Jaundice

Jaundice, or icterus, is a condition characterised by a yellowish or greenish discoloration of the skin and sclera resulting from elevated bilirubin levels in the bloodstream. This biochemical state, termed hyperbilirubinaemia, reflects an underlying disturbance in bilirubin production, metabolism or excretion. While jaundice in adults is comparatively uncommon and usually signals a significant underlying disorder, neonatal jaundice is exceedingly common, affecting the majority of newborns during their first week of life. Clinical recognition of jaundice plays an essential diagnostic role in hepatology, haematology and paediatrics.

Overview of Bilirubin Biology

Bilirubin derives largely from the breakdown of haem-containing proteins, especially aged erythrocytes. It exists in two principal forms: unconjugated bilirubin, which is lipid-soluble and transported in the bloodstream bound to albumin, and conjugated bilirubin, which is water-soluble following hepatic enzymatic modification. Normal serum bilirubin levels are typically below 1.0 mg/dL (approximately 17 µmol/L). Visible jaundice usually develops when total bilirubin exceeds about 2–3 mg/dL. The division between conjugated and unconjugated bilirubin aids clinicians in determining the likely origin of jaundice.
Elevations in unconjugated bilirubin may result from conditions such as haemolytic anaemia, extensive bruising, genetic syndromes including Gilbert’s syndrome, fasting, thyroid disease or neonatal immaturity of bilirubin-metabolising enzymes. Conjugated hyperbilirubinaemia more commonly reflects intrinsic liver disease—such as hepatitis or cirrhosis—or mechanical obstruction of the bile ducts due to gallstones, malignancy or inflammation.
Not all yellowish skin discolouration signifies jaundice; conditions such as carotenemia or the pigmentary effects of certain medications, including rifampin, may mimic jaundice without elevated bilirubin.

Signs and Symptoms

The classical sign of jaundice is a visible yellowing of the sclerae and skin. Discolouration of the sclerae, more accurately termed conjunctival icterus, typically emerges when bilirubin exceeds about 3 mg/dL. Dark urine due to bilirubin excretion and pale stools resulting from reduced stercobilin may also accompany jaundice. Many patients experience pruritus because bilirubin and associated bile salts act as skin irritants.
Clinical assessment must take account of skin tone, as jaundice may be subtle in individuals with darker skin and is more reliably detected in the sclerae, oral mucosa, palms and soles. In paediatric populations, prolonged neonatal hyperbilirubinaemia may cause yellow or green staining of developing teeth and, in some cases, enamel hypoplasia.

Causes of Jaundice

Jaundice can be classified into prehepatic, hepatic and posthepatic categories corresponding to stages of bilirubin metabolism.
Prehepatic (haemolytic) jaundiceThis form arises from increased haem breakdown due to enhanced erythrocyte destruction. The resulting surge in bilirubin production overwhelms the liver’s conjugation capacity, leading to elevated circulating unconjugated bilirubin. Causes include haemolytic anaemia, severe malaria and extensive haematoma resorption.
Hepatic (hepatocellular) jaundiceHepatic jaundice results from impaired hepatic uptake, conjugation or secretion of bilirubin. Conditions causing hepatocellular injury—including viral hepatitis, autoimmune hepatitis, alcoholic and non-alcoholic liver disease, drug-induced liver injury and inherited metabolic defects—can all disrupt bilirubin processing. Among the general population, benign hereditary conditions such as Gilbert’s syndrome may lead to mild, fluctuating unconjugated hyperbilirubinaemia.
Posthepatic (obstructive) jaundicePosthepatic jaundice, also referred to as obstructive jaundice, develops when bile flow is impeded after bilirubin has been conjugated by the liver. Gallstones represent the most common cause, but other obstructive lesions such as pancreatic head tumours, biliary strictures and parasitic infections (e.g., liver flukes) may also prevent normal bile excretion.

Normal Heme Metabolism

The pathophysiology of jaundice is best understood within the context of normal haem metabolism. Senescent erythrocytes, typically surviving around 120 days, are cleared by macrophages of the reticuloendothelial system. Haemoglobin released from these cells is dismantled into globin, iron and haem. The haem fraction undergoes oxidation by haem oxygenase, yielding biliverdin, which is subsequently reduced to unconjugated bilirubin by biliverdin reductase.
Unconjugated bilirubin circulates tightly bound to albumin due to its water-insoluble nature. Upon reaching the liver, hepatocytes conjugate bilirubin with glucuronic acid via UDP-glucuronyltransferase, forming conjugated bilirubin. This water-soluble molecule is secreted into bile canaliculi, stored briefly in the gallbladder and delivered into the small intestine.
Intestinal bacteria convert conjugated bilirubin into urobilinogen. The majority proceeds to stercobilin, imparting the characteristic brown colour of stool. A fraction of urobilinogen is reabsorbed, with most re-excreted into bile through enterohepatic circulation, and a smaller portion filtered by the kidneys, where it is converted to urobilin and excreted, producing the yellow colour of urine.

Pathophysiology of Jaundice

The pathophysiological mechanisms underlying jaundice reflect abnormalities in production, metabolism or excretion of bilirubin.
Prehepatic mechanismsExcessive production of bilirubin overwhelms hepatic conjugating capacity. Elevated unconjugated bilirubin circulates in the bloodstream, depositing in tissues and producing characteristic discolouration. Liver function typically remains intact in such cases.
Hepatic mechanismsHepatocellular disorders impair the liver’s ability to conjugate or secrete bilirubin. Inflammation, necrosis or cholestasis disrupt normal hepatocyte function, leading to mixed elevations of unconjugated and conjugated bilirubin. Additional features may include impaired protein synthesis, coagulopathy or hepatic encephalopathy depending on disease severity.
Posthepatic mechanismsMechanical obstruction prevents the flow of conjugated bilirubin into the gastrointestinal tract. Conjugated bilirubin regurgitates into the circulation, causing jaundice, dark urine and pale stools due to reduced stercobilin. Persistent obstruction may produce complications such as ascending cholangitis or secondary biliary cirrhosis.

Management

Treatment of jaundice depends entirely on the underlying cause. Obstructive jaundice often requires surgical or interventional procedures to relieve blockages, such as removal of gallstones or stenting of obstructed ducts. In hepatic causes, management focuses on treating viral infections, withdrawing hepatotoxic medications or addressing autoimmune processes. Prehepatic forms require treatment of the underlying cause of haemolysis, such as malaria or haematological disorders.
Neonatal jaundice is commonly managed with phototherapy, which converts bilirubin into water-soluble isomers that can be excreted without conjugation. Severe neonatal cases may require exchange transfusion. Symptomatic relief of pruritus may be attempted using agents such as ursodeoxycholic acid or opioid antagonists including naltrexone.