What are the most common causes of physiological and pathological jaundice?

Physiological vs. Pathological Jaundice: Key Distinctions and Common Causes

Physiological jaundice is a benign, self-limited condition in neonates caused by normal red blood cell breakdown and immature hepatic conjugation, while pathological jaundice results from disease processes requiring immediate investigation—including biliary obstruction, hepatic inflammation, hemolysis, or metabolic disorders—that can lead to permanent organ damage if untreated. 1, 2

Physiological Jaundice

Definition and Mechanism

• Physiological jaundice occurs in the majority of term and preterm neonates as a transitional event from normal red blood cell breakdown combined with immature liver conjugation systems 2
• This represents unconjugated hyperbilirubinemia that typically appears after 24 hours of life and resolves within 2 weeks in term infants 2, 3
• The condition is benign and responds to short-course phototherapy when bilirubin levels warrant intervention 2

Risk Factors Requiring Monitoring

• Gestational age <38 weeks, exclusive breastfeeding with poor intake, and East Asian ethnicity increase risk and necessitate aggressive monitoring protocols 1
• Visual inspection remains the primary screening method in UK practice, though this approach lacks standardization 3

Pathological Jaundice

Neonatal Pathological Causes

Conjugated hyperbilirubinemia (cholestasis):

• Biliary atresia is the critical diagnosis to exclude—any infant with jaundice persisting beyond 14 days must have conjugated bilirubin measured 2
• Genetic/metabolic causes account for 25-30% of neonatal cholestasis cases, with incidence of 1 in 2,500 live births 1
• Preterm infants on prolonged parenteral nutrition develop conjugated jaundice that improves with enteral feeding 2

Unconjugated hyperbilirubinemia:

• Rapidly rising bilirubin levels place infants at risk for kernicterus (bilirubin neurotoxicity) and require urgent treatment 2
• Hemolytic disease and metabolic disorders cause pathological unconjugated hyperbilirubinemia 4

Adult Pathological Causes

The American College of Radiology identifies four primary categories of adult jaundice based on pathophysiology 5, 1:

1. Hepatic Inflammation (Unconjugated/Mixed Pattern)

• Sepsis is the most common cause of new-onset jaundice in U.S. adults (22%) 5
• Decompensation of pre-existing chronic liver disease/cirrhosis (20.5%) 5
• Alcoholic hepatitis (16%) 5
• Viral hepatitis and drug-induced liver injury 5

2. Biliary Obstruction (Conjugated Pattern)

• Common bile duct stones (14% of cases) 5
• Malignancy (6.2% in U.S. studies, though European studies show malignancy as the most common cause of severe jaundice) 5
• Geographic and demographic factors significantly influence the dominant etiology 5

3. Bilirubin Overproduction (Unconjugated)

• Hemolysis (2.5% of cases) 5

4. Impaired Conjugation (Unconjugated)

• Gilbert syndrome (5.6%) 5

Clinical Differentiation Algorithm

Laboratory Approach

Initial workup must include 1, 6:

• Fractionated bilirubin (conjugated vs. unconjugated)—this is the critical first step
• Hepatic profile: alkaline phosphatase, ALT, AST, total protein
• Complete blood count
• Prothrombin time/INR and albumin

Pattern Recognition

• Unconjugated (nonobstructive) hyperbilirubinemia suggests hepatitis/sepsis, alcoholic liver disease, drug-induced liver disease, or hemolysis 5
• Conjugated (obstructive) hyperbilirubinemia indicates CBD obstruction from stones or tumor 5

Imaging Strategy

• Abdominal ultrasound is the mandatory first-line imaging with sensitivity of 65-95% for cirrhosis and variable sensitivity (32-100%) for biliary obstruction 5, 1
• MRCP follows when biliary obstruction is suspected but ultrasound is inconclusive 1
• ERCP is both diagnostic and therapeutic for stone extraction or malignant stenting 1

Critical Pitfalls to Avoid

• Never rely solely on visual inspection for assessing jaundice severity—serum bilirubin measurement is essential 3
• Always measure conjugated bilirubin in neonates with jaundice persisting beyond 14 days to avoid missing biliary atresia 2
• Recognize that CBD stones have lower ultrasound sensitivity (22.5-75%) compared to gallbladder stones due to bowel gas obscuration 5
• Geographic and clinical setting dramatically affect etiology—tertiary centers see more malignancy while community hospitals see more sepsis and alcoholic liver disease 5