DESCRIPTION

Yellow pigmentation of tissues and body fluids due to hyperbilirubinemia, usually present at levels of > 2.5 mg/dL

ETIOLOGY

• Unconjugated (indirect) hyperbilirubinemia: Unconjugated bilirubin is the direct breakdown product of heme, is water insoluble, and is measured as indirect bilirubin:
  • Hemolytic:
    • Excessive production of unconjugated bilirubin
  • Hepatic:
    • Decreased hepatobiliary excretion of bilirubin by:
      • Defective uptake (drugs, Crigler–Najjar syndrome)
      • Defective conjugation (Gilbert syndrome drugs)
      • Defective excretion of bilirubin by the liver cell (drugs, Dubin–Johnson syndrome)
• Conjugated (direct) hyperbilirubinemia:
  • Conjugated bilirubin is water soluble and measured as direct bilirubin.
  • In conjugated hyperbilirubinemia, bilirubin is returned to the bloodstream after conjugation in the liver instead of draining into the bile ducts.
  • Hepatocellular dysfunction:
    • Hepatitis
    • Cirrhosis
    • Tumor invasion
    • Toxic injury
  • Intrahepatic (nonobstructive) cholestasis
  • Extrahepatic (obstructive) cholestasis

[Outline]

• DESCRIPTION
• ETIOLOGY

SIGNS AND SYMPTOMS

History

• Cholestasis:
  • Pruritus
  • Pale stools
  • Dark urine
• Malignancy:
  • Anorexia
  • Weight loss
  • Malaise
• Abdominal pain

Physical Exam

• Icterus of sclera and tongue base (levels > 2.5 mg/dL)
• Right upper quadrant tenderness:
  • Courvoisier rule:
    • Painless jaundice and a palpable, nontender gallbladder represent malignant common duct obstruction.
• Stigmata of cirrhosis:
  • Abdominal collateral circulation including caput medusae, hepatosplenomegaly, or hepatic atrophy
  • Ascites
  • Spider telangiectasia
  • Palmar erythema
  • Dupuytren contractures
  • Asterixis
  • Encephalopathy
  • Gynecomastia
• Palpable gallbladder
• Hepatomegaly
• Splenomegaly
• Abdominal mass
• Evidence of cachexia
• Excoriations (primary biliary cirrhosis, obstruction)
• Kayser–Fleischer rings:
  • Wilson disease

ESSENTIAL WORKUP

• History and physical exam, together with routine lab tests, will suggest the diagnosis in ~80% of patients with jaundice.
• Bilirubin level—severity may suggest cause:
  • Malignancy causes highest levels (10–30 mg/dL).
  • Choledocholithiasis rarely exceeds 15 mg/dL.

DIAGNOSIS TESTS & INTERPRETATION

Lab

• Urine dipstick is 74% sensitive for bilirubin.
• Alkaline phosphatase:
  • If no bone disease and not pregnant, then elevation suggests impaired biliary tract function.
  • 2X normal: Hepatitis and cirrhosis
  • 3X normal: Extrahepatic biliary obstruction (i.e., choledocholithiasis) and intrahepatic cholestasis (i.e., drug-induced and biliary cirrhosis)
• Aminotransferases—provide evidence of hepatocellular damage:
  • Alanine aminotransferase (ALT, SGPT): Primarily in the liver
  • Aspartate aminotransferase (AST, SGOT): Liver, heart, kidney, muscle, and brain
• γ-Glutamyl transpeptidase—throughout hepatobiliary system, pancreas, heart, kidneys, and lungs:
  • May be the most sensitive indicator of biliary tract disease.
  • Confirms hepatic origin of an elevated alkaline phosphatase.
• 5'-Nucleotidase—widespread tissue distribution:
  • Confirms hepatic origin of an elevated alkaline phosphatase level.
• Albumin: Decreased with severe liver disease
• PT: Elevation is an important prognostic indicator in patients with acute hepatitis.

Imaging

• US: Most effective initial imaging technique:
  • > 90% effective in identifying cholelithiasis
  • Ductal dilation is a reliable indicator of extrahepatic obstruction:
    • A dilated common bile duct (CBD) and gallbladder suggest distal obstruction, whereas dilation of the intrahepatic ducts (without CBD dilation) suggests proximal obstruction.
• Tumors of the liver and head of pancreas are usually well visualized.
• Distinguishes solid liver tumors from cystic structures.
• Plain radiographs:
  • May show evidence of hepatic and splenic enlargement or biliary calcifications
• Hepatic nuclear scan (hepatobiliary iminodiacetic acid scan):
  • Accurate method of diagnosing acute cholecystitis or cystic duct obstruction
  • Time consuming (usually several hours)
• CT:
  • Superior to US in detecting pancreatic and intra-abdominal tumors.
  • Can help differentiate fluid-containing structures.

Diagnostic Procedures/Surgery

Endoscopic retrograde cholangiopancreatography (ERCP):

• Diagnostic:
  • Stones are seen as filling defects within bile duct lumen.
  • Malignancies are seen as strictures.
• Therapeutic:
  • Extraction of CBD stones and insertion of stents to bypass malignant obstructions
  • Biopsy under direct vision

DIFFERENTIAL DIAGNOSIS

• Prehepatic:
  • Hemolysis (sickle cell, other hemoglobinopathies)
  • Ineffective erythropoiesis
  • Drugs
  • Gilbert syndrome: Usually benign inherited form of unconjugated hyperbilirubinemia
  • Crigler–Najjar syndrome
  • Prolonged fasting
• Hepatocellular:
  • Hepatitis (infectious, alcoholic, autoimmune, toxin, drug induced)
  • Cirrhosis
  • Postischemic
  • Hemochromatosis
• Intrahepatic cholestasis:
  • Idiopathic cholestasis of pregnancy
  • Drugs
  • Dubin–Johnson syndrome
  • Rotor syndrome
  • Benign recurrent cholestasia
  • Familial syndromes
  • Sepsis
  • Postoperative jaundice
  • Lymphoma
• Extrahepatic obstruction:
  • Common duct stone
  • Biliary stricture
  • Bacterial cholangitis
  • Sclerosing cholangitis
  • Carcinoma (ampulla, gallbladder, pancreas), cholangiosarcoma
  • Pancreatitis, pancreatic pseudocyst
  • Hemobilia
  • Duodenal diverticula
  • Ascariasis
  • Postlaparoscopic cholecystectomy complications
  • Congenital biliary atresia
  • Congenital choledochal cyst

Pediatric Considerations

Intrahepatic cholestasis:

• Cardiovascular (congenital heart disease, congestive heart failure, shock, asphyxia)
• Metabolic or genetic (α₁-antitrypsin deficiency, trisomy 18 and 21, cystic fibrosis, Gaucher disease, Niemann–Pick disease, glycogen storage disease type IV)
• Infectious (bacterial sepsis, cytomegalovirus, enterovirus, herpes simplex virus, rubella, syphilis, TB, varicella, viral hepatitis)
• Hematologic (severe isoimmune hemolytic disease)

[Outline]

• SIGNS AND SYMPTOMS
• ESSENTIAL WORKUP
• DIAGNOSIS TESTS & INTERPRETATION
• DIFFERENTIAL DIAGNOSIS

INITIAL STABILIZATION/THERAPY

• Isotonic IV fluid therapy if dehydrated
• Toxic-appearing patients:
  • Supplemental oxygen, cardiac monitoring
  • Nasogastric suction and bladder catheterization

ED TREATMENT/PROCEDURES

• For bacterial cholangitis/sepsis, obtain blood cultures and administer parenteral antibiotics:
  • Ampicillin, gentamicin, and metronidazoleor
  • Ticarcillin, or piperacillin, and metronidazole or
  • Cefoxitin and tobramycin
• Obstructive extrahepatic jaundice:
  • Surgical consult
• Choledocholithiasis:
  • ERCP papillotomy, balloon or basket retrieval, or open surgery
• Obstructive intrahepatic or nonobstructive jaundice:
  • Medical management:
    • Withdraw causative drug, ethanol
    • Interferon for chronic hepatitis B and C
    • Penicillamine and phlebotomy for Wilson disease and hemochromatosis
    • Corticosteroids for chronic hepatitis of autoimmune origin

Pediatric Considerations

• Exchange transfusion:
  • Emergent treatment of markedly elevated bilirubin (> 20 mg/dL in full-term infants) and for correction of anemia caused by isoimmune hemolytic disease
• Phototherapy—for neonatal jaundice when bilirubin = 17 mg/dL:
  • Measure bilirubin once to twice daily and stop when bilirubin has been reduced by about 4–5 mg/dL.
• Phenobarbital: In sepsis and drug-induced causes; decreases conjugated bilirubin.
• Metalloporphyrins: Investigational inhibitors of heme oxygenase

MEDICATION

• Ampicillin: 2 g IV q6h (peds: 25 mg/kg IV q6–8h)
• Cefoxitin: 2 g IV q6h (peds: 40–160 mg/kg/d div. q6–12h)
• Gentamicin: 5–2 mg/kg IV q8h
• Metronidazole: 7.5 mg/kg IV q6h (peds: Same)
• Piperacillin/tazobactam: 3.375 g IV q6h (peds: 300 mg/kg/d div. q6h [> 2 mo of age])
• Ticarcillin/clavulanate: 3.1 g IV q6h (peds: 75–100 mg/kg/d div. q6h)
• Tobramycin: 1 mg/kg IV q6h (peds: Same)

[Outline]

• INITIAL STABILIZATION/THERAPY
• ED TREATMENT/PROCEDURES
• MEDICATION

DISPOSITION

Admission Criteria

• Bacterial cholangitis
• Intractable pain
• Intractable emesis
• Associated pancreatitis
• Elevated PT

Discharge Criteria

• No evidence of infection (evaluate as outpatient)
• Tolerating liquids

ICD9

• 277.4 Disorders of bilirubin excretion
• 774.6 Unspecified fetal and neonatal jaundice
• 782.4 Jaundice, unspecified, not of newborn

ICD10

• E80.6 Other disorders of bilirubin metabolism
• P59.9 Neonatal jaundice, unspecified
• R17 Unspecified jaundice

[Outline]

• ICD9
• ICD10

• Addley J, Mitchell RM. Advances in the investigation of obstructive jaundice. Curr Gastroenterol Rep. 2012;14:511–519
• Maisels MJ, McDonagh AF. Phototherapy for neonatal jaundice. N Engl J Med. 2008;358:920–928.
• Roche SP, Kobos R. Jaundice in the adult patient. Am Fam Physician. 2004;69:299–304.
• Udell JA, Wang CS, Tinmouth J, et al. Does this patient with liver disease have cirrhosis? JAMA. 2012;307(8):832–842.
• Wang Q, Gurusamy KS, Lin H, et al. Preoperative biliary drainage for obstructive jaundice. Cochrane Database Syst Rev. 2008;16(3):CD005444.

Andrew K. Chang

Albert Izzo