Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Etiologies often involve the liver and can be prehepatic, intrahepatic, or posthepatic. Other symptoms of hyperbilirubinemia include pruritus, pale stools, and darkened urine. The diagnosis is made based on liver function tests and imaging. Management is focused on treatment of the underlying condition.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp


  • Jaundice
    • Discoloration of the skin and mucous membranes
    • Begins at serum bilirubin > 4–5 mg/dL
  • Scleral icterus
    • Discoloration of the sclera (eyes)
    • Begins at serum bilirubin > 2–3 mg/dL


Jaundice is caused by an elevation of serum bilirubin (hyperbilirubinemia), which can be caused by:

  • Prehepatic pathologies
    • Often occur due to increased hemolysis
    • Causes increased unconjugated (indirect) bilirubin
    • Includes physiologic neonatal jaundice
      • Caused by immature UDP-glucuronosyltransferase; occurs within 24 hours of birth and often resolves without treatment in 12 weeks
  • Intrahepatic pathologies
    • May be due to 
      • Defective hepatic uptake
      • Defective bilirubin conjugation
    • Causes an increase in both conjugated (direct) and unconjugated (indirect) bilirubin
  • Posthepatic pathologies
    • Often occur due to 
      • Decreased bilirubin elimination (via the biliary tract)
      • Increased reuptake of bilirubin
    • Causes an increase in conjugated (direct) bilirubin
Normal extrahepatic circulation of bilirubin

Normal extrahepatic circulation of bilirubin

Image by Lecturio. License: CC BY-NC-SA 4.0


Common causes of hyperbilirubinemia can be remembered with the mnemonic HOT Liver:

  • Hemolysis
  • Obstruction
  • Tumor
  • Liver disease


Etiologies of jaundice can be broken down as conditions that cause either an elevation in indirect, direct, or mixed hyperbilirubinemia (see table below).

Causes of isolated hyperbilirubinemia
Indirect (unconjugated) hyperbilirubinemia Hemolytic disorders Inherited:
  • Spherocytosis
  • Glucose-6-phosphate dehydrogenase deficiency
  • Pyruvate kinase deficiency
  • Sickle cell anemia
  • Hemolytic anemia
  • Paroxysmal nocturnal hemoglobinuria
  • Parasitic infections (malaria, babesiosis)
  • Antimalarials (e.g., dapsone)
Ineffective erythropoiesis Inherited:
  • Thalassemia
  • Vitamin B12 deficiency
  • Severe iron deficiencies
Increased bilirubin production Secondary to:
  • Massive blood transfusion
  • Resorption of hematoma
Decreased bilirubin conjugation
  • Physiologic jaundice of the newborn
  • Crigler-Najjar types I and II
  • Gilbert’s syndrome
  • Rifampin
  • Acetaminophen overdose
  • Probenecid
  • Sulfonamides
Direct (conjugated) hyperbilirubinemia Biliary tract obstruction Secondary to:
  • Gallstones
  • Cholangiocarcinoma
  • Pancreatic/liver cancer
  • Liver fluke
  • Postoperative bile leaks or biliary strictures
Biliary tract disease
  • Primary sclerosing cholangitis
  • Primary biliary cholangitis
Decreased excretion/reuptake of bilirubin:
  • Dubin-Johnson syndrome
  • Rotor syndrome
Mixed (both indirect and direct) hyperbilirubinemia Chronic conditions
  • Hepatitis (viral, autoimmune, toxic, and alcoholic)
  • Cirrhosis

Etiologies of jaundice can also be broken down based on the organ system (hepatic and cholestatic conditions).

Hepatocellular conditions

  • Viral hepatitis:
    • Hepatitis A, B, C, D, and E
    • Epstein-Barr virus
    • Cytomegalovirus
  • Alcoholic hepatitis
  • Drug toxicity
    • Predictable, dose-dependent (e.g., acetaminophen)
    • Unpredictable, idiosyncratic (e.g., isoniazid)
  • Environmental toxins:
    • Vinyl chloride
    • Wild mushrooms (amanita)
  • Wilson’s disease
  • Autoimmune hepatitis

Cholestatic conditions


  • Viral hepatitis
  • Alcoholic hepatitis
  • Drug toxicity:
    • Pure cholestasis: anabolic and contraceptive steroids
    • Cholestatic hepatitis: chlorpromazine and erythromycin estolate
    • Chronic cholestasis: chlorpromazine and prochlorperazine
  • Primary biliary cirrhosis
  • Primary sclerosing cholangitis
  • Vanishing bile duct syndrome:
    • Chronic rejection of liver transplants
    • Sarcoidosis
    • Drugs
  • Congestive hepatopathy
  • Ischemic hepatitis
  • Cholestasis of pregnancy
  • Total parenteral nutrition
  • Graft-versus-host disease
  • Infiltrative diseases:
    • Tuberculosis
    • Lymphoma
    • Amyloidosis
  • Infections:
    • Malaria
    • Leptospirosis


  • Malignancy:
    • Cholangiocarcinoma
    • Pancreatic cancer
    • Gallbladder cancer
  • Benign:
    • Choledocholithiasis
    • Postoperative biliary strictures
    • Primary sclerosing cholangitis
  • Chronic pancreatitis
  • AIDS cholangiopathy
  • Mirizzi’s syndrome
  • Parasitic disease (ascariasis)

Clinical Presentation and Diagnosis

Clinical presentation

  • Jaundice
  • Pruritus
    • Occurs due to bile salt deposition
    • Most often seen in posthepatic pathologies
  • Pale, clay-colored stools and darkened urine
    • Occurs primarily due to elevated direct bilirubin 
  • In infants, may cause kernicterus: deposition of unconjugated bilirubin in the brain

These symptoms may be associated with:

  • Fever, chills, right upper quadrant (RUQ) pain: may suggest acute cholangitis
  • Anorexia, malaise, myalgias: may suggest viral hepatitis
  • RUQ abdominal pain: may suggest biliary tract obstruction 
  • Hyperpigmentation: may suggest hemochromatosis
  • Kayser-Fleischer rings: may suggest Wilson’s disease
  • Xanthomas: may suggest primary biliary cholangitis
  • Signs of chronic liver failure
    • Ascites
    • Splenomegaly
    • Spider angiomata
    • Gynecomastia
  • Courvoisier sign on physical exam: palpable gallbladder; often indicates cystic duct malignancy


  • Liver function tests: 
    • Alkaline phosphatase (ALP), normal range: 40–129 U/L
    • Alanine transaminase (ALT), normal range: 7–55 U/L
    • Aspartate transaminase (AST), normal range: 8–48 U/L
    • AST/ALT ratio: 2:1 ratio or above is suggestive of alcoholic liver disease.
    • Gamma-glutamyltransferase (GGT), normal range: 8–61 U/L
    • Serum bilirubin (total and unconjugated)
    • Albumin
    • PR/INR (prothrombin time/international normalized ratio)
    • LDH (lactate dehydrogenase)
    • Haptoglobin
    • Hepatitis serology
    • Consider autoantibodies (see image below)
  • Imaging may include:
    • Ultrasound:
      • Extrahepatic cholestasis: dilated bile ducts (e.g., stones, tumors, cysts, cholangitis)
      • Intrahepatic cholestasis: most commonly has non-dilated bile ducts
    • ERCP (endoscopic retrograde cholangiopancreatography) or MRCP (magnetic resonance cholangiopancreatography)
    • Abdominal computed tomography (CT) scan

Further workups are outlined in the image below.

Jaundice diagnosis diagram

Key abbreviations:
ANA: antinuclear antibody
SMA: smooth-muscle antibody
SPEP: serum protein electrophoresis
AMA: antimitochondrial antibody
MRCP: magnetic resonance cholangiopancreatography

Image by Lecturio. License: CC BY-NC-SA 4.0
Types of jaundice (based on lab markers)
Prehepatic Intrahepatic Posthepatic
Stool color Dark Pale, clay-colored Pale, clay-colored
Blood work Indirect bilirubin ↑↑ Normal
Direct bilirubin Normal ↑↑
Anemia Present Absent Absent
Alkaline phosphatase Normal ↑↑
Transaminases Normal ↑↑
Urinalysis Color Normal or dark Dark Dark or very dark
Urobilinogen ↑↑ Normal or ↑ Low or absent
Bile salt Absent Absent Present


Management is based on treatment of the underlying condition.

  • Cirrhosis: The goal is to slow or reverse the progression and prevent superimposed insults to the liver.
    • Modify medication as necessary.
    • Correct laboratory abnormalities.
    • Manage symptoms.
    • Ultimately, liver transplant is required.
  • Hepatitis B and C: medical management using antivirals and interferon therapy
  • Alcoholic liver disease: alcohol cessation
  • Primary biliary cholangitis and primary sclerosing cholangitis: ursodeoxycholic acid
  • Malignancy: staging and resection or palliative treatment
  • Cholelithiasis and cholecystitis: ERCP removal or cholecystectomy
  • Biliary cysts: surgical excision

Differential Diagnosis

Pseudojaundice (carotenosis): yellow or orange discoloration of the skin caused by deposition of carotene. Can be distinguished from true jaundice because it does not cause discoloration of the conjunctival membranes of the sclerae. Usually secondary to excessive intake of substances rich in carotenoids (e.g., multivitamin supplements, oranges, carrots, apples, broccoli, papayas, kale).


  1. Namita Roy-Chowdhury, PhD, FAASLD, Jayanta Roy-Chowdhury, MD, MRCP, AGAF, FAASLD. Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia. Retrieved from https://www.uptodate.com/contents/diagnostic-approach-to-the-adult-with-jaundice-or-asymptomatic-hyperbilirubinemia?search=jaundice&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
  2. Kasper, D. L., & Braunwald, F. (2017). Harrison’s Principle of Internal Medicine 19th edition, Volume I. Pages 279–285.
  3. Billing BH, Black M. 1969. Bilirubin metabolism. Gut. 10;250-254. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1552848/pdf/gut00694-0010.pdf
  4. Reece, J. B., & Campbell, N. A. (2011). Campbell biology. Boston: Benjamin Cummings/Pearson.
  5. Roy-Chowdhury, Namita, Yang Lu, and Jayanta Roy-Chowdhury. 2007. “Bilirubin metabolism.” Textbook of Hepatology. From Basic Science to Clinical Practice. eds Rodes, Juan et al. 3rd Edition. Blackwell Publishing. Pages 165-174.
  6. Voet, D. & Voet, J.G. (2011). Biochemistry. 4th Edition. New York: J. Wiley and Sons.

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.