Author:
and rew K.Chang
Sean P.Geary
Description
- Yellow staining of tissues and body fluids due to hyperbilirubinemia, usually present at levels of >2.5 mg/dL
- Unconjugated (indirect) hyperbilirubinemia:
- Direct breakdown product of hemoglobin
- Water insoluble, circulates bound to albumin
- Hemolytic:
- Excessive production of unconjugated bilirubin
- Hepatic:
- Decreased hepatobiliary excretion of bilirubin
- 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
Etiology
- Prehepatic:
- Hemolysis (sickle cell, other hemoglobinopathies, G6PD deficiency)
- Ineffective erythropoiesis
- Drugs
- Gilbert syndrome: Usually benign inherited form of unconjugated hyperbilirubinemia
- Crigler-Najjar syndrome
- Prolonged fasting
- Cardiopulmonary bypass (ECMO)
- Hematoma reabsorption
- Hepatocellular:
- Hepatitis (infectious, alcoholic, autoimmune, toxin, drug induced)
- Cirrhosis
- Postischemic
- Hemochromatosis
- Intrahepatic cholestasis:
- Idiopathic cholestasis of pregnancy
- Drugs (TPN, statins, etc.)
- 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)
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Signs and Symptoms
- Deep yellow color of the skin and sclerae:
- Develops greenish hue when long stand ing
- Most pronounced in the face, trunk, and sclerae
- Less visible in artificial light than in daylight
- Pruritus:
- Proportional to bilirubin level and duration of jaundice
- Dark yellow or brown urine if conjugated hyperbilirubinemia
- Acholic feces:
- White, gray, or clay colored
- Complete biliary obstruction
History
- Cholestasis:
- 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:
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
Diagnostic 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
- 2× normal: Hepatitis and cirrhosis
- 3× normal: Extrahepatic biliary obstruction (i.e., choledocholithiasis) and intrahepatic cholestasis (i.e., drug-induced and biliary cirrhosis)
- Alk phos: Total bili ratio <10 predictive for WD
- 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
- Abdominal US:
- Most effective initial imaging technique
- >90% effective in identifying cholelithiasis
- Tumors of the liver and head of pancreas are usually well visualized
- Distinguishes solid liver tumors from cystic structures
- 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
- Plain x-rays:
- 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
- MRCP - Magnetic resonance cholangiopancreatography
- Advantages: Can identify causes of ductal dilatations in 80-100% and eliminates risk of perforation and pancreatitis from endoscopy and ductal intubation
- Disadvantage: Diagnostic but not therapeutic
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
- Yellowish pallor of severe anemia
- Carotenemia:
- Increased β-carotene levels in the blood
- Excessive consumption of carotene-rich foods such as carrots, squash, or melon
- Common finding in children
- Particularly noticeable in areas with marked sweating
- Sclerae are always spared
- Excess ingestion of chemicals:
- Quinacrine
- Mepacrine
- Dinitrophenol
- Saffron, tetryl
- Picric acid
- Canthaxanthin
- Lycopenemia:
- Orange-yellow skin discoloration
- Ingestion of large amounts of tomatoes, or more rarely, watermelon or pink grapefruit
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:
- Piperacillin/tazobactam or ampicillin/sulbactam
- Carbapenem if life threatening
- Alternate - cipro/metronidazole or third gen cephalosporin/metronidazole
- Obstructive extrahepatic jaundice:
- Surgical consult for definitive management
- GI consultation for temporization with ERCP/stenting
- Choledocholithiasis:
- ERCP papillotomy, balloon or basket retrieval, open cholecystectomy with bile duct exploration, percutaneous transhepatic cholangiography with drain placement (PTC) or percutaneous cholecystostomy tube placement
- Obstructive intrahepatic or nonobstructive jaundice:
- Medical management:
- Withdraw causative drug, ethanol
- Penicillamine and phlebotomy for WD and hemochromatosis
- Corticosteroids for chronic hepatitis of autoimmune origin
- Direct-acting antivirals +/− interferon for hepatitis B and C
Pediatric Considerations |
- Decision to start therapy:
- Infants are categorized as low, medium, or high risk based on prematurity and comorbidities
- Use either a neonatal bilirubin calculator or the AAP neonatal bilirubin nomogram
- Therapeutic options:
- Phototherapy can drop total bilirubin 2-3 mg/Dl in 4-6 hr and result in a 30-40% reduction over the first 24 hr
- Exchange transfusion:
- Any evidence of bilirubin-induced neurologic dysfunction or failure of improvement despite aggressive phototherapy
- Bilirubin/albumin ratio >6.8 (high-risk infants); >7.2 (moderate-risk infants); >8.0 (low-risk infants)
- IVIG - can be considered if total bilirubin levels rising despite phototherapy or when levels within 2-3 mg/Dl of exchange levels
- Phenobarbital: In sepsis and drug-induced causes; decreases conjugated bilirubin
- Metalloporphyrins: Investigational inhibitors of heme oxygenase
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Medication
- Ampicillin: (peds: 25 mg/kg IV q6-8h)
- Cefoxitin: 2 g IV q6h (peds: 40-160 mg/kg/d div. q6-12h)
- Gentamicin: 1.5-2 mg/kg IVq8h
- 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])
- Meropenem: 1g IV q8h (peds: 20mg/kg q8)
- Ertapenem 1g q24h (no peds dosing established)