• Information
  1. Evaluation

  UNCONJUGATED (INDIRECT) HYPERBILIRUBINEMIA

  1. Overproduction of Bilirubin
  2. Abnormal Uptake or Conjugation
  3. Escape Through Collateral Vessels

CONJUGATED (DIRECT) HYPERBILIRUBINEMIA

• 1. Initial Distinctions
  2. Dilated Bile Ducts
  3. Nondilated Ducts

A. Evaluation

1. Measure serum total, direct, indirect bilirubin
2. Jaundice is total bilirubin >2.5-3.0mg/dL (42.8-51.3 microMol/L) [2]
3. Indirect bilirubin increase is unconjugated hyperbilirubinemia
4. Direct bilirubin increase is conjugated hyperbilirubinemia
5. Full liver function testing (LFT) should be done
   1. Parenchymal cell function: AST (SGOT), ALT (SGPT)
   2. Biliary system function: alkaline phosphatase (heat stabile), 5'-nucleotidase (5'NT), GGT
   3. Liver synthetic function: albumin level, prothrombine time (PT)
6. Liver biopsy may be required after serologies, ultrasound, computerized tomography (CT)

1. Hemolysis
2. Blood Extravasation (and resorption)
3. Abnormal erythropoieses - polycythemia vera, sideroblastic anemia

B. Abnormal Uptake or Conjugation

1. Gilbert's Syndrome
   1. Increased bilirubin with fasting
   2. Normal conjugated bilirubin
   3. Benign disease
2. Crigler-Najjar Syndrome Type 1
   1. No glucuronyl transferase
   2. Neonatal severe jaundice (kernicterus)
   3. Early death without treatment
   4. Liver or hepatocyte transplantation is required [3]
3. Crigler-Najjar Syndrome Type 2
   1. Low glucuronyl transferase
   2. Relatively normal lifespan
4. Dubin-Johnson Syndrome (DJS) [4]
   1. Chronic jaundice
   2. Benign, autosomal disorder
   3. DJS due to point mutation in MRP2 (canalicular multispecific organic ion transporter)
   4. Increased indirect bilirubin
   5. Vague constitutional or gastrointestinal symptoms
   6. Dark pigment in liver cells, melanin-like or epinephrine polymers
   7. Rotor Syndrome is similar to DJS, except that there is no dark pigment in liver cells

C. Escape Through Collateral Vessels

1. Portocaval Shunt
2. Cirrhosis

1. Cellular Injury Prominant - increased AST (SGOT) and ALT (SGPT)
   1. Acute versus chronic hepatitis
   2. Level of alkaline phosphatase present
2. Cholestasis Prominant - minimal or no elevation in transaminases
3. For prominant cholestasis, ultrasound or CT scan done to evaluate bile ducts
4. If no dilated ducts are seen on CT or ultrasound, consider ERCP (endoscopic retrograde cholangiopancreatography)

B. Dilated Bile Ducts

1. Intrahepatic Only
   1. Intrahepatic Bile Duct Stone
   2. Klatskin Tumor - cholangiocarcinoma
   3. Caroli's Disease
2. Intrahepatic and Extrahepatic
   1. Pancreatic and/or ampullary carcinomas
   2. Cholangiocarcinoma
   3. Gallstone
   4. Pancreatitis (usually gallstone related)
3. Neoplasia Differential [5]
   1. Insulin-like growth factor 1 (IGF-1) levels elevated in cholangiocarcioma
   2. Biliary IGF-1 highly elevated in cholangiocarciona but not in pancreatic cancer or gallstones
   3. Serum vascular endothelial growth factor (VEGF) levels about 3X elevated in either cancer compared with benign biliary abnormalities

C. Nondilated Ducts

1. Hepatocellular Disease (most common causes)
   1. Viral infections: hepatitis A, B, C (others in immunocompromised patients)
   2. Chronic alcohol abuse
   3. Chronic autoimmune hepatitis, related disorders
2. Drug Induced Cholestasis
   1. Inflammatory - chlorpormazine, erythromycin, amoxicillin-clavulanate
   2. Non-inflammatory - oral contraceptives (conjugated estrogens), rifampicin
   3. Granulomatous Inflammation
   4. Steatohepatitis - tetracyclines, amiodarone, valproate, alcohol, others
3. Autoimmune Duct Diseases
   1. Primary Biliary Cirrhosis
   2. Sclerosing Cholangitis
4. Intrahepatic cholestasis
5. Parentral Nutrition - cholestatic likely due to suppressed cholecystikinin
6. Hepatic Granulomatous Disease
   1. Sarcoidosis
   2. Tuberculosis or fungal infection
   3. Granulomatous hepatitis

References

1. Roche SP and Kobos. 2004. Am Fam Phys. 69(2):299
2. Greenstone CL, Saint S, Moseley RH. 2007. NEJM> 356(23):2407 (Case Discussion)
3. Fox IJ, Chowdhury JR, Kaufman SS, et al. 1998. NEJM. 338(20):1422
4. Trauner M, Meier PJ, Boyer JL. 1998. NEJM. 339(17):1217
5. Alvaro D, Macarri G, Mancino MG, et al. 2007. Ann Intern Med. 147(7):451