Jaundice and cholestasis

Jaundice, or icterus, is a yellowish discoloration of tissue caused by the accumulation of bilirubin deposits. Bilirubin deposition most commonly occurs in the skin and the sclerae and becomes apparent when bilirubin levels reach > 2 mg/dL. Jaundice can be divided into prehepatic, intrahepatic, and posthepatic etiologies. Prehepatic jaundice is caused by the accumulation of unconjugated bilirubin, which is due to either increased hemoglobin breakdown or impaired hepatic uptake. Intrahepatic jaundice may be caused by intrahepatic cholestasis, impaired bilirubin conjugation, or impaired excretion of bilirubin by the liver. Posthepatic jaundice is caused by the accumulation of conjugated hyperbilirubinemia usually due to extrahepatic cholestasis from biliary obstruction. In jaundice that arises from cholestasis, patients may present with pruritus, dark urine, and pale stools. Diagnosis is based on laboratory studies (e.g., liver function tests) and, in most cases, a transabdominal right upper quadrant (RUQ) ultrasound. The treatment of jaundice is determined by the underlying disease process and can often be complemented with symptomatic treatment (e.g., for pruritus) or ursodeoxycholic acid.

See also “Neonatal jaundice.”

• Jaundice: yellowish discoloration of the skin, sclerae, and mucous membranes due to the deposition of bilirubin
• Cholestasis: impaired production, secretion, or outflow of bile
• Hyperbilirubinemia: an increased serum concentration of bilirubin (See “Unconjugated hyperbilirubinemia” and “Conjugated hyperbilirubinemia” for details.)

Adult jaundice can be divided into prehepatic, intrahepatic, and posthepatic etiologies. See “Overview of mechanisms of neonatal jaundice” for etiologies of jaundice and kernicterus in neonates, e.g., hemolytic disease of the newborn, congenital hypothyroidism, biliary atresia.

The most common causes of adult hyperbilirubinemia can be remembered with the mnemonic “HOT Liver”: Hemolysis, Obstruction, Tumor, and Liver disease.

Prehepatic jaundice

Prehepatic jaundice is characterized by unconjugated hyperbilirubinemia most commonly caused by increased hemoglobin breakdown.

Consider choledocholithiasis as an alternative explanation for jaundice in patients with chronic hemolysis, since they have a high incidence of pigmented gallstones (see “Posthepatic jaundice”). ^[1]

Intrahepatic jaundice

Intrahepatic jaundice can vary from unconjugated hyperbilirubinemia to conjugated hyperbilirubinemia to a combination based on the etiology. See also “Acute liver failure.”

Hepatitis and cirrhosis can cause both conjugated and unconjugated hyperbilirubinemia.

Posthepatic jaundice

Posthepatic jaundice is characterized by conjugated hyperbilirubinemia caused by extrahepatic cholestasis from biliary obstruction.

• Jaundice is due to an elevated level of serum bilirubin, which may be caused by prehepatic, intrahepatic, or posthepatic defects.
• Serum bilirubin concentration depends on the rate of formation and hepatobiliary elimination of bilirubin.
• Any pathology that impairs the process could increase serum bilirubin level: See “Unconjugated hyperbilirubinemia” and “Conjugated hyperbilirubinemia” for details. ^[6]

• Jaundice
  • Scleral icterus (yellow discoloration of the sclerae) develops at serum bilirubin levels > 2–3 mg/dL.
  • Skin discoloration becomes apparent at serum bilirubin levels > 4–5 mg/dL.
• Accompanying features: vary depending on the underlying etiology
  • Features associated with cholestasis ^[7]
    • Pale, clay-colored (acholic) stool
    • Darkening of urine
    • Pruritus ^[8]
    • Fat malabsorption (steatorrhea, weight loss)
    • RUQ abdominal pain
    • Chronic biliary obstruction leading to backflow of bile may result in inflammation and hepatomegaly. ^[6]
  • Features associated with hemolysis: pallor, fatigue, exertional dyspnea (see “Clinical features of hemolytic anemia”)
  • Features associated with acute liver failure: anorexia, fatigue, nausea, abdominal pain (see “Clinical features of acute liver failure”)

Cholestasis may be seen in the absence of jaundice, particularly during the early stages of cholestasis. Depending on the clinical scenario, jaundice and cholestasis may occur separately or concurrently.

Approach ^[1]

• All patients
  • Perform a detailed clinical evaluation (including medication history) to identify features of cholestasis, hemolysis, or liver disease.
  • Assess for hepatomegaly and identify RUQ pain.
  • Obtain liver chemistries (including total, direct and indirect bilirubin) along with other routine laboratory studies (e.g., CBC, BMP, urinalysis).
• Predominant elevation of indirect bilirubin elevation: See “Unconjugated hyperbilirubinemia for details.”
  • Obtain a hemolysis workup
  • Consider specialized testing for hereditary conditions in select cases
• Predominant elevation of direct bilirubin: See “Conjugated hyperbilirubinemia for details.”
  • Distinguish between hepatocellular injury and cholestasis.
  • Obtain additional laboratory studies and imaging based on the suspected etiology, e.g., RUQ ultrasound for cholestasis.

Ultrasound abdomen ^[10][11]

• Commonly obtained for initial evaluation of all patients with jaundice
• Preferred initial image for suspected cholestasis

Additional imaging ^[10][11][13]

• Modalities: CT abdomen with IV contrast, MRCP
• Common indications
  • Second-line imaging if ultrasound is inconclusive
  • Often requested for better assessment of cholestasis
  • To guide diagnostic or therapeutic interventions and procedures
• Findings: depend on the etiology
  • Hepatocellular injury: fibrotic changes, cirrhosis (e.g., nodular surface), general hepatic inflammation
  • Cholestasis
    • Dilated bile ducts
    • Cause of obstruction, e.g., stones , masses

Diagnostic procedures ^[10][11]

Depending on clinical suspicion, and in consultation with a specialist, additional diagnostic procedures may be necessary, including:

• ERCP
• Endoscopic ultrasound
• Percutaneous liver biopsy

• See “Etiology” for a list of underlying causes of adult jaundice.
• Pseudojaundice ^[14]
  • Carotenoderma
    • Deposition of carotene in the skin can also cause yellow-orange discoloration of the skin.
    • Due to excessive consumption of multivitamin supplements or foods that are rich in beta carotene (e.g., carrots, sweet potatoes, kale, oranges)
  • Addison disease: hyperpigmentation of the skin caused by increased melanin synthesis

In contrast to jaundice, pseudojaundice does not result in scleral icterus.

The differential diagnoses listed here are not exhaustive.

Background

• Definition: elevated total bilirubin with < 15% direct bilirubin (normal serum total bilirubin: 0.1–1.0 mg/dL)
• Pathophysiology
  • Prehepatic
    • ↑ Hemoglobin breakdown
    • ↓ Hepatic uptake of bilirubin
  • Intrahepatic: ↓ Conjugation of bilirubin

Gilbert syndrome is a cause of intrahepatic jaundice that causes unconjugated hyperbilirubinemia

Diagnostics

• Perform hemolysis workup
  • Laboratory studies suggestive of hemolysis present: Manage according to the underlying cause and consult hematology.
  • Normal results in hemolysis workup: Consider specialized testing for hereditary hyperbilirubinemia, e.g., Crigler-Najjar syndrome, Gilbert syndrome. ^[15]
• See also “Diagnostics for hemolytic anemia.”

Common laboratory findings for hemolysis: ↑ indirect bilirubin, ↑ LDH, and ↓ haptoglobin

Management

Identify and treat the underlying cause of unconjugated hyperbilirubinemia.

Conditions associated with unconjugated hyperbilirubinemia can manifest with varying degrees of jaundice and abnormally elevated indirect bilirubin. Those that cause prehepatic jaundice can have low elevations (< 15%) of direct bilirubin. Most conditions that cause intrahepatic jaundice (with the exception of Gilbert syndrome) can also have some degree of unconjugated hyperbilirubinemia, but typically exhibit significantly elevated direct bilirubin (see “Conjugated hyperbilirubinemia”).

Background

• Definition: elevated direct bilirubin (normal serum direct bilirubin: ≤ 0.3 mg/dL) ^[20]
• Pathogenesis: associated with intrahepatic and/or posthepatic conditions
  • ↓ Drainage of bilirubin via biliary tract
  • ↑ Reuptake of bilirubin

Diagnostics

Determine whether the liver chemistries suggest a hepatocellular or cholestatic etiology. Consult gastroenterology for further guidance if the cause is unclear.

• AST and ALT elevated out of proportion to ALP: suggestive of hepatocellular injury
  • Obtain laboratory studies according to clinical suspicion; usually includes:
    • Viral serologies: acute viral hepatitis panel, EBV, CMV
    • Serum ceruloplasmin
    • Autoimmune antibodies: antinuclear antibody, smooth muscle antibody
  • Obtain a transabdominal RUQ ultrasound. ^[11]
• ALP elevated out of proportion to AST and ALT: suggestive of cholestasis ^[21]
  • Obtain a transabdominal RUQ ultrasound to differentiate between intrahepatic or extrahepatic cholestasis.
  • Consider advanced diagnostics, e.g., CT, MRCP, or ERCP, depending on ultrasound findings.
• Isolated conjugated hyperbilirubinemia: Consider testing for inherited hyperbilirubinemia (e.g., Dubin-Johnson syndrome, Rotor syndrome) in consultation with a specialist. ^[15]

Common laboratory findings for cholestasis: ↑ alkaline phosphatase (ALP), ↑ gamma-glutamyltransferase (GGT), and ↑ direct bilirubin

Hepatocellular injury

Provide supportive care and identify and treat the underlying condition in all patients. See also “Acute liver failure.”

Elevated hepatocellular enzymes (e.g., AST, ALT) and varying degrees of jaundice are commonly seen in conditions that cause hyperbilirubinemia due to hepatocellular injury. Although elevations of both direct and indirect bilirubin are possible, a predominantly high direct bilirubin is most common, leading to mostly conjugated hyperbilirubinemia.

An AST:ALT ratio > 1.5:1 suggests alcoholic hepatitis.

Cholestasis

Definitions

• Cholestasis: impaired production, secretion, or outflow of bile
• Nonobstructive intrahepatic cholestasis: impaired bile formation or secretion
• Obstructive intrahepatic cholestasis: biliary obstruction within the liver
• Obstructive extrahepatic or posthepatic cholestasis: obstruction of the biliary ducts between the liver and the duodenum

Management

• Identify and treat the underlying cholestatic causes of conjugated hyperbilirubinemia.
• Consider invasive intervention (e.g., cholecystectomy, ERCP) for select patients with symptomatic gallstones, biliary strictures, or other obstructing masses.
• Management of cholestasis-associated pruritus ^[8][27][28]
  • Mild: emollient solutions for skin hydration
  • Moderate to severe
    • Cholestyramine (first-line)
    • Rifampin (off-label) ^[27][28]
    • Opioid antagonists: e.g., naltrexone (off-label) ^[27][28]

Varying degrees of jaundice and elevations of cholestatic enzymes (including ALP, GGT, and direct bilirubin) are seen in conditions that cause conjugated hyperbilirubinemia due to cholestasis.