Jaundice, also known as icterus, is a yellowish or, less frequently, greenish pigmentation of the skin and conjunctivae due to high bilirubin levels. Jaundice in adults typically indicates the presence of underlying diseases involving abnormal heme metabolism, liver dysfunction, or biliary-tract obstruction. The prevalence of jaundice in adults is rare, while jaundice in babies is common, with an estimated 80% affected during their first week of life. The most commonly associated symptoms of jaundice are itchiness, pale feces, and dark urine.
Normal levels of bilirubin in blood are below 1.0 mg/dl (17 μmol/L), while levels over 2–3 mg/dl (34–51 μmol/L) typically result in jaundice. High blood bilirubin is divided into two types: unconjugated and conjugated bilirubin.
Causes of jaundice vary from relatively benign to potentially fatal. High unconjugated bilirubin may be due to excess red blood cell breakdown, large bruises, genetic conditions such as Gilbert's syndrome, not eating for a prolonged period of time, newborn jaundice, or thyroid problems. High conjugated bilirubin may be due to liver diseases such as cirrhosis or hepatitis, infections, medications, or blockage of the bile duct, due to factors including gallstones, cancer, or pancreatitis. Other conditions can also cause yellowish skin, but are not jaundice, including carotenemia, which can develop from eating large amounts of foods containing carotene—or medications such as rifampin.
Treatment of jaundice is typically determined by the underlying cause. If a bile duct blockage is present, surgery is typically required; otherwise, management is medical. Medical management may involve treating infectious causes and stopping medication that could be contributing to the jaundice. Jaundice in newborns may be treated with phototherapy or exchanged transfusion depending on age and prematurity when the bilirubin is greater than 4–21 mg/dl (68–365 μmol/L). The itchiness may be helped by draining the gallbladder, ursodeoxycholic acid, or opioid antagonists such as naltrexone. The word jaundice is from the French jaunisse, meaning 'yellow disease'.
Signs and symptoms
The most common signs of jaundice in adults are a yellowish discoloration of the white area of the eye (conjunctivae) and skin, with conjunctival icterus presence indicating a serum bilirubin of at least 3 mg/dl. Other common signs include dark urine (bilirubinuria) and pale (acholia) fatty stool (steatorrhea). Because bilirubin is a skin irritant, jaundice is commonly associated with severe itchiness.
Eye conjunctiva has a particularly high affinity for bilirubin deposition due to high elastin content. Slight increases in serum bilirubin can, therefore, be detected early on by observing the yellowing of conjunctivae. Traditionally referred to as scleral icterus, this term is actually a misnomer, because bilirubin deposition technically occurs in the conjunctival membranes overlying the avascular sclera. Thus, the proper term for the yellowing of "white of the eyes" is conjunctival icterus.
In individuals with darker skin tones, jaundice may be less readily apparent on the skin and is more reliably observed in areas such as the conjunctivae, palms, soles, and oral mucosa. Educational resources have increasingly highlighted this variation to support accurate clinical assessment across diverse populations.
A rare sign of jaundice in childhood is the appearance of yellowish or greenish teeth. In developing children, hyperbilirubinemia can lead to yellow or green tooth discoloration as bilirubin deposits during tooth calcification. While this may occur in children with hyperbilirubinemia, tooth discoloration due to hyperbilirubinemia is not observed in individuals with adult-onset liver disease. Disorders associated with a rise in serum levels of conjugated bilirubin during early development can also cause dental hypoplasia.
Causes
Jaundice is a sign indicating the presence of underlying diseases involving abnormal bilirubin metabolism, liver dysfunction, or biliary-tract obstruction. In general, jaundice is present when blood levels of bilirubin exceed 3 mg/dl. Jaundice is classified into three categories, depending on which part of the physiological mechanism the pathology affects. The three categories are:
CategoryDefinitionPrehepatic/hemolyticThe pathology occurs prior to the liver metabolism, due to either intrinsic causes to red blood cell rupture or extrinsic causes to red blood cell rupture.Hepatic/hepatocellularThe pathology is due to damage of parenchymal liver cells.Posthepatic/cholestaticThe pathology occurs after bilirubin conjugation in the liver, due to obstruction of the biliary tract and/or decreased bilirubin excretion.
Prehepatic causes Prehepatic jaundice is most commonly caused by a pathological increased rate of red blood cell (erythrocyte) hemolysis. The increased breakdown of erythrocytes → increased unconjugated serum bilirubin → increased deposition of unconjugated bilirubin into mucosal tissue. These diseases may cause jaundice due to increased erythrocyte hemolysis: Sickle-cell anemia Spherocytosis Thalassemia Pyruvate kinase deficiency Glucose-6-phosphate dehydrogenase deficiency Microangiopathic hemolytic anemia Hemolytic–uremic syndrome Some infections can also cause increased red blood cell turnover, including malaria and bartonellosis
Hepatic causes
Hepatic jaundice is caused by abnormal liver metabolism of bilirubin. The major causes of hepatic jaundice are significant damage to hepatocytes due to infectious, drug/medication-induced, autoimmune etiology, or less commonly, due to inheritable genetic diseases. The following is a partial list of hepatic causes to jaundice: Acute hepatitis Chronic hepatitis Hepatotoxicity Cirrhosis Drug-induced hepatitis Alcoholic liver disease Gilbert's syndrome (found in about 5% of the population, results in induced mild jaundice) Crigler–Najjar syndrome, type I Crigler–Najjar syndrome, type II Leptospirosis
Posthepatic causes (obstructive jaundice) Posthepatic jaundice (obstructive jaundice) is caused by a blockage of bile ducts that transport bile containing conjugated bilirubin out of the liver for excretion. This is a list of conditions that can cause posthepatic jaundice: Choledocholithiasis (common bile duct gallstones). It is the most common cause of obstructive jaundice. Pancreatic cancer of the pancreatic head Biliary tract strictures Biliary atresia Primary biliary cholangitis Cholestasis of pregnancy Acute Pancreatitis Chronic Pancreatitis Pancreatic pseudocysts Mirizzi's syndrome Parasites ("liver flukes" of the Opisthorchiidae and Fasciolidae)
Pathophysiology Jaundice is typically caused by an underlying pathological process that occurs at some point along the normal physiological pathway of heme metabolism. A deeper understanding of the anatomical flow of normal heme metabolism is essential to appreciate the importance of prehepatic, hepatic, and posthepatic categories. Thus, an anatomical approach to heme metabolism precedes a discussion of the pathophysiology of jaundice.
Normal heme metabolism
Prehepatic metabolism When red blood cells complete their lifespan of about 120 days, or if they are damaged, they rupture as they pass through the reticuloendothelial system, and cell contents including hemoglobin are released into circulation. Macrophages phagocytose free hemoglobin and split it into heme and globin. Two reactions then take place with the heme molecule. The first oxidation reaction is catalyzed by the microsomal enzyme heme oxygenase and results in biliverdin (green color pigment), iron, and carbon monoxide. The next step is the reduction of biliverdin to a yellow color tetrapyrrole pigment called bilirubin by cytosolic enzyme biliverdin reductase. This bilirubin is "unconjugated", "free", or "indirect" bilirubin. Around 4 mg of bilirubin per kg of blood are produced each day. The majority of this bilirubin comes from the breakdown of heme from expired red blood cells in the process just described. Roughly 20% comes from other heme sources, however, including ineffective erythropoiesis, and the breakdown of other heme-containing proteins, such as muscle myoglobin and cytochromes. The unconjugated bilirubin then travels to the liver through the bloodstream. Because this bilirubin is not soluble, it is transported through the blood bound to serum albumin.
Hepatic metabolism Once unconjugated bilirubin arrives in the liver, liver enzyme UDP-glucuronyl transferase conjugates bilirubin + glucuronic acid → bilirubin diglucuronide (conjugated bilirubin). Bilirubin that has been conjugated by the liver is water-soluble and excreted into the gallbladder.
Posthepatic metabolism Bilirubin enters the intestinal tract via bile. In the intestinal tract, bilirubin is converted into urobilinogen by symbiotic intestinal bacteria. Most urobilinogen is converted into stercobilinogen and further oxidized into stercobilin. Stercobilin is excreted via feces, giving stool its characteristic brown coloration. A small portion of urobilinogen is reabsorbed back into the gastrointestinal cells. Most reabsorbed urobilinogen undergoes hepatobiliary recirculation. A smaller portion of reabsorbed urobilinogen is filtered into the kidneys. In the urine, urobilinogen is converted to urobilin, which gives urine its characteristic yellow color.
Abnormalities in heme metabolism and excretion One way to understand jaundice pathophysiology is to organize it into disorders that cause increased bilirubin production (abnormal heme metabolism) or decreased bilirubin excretion (abnormal heme excretion).
Prehepatic pathophysiology Prehepatic jaundice results from a pathological increase in bilirubin production, most often as a result of an increased rate of red blood cell hemolysis, leading to an increased deposition of bilirubin in mucosal tissues and the appearance of a yellow hue.
Hepatic pathophysiology Hepatic jaundice (hepatocellular jaundice) is due to significant disruption of liver function, leading to hepatic cell death and necrosis and impaired bilirubin transport across hepatocytes. Bilirubin transport across hepatocytes may be impaired at any point between hepatocellular uptake of unconjugated bilirubin and hepatocellular transport of conjugated bilirubin into the gallbladder. In addition, subsequent cellular edema due to inflammation causes mechanical obstruction of the intrahepatic biliary tract. Most commonly, interferences in all three major steps of bilirubin metabolism—uptake, conjugation, and excretion—usually occur in hepatocellular jaundice. Thus, an abnormal rise in both unconjugated and conjugated bilirubin (formerly called cholemia) will be present. Because excretion (the rate-limiting step) is usually impaired to the greatest extent, conjugated hyperbilirubinemia predominates.
The unconjugated bilirubin still enters the liver cells and becomes conjugated in the usual way. This conjugated bilirubin is then returned to the blood, probably by rupture of the congested bile canaliculi and direct emptying of the bile into the lymph exiting the liver. Thus, most of the bilirubin in the plasma becomes the conjugated type rather than the unconjugated type, and this conjugated bilirubin, which did not go to the intestine to become urobilinogen, gives the urine a dark color.