From the Guidelines
Bilirubin elevation is primarily caused by conditions that interfere with the normal production, processing, or excretion of bilirubin, with the most common causes including liver diseases, biliary obstruction, hemolytic disorders, genetic conditions, and drug-induced liver injury, as reported in the most recent study 1.
Causes of Bilirubin Elevation
The causes of bilirubin elevation can be categorized into several groups, including:
- Liver diseases such as hepatitis, cirrhosis, and alcoholic liver disease, which impair the liver's ability to process bilirubin 1
- Biliary obstruction from gallstones, tumors, or strictures, which can block bilirubin excretion into the intestines 1
- Hemolytic disorders like sickle cell anemia and autoimmune hemolytic anemia, which increase bilirubin production by accelerating red blood cell breakdown 1
- Genetic conditions such as Gilbert's syndrome, Crigler-Najjar syndrome, and Dubin-Johnson syndrome, which affect bilirubin metabolism 1
- Medications including certain antibiotics, anti-seizure drugs, and anabolic steroids, which can cause drug-induced liver injury leading to hyperbilirubinemia 1
Mechanism of Bilirubin Elevation
The underlying mechanism of bilirubin elevation involves either increased bilirubin production, decreased liver uptake, impaired conjugation, or reduced excretion, with the specific pattern of elevation (direct/conjugated vs. indirect/unconjugated) helping to narrow down the diagnosis 1.
Diagnosis and Management
Diagnosis and management of bilirubin elevation require a detailed history, targeted physical examination, and pertinent laboratory studies, including a hepatic profile, conjugated versus unconjugated bilirubinemia, complete blood count, and imaging studies such as abdominal ultrasound, CT, or MRCP 1.
Key Points
- Bilirubin elevation can be caused by a variety of conditions, including liver diseases, biliary obstruction, hemolytic disorders, genetic conditions, and drug-induced liver injury
- The underlying mechanism involves either increased bilirubin production, decreased liver uptake, impaired conjugation, or reduced excretion
- Diagnosis and management require a detailed history, targeted physical examination, and pertinent laboratory studies, including imaging studies
- The specific pattern of elevation (direct/conjugated vs. indirect/unconjugated) can help narrow down the diagnosis, as reported in the most recent study 1.
From the Research
Causes of Bilirubin Elevation
- 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
- Liver lesions of any cause can reduce hepatocyte cell number and impair the uptake of indirect bilirubin from plasma and diminish direct bilirubin transport and clearance through the bile ducts 2
- Jaundice, the physical finding associated with hyperbilirubinemia, results when the liver is unable to properly metabolize or excrete bilirubin 3
- An elevated level of bilirubin almost always indicates the presence of an underlying disease state, such as hepatobiliary disease 3, 4
- Hemolytic anemia can also cause liver injury and lead to elevated bilirubin levels, as seen in conditions such as sickle cell anemia, paroxysmal nocturnal hemoglobinuria, and glucose-6-phosphate dehydrogenase deficiency 5
Mechanisms of Bilirubin Elevation
- Bile acids can decrease intracellular bilirubin levels in the cholestatic liver, making hepatocytes more susceptible to oxidative damage 6
- Bilirubin is a strong antioxidant, but its levels can be compromised by bile acids in the cholestatic liver 6
- The presence of esterified bilirubins in serum can be an indicator of hepatobiliary disease, and can be detected by alkaline methanolysis and normal-phase high-performance liquid chromatography (AMHPLC) 4