What causes an elevation in total bilirubin (TBILI) levels?

Causes of Total Bilirubin Elevation

Total bilirubin (TBILI) elevations are primarily caused by disorders affecting bilirubin production, hepatic uptake, conjugation, or biliary excretion, with specific diagnosis requiring fractionation into conjugated and unconjugated components. 1

Classification of Hyperbilirubinemia

Hyperbilirubinemia is classified based on the percentage of conjugated (direct) bilirubin:

• Predominantly unconjugated hyperbilirubinemia (<20-30% conjugated)
• Predominantly conjugated hyperbilirubinemia (>35% conjugated)

Causes of Predominantly Unconjugated Hyperbilirubinemia

1. Increased bilirubin production

   • Hemolytic disorders (accelerated breakdown of erythrocytes) 2
   • Ineffective erythropoiesis
   • Hematoma resorption

2. Impaired hepatic uptake

   • Certain medications
   • Post-hepatic cirrhosis 3

3. Impaired conjugation

   • Gilbert's syndrome (genetic deficiency in UDP-glucuronosyltransferase) 4
   • Crigler-Najjar syndrome (severe deficiency in UDP-glucuronosyltransferase) 5
   • Neonatal jaundice (physiologic immaturity of conjugation enzymes)

Causes of Predominantly Conjugated Hyperbilirubinemia

1. Biliary obstruction

   • Choledocholithiasis (gallstones)
   • Strictures
   • Cholangitis
   • Malignancies (cholangiocarcinoma, pancreatic cancer)
   • Primary sclerosing cholangitis (PSC) 6

2. Hepatocellular injury

   • Viral hepatitis
   • Alcoholic liver disease
   • Non-alcoholic fatty liver disease
   • Drug-induced liver injury (DILI)
   • Autoimmune hepatitis

3. Genetic disorders

   • Dubin-Johnson syndrome
   • Rotor syndrome

Diagnostic Approach

When evaluating elevated total bilirubin:

1. Fractionate bilirubin to determine if predominantly conjugated or unconjugated 1

2. Check other liver enzymes:

   • ALT/AST (hepatocellular injury)
   • ALP/GGT (cholestatic pattern)
   • Albumin and INR (synthetic function)

3. For cholestatic patterns:

   • Confirm hepatobiliary origin of ALP with GGT or ALP isoenzyme fractionation 6
   • Consider abdominal ultrasound (first-line imaging for suspected biliary obstruction) 1
   • Evaluate for dominant stricture with MRC or ERCP if PSC is suspected 6

4. For unconjugated hyperbilirubinemia:

   • Check CBC for evidence of hemolysis
   • Consider genetic testing for UDP-glucuronosyltransferase mutations if Gilbert's syndrome is suspected 1

Special Considerations

• In PSC, episodes of cholangitis can mimic drug-induced liver injury with abrupt elevations in ALP, total bilirubin, and/or aminotransferases 6
• Total bilirubin elevations are usually <15 mg/dL in cholangitis but may exceed this with complete bile duct obstruction 6
• In alcoholic cirrhosis, elevated bilirubin may result from both overproduction and decreased biliary transport capacity 3
• Patients with Gilbert's syndrome typically have mild unconjugated hyperbilirubinemia with otherwise normal liver function tests 4
• Hepatic encephalopathy is associated with significantly increased glucuronidated (direct) bilirubin levels 7

Monitoring Recommendations

• For suspected liver disease: Monitor fractionated bilirubin, CBC, liver enzymes, albumin, and PT/INR 1
• Poor prognostic indicators include development of hepatic encephalopathy, INR >1.5, and failure to improve with initial therapy 1

Remember that bilirubin elevation should always be interpreted in the context of patient history, the degree of elevation, and concurrent biochemical alterations for accurate diagnosis 2.