What is the pathophysiology and etiology of jaundice?

Pathophysiology and Etiology of Jaundice

Jaundice results from systemic hyperbilirubinemia exceeding 2.5-3 mg/dL, causing yellow pigmentation of tissues through either bilirubin overproduction, impaired hepatic conjugation, biliary obstruction, or hepatocellular dysfunction. 1

Pathophysiology

Bilirubin Metabolism and Processing

Bilirubin is predominantly produced from breakdown of the haem component of hemoglobin by the reticuloendothelial system. 2 The substance exists in two critical forms:

• Unconjugated bilirubin is transported to the liver in its insoluble form, bound to albumin 2
• Conjugated bilirubin is the soluble form created in the liver via glucuronyltransferase enzyme activity, allowing excretion into bile 2

Mechanisms of Hyperbilirubinemia

The pathophysiology divides into distinct mechanisms based on where the defect occurs:

Unconjugated hyperbilirubinemia results from:

• Hemolysis producing bilirubin overproduction (accounts for 2.5% of cases) 3
• Impaired conjugation due to reduced glucuronyltransferase activity 2, 3
• Gilbert's syndrome, the most common cause of isolated elevated bilirubin, involves inherited reduced enzyme activity 2

Conjugated hyperbilirubinemia results from:

• Parenchymal liver disease causing hepatocellular dysfunction 2
• Biliary system obstruction preventing bilirubin excretion 2
• Bile duct disorders including choledocholithiasis and cholangiocarcinoma 3

Clinical Presentation Pattern

Jaundice becomes first visible in the sclera due to high elastin content with particular affinity for bilirubin, followed by generalized skin involvement as levels rise further. 1

Etiology

Most Common Causes by Category

The four most common etiologies across all types are: hepatitis/sepsis, alcoholic liver disease, common bile duct obstruction (stone or tumor), and drug-induced liver injury. 2

Prehepatic Causes (Unconjugated)

• Hemolysis from various causes produces unconjugated hyperbilirubinemia 3, 4
• Hematoma resorption leads to elevated unconjugated bilirubin 4
• Inherited disorders including Gilbert's syndrome (most common), Crigler-Najjar syndrome types 1 and 2 2, 5

Intrahepatic Causes (Mixed or Conjugated)

Hepatocellular dysfunction produces both unconjugated and conjugated hyperbilirubinemia with variable clinical presentations. 6

• Hepatitis accounts for 16% of jaundice cases 3
• Alcoholic liver disease represents 20.5% of cases 3
• Cirrhosis decompensation causes jaundice through multiple mechanisms 3
• Drug-induced liver disease from toxic reactions to medications or herbs 2, 6
• Sepsis creates mixed patterns through both hemolysis and hepatic dysfunction 6

Posthepatic Causes (Conjugated/Obstructive)

Malignancy is documented as one of the most common causes of jaundice, particularly severe jaundice, in European studies. 3 However, in U.S. studies, malignancy accounts for only 6.2% of all cases 3.

Mechanical obstruction of the biliary tract causes dark urine and pale/clay-colored stools as conjugated bilirubin cannot be excreted into intestines. 6

• Choledocholithiasis (gallstones in common bile duct) is the most common benign posthepatic cause 3, 4
• Pancreatic disorders including pancreatitis and pancreatic malignancy cause biliary obstruction 3, 6
• Cholangiocarcinoma and other biliary malignancies 3
• Biliary strictures from various causes 6

Diagnostic Framework

Laboratory Differentiation

The majority of measurable bilirubin should be conjugated except in neonates; if predominantly unconjugated in adults without hemolysis, the cause is virtually always Gilbert's syndrome. 2

Alkaline phosphatase elevation suggests cholestatic (posthepatic) causes, while transaminase elevation suggests hepatocellular (intrahepatic) causes. 6

Critical Pitfalls to Avoid

• In neonates and infants with conjugated bilirubin >25 μmol/L, urgent referral to a pediatrician for assessment of possible liver disease is essential to avoid missing biliary atresia 2
• Sepsis patients can have both hemolysis and hepatic dysfunction, creating mixed patterns requiring bilirubin fractionation 6
• Albumin reduction occurs in many non-hepatic conditions (sepsis, nephrotic syndrome, malabsorption), so overinterpretation as liver disease severity marker is not merited 2
• In mixed laboratory patterns where severe hepatic disease mimics posthepatic obstruction, correlation with imaging (ultrasound as initial test) is necessary 6