Jaundice

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 updated: October 13, 2022

CONTENTS

Definition
Pathophysiology
Etiology
Clinical Presentation and Diagnosis
Management
Differential Diagnosis
References

Definition
 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

Pathophysiology
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 1–2 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

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

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

Hemolysis
Obstruction
Tumor
Liver disease

Etiology
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) Hemolytic disorders Inherited:
hyperbilirubinemia Spherocytosis
Glucose-6-phosphate
dehydrogenase
deficiency
Pyruvate kinase
deficiency
Sickle cell anemia
Acquired:
Hemolytic anemia
Paroxysmal nocturnal
hemoglobinuria
Parasitic infections
(malaria, babesiosis)
Antimalarials (e.g.,
dapsone)

Ineffective Inherited:
erythropoiesis Thalassemia
Acquired
Vitamin B12 deficiency
Severe iron deficiencies

Increased bilirubin Secondary to:

production Massive blood
transfusion
Resorption of hematoma

Decreased bilirubin Physiologic jaundice of

conjugation the newborn
Crigler-Najjar types I and
II
Gilbert's syndrome

Drugs 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 Dubin-Johnson syndrome

excretion/reuptake of Rotor syndrome
bilirubin:

Mixed (both indirect and Chronic conditions Hepatitis (viral,

direct) autoimmune, toxic, and
hyperbilirubinemia 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
Intrahepatic
 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

Extrahepatic

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

Diagnosis
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
PT/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.

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- Pale, clay-

colored colored

Blood Indirect bilirubin ↑↑ ↑ Normal

work

Direct bilirubin Normal ↑ ↑↑

Anemia Present Absent Absent

Alkaline Normal ↑ ↑↑
phosphatase

Transaminases Normal ↑↑ ↑

Urinalysis Color Normal or Dark Dark or very

dark dark

Urobilinogen ↑↑ Normal or ↑ Low or

absent

Bile salt Absent Absent Present

Management
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).

References

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.