disease, hepatitis 2
- Biliary tract disease, such as biliary strictures, choledocholithiasis 2
- Hemolysis 2
- Drug-induced liver injury 2
- Inability of the liver to properly metabolize or excrete bilirubin 3
Diagnostic Evaluation
The diagnostic evaluation of hyperbilirubinemia typically starts with:
- A careful history and physical examination 3, 2
- Laboratory tests, including assays for bilirubin (total and fractionated), complete blood cell count, liver function tests (e.g., aspartate transaminase, alanine transaminase, gamma-glutamyltransferase, alkaline phosphatase), and coagulation studies (e.g., prothrombin time, international normalized ratio) 2
- Imaging studies, such as ultrasonography, computed tomography, or magnetic resonance cholangiopancreatography, to evaluate the biliary tree and liver 3, 2
Underlying Disease States
An elevated level of bilirubin almost always indicates the presence of an underlying disease state 3, and the best approach to evaluating a patient with jaundice is to start with a careful history and physical examination, followed by directed imaging and laboratory testing 3, 2