(See also Liver Structure and Function Liver Structure and Function The liver is a metabolically complex organ. Hepatocytes (liver parenchymal cells) perform the liver’s metabolic functions: Formation and excretion of bile as a component of bilirubin metabolism... read more and Evaluation of the Patient With a Liver Disorder Evaluation of the Patient With a Liver Disorder History and physical examination often suggest a cause of potential liver disorders and narrow the scope of testing for hepatic and biliary disorders. Various symptoms may develop, but few are... read more .)
Pathophysiology of Jaundice
Most bilirubin is produced when hemoglobin (Hb) is broken down into unconjugated bilirubin (and other substances). Unconjugated bilirubin binds to albumin in the blood for transport to the liver, where it is taken up by hepatocytes and conjugated with glucuronic acid to make it water soluble. Conjugated bilirubin is excreted in bile into the duodenum. In the intestine, bacteria metabolize bilirubin to form urobilinogen. Some urobilinogen is eliminated in the feces, and some is reabsorbed, extracted by hepatocytes, reprocessed, and re-excreted in bile (enterohepatic circulation—see Overview of Bilirubin Metabolism Overview of bilirubin metabolism The liver is a metabolically complex organ. Hepatocytes (liver parenchymal cells) perform the liver’s metabolic functions: Formation and excretion of bile as a component of bilirubin metabolism... read more ).

Mechanisms of hyperbilirubinemia
Hyperbilirubinemia may involve predominantly unconjugated or conjugated bilirubin.
Unconjugated hyperbilirubinemia is most often caused by ≥ 1 of the following:
Increased production
Decreased hepatic uptake
Decreased conjugation
Conjugated hyperbilirubinemia is most often caused by ≥ 1 of the following:
Dysfunction of hepatocytes (hepatocellular dysfunction)
Slowing of bile egress from the liver (intrahepatic cholestasis)
Obstruction of extrahepatic bile flow (extrahepatic cholestasis)
Consequences
Outcome is determined primarily by the cause of jaundice and the presence and severity of hepatic dysfunction. Hepatic dysfunction can result in coagulopathy, encephalopathy, and portal hypertension Portal Hypertension Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in North America), schistosomiasis (in endemic areas), or hepatic vascular abnormalities. Consequences... read more (which can lead to gastrointestinal bleeding).
Etiology of Jaundice
Although hyperbilirubinemia can be classified as predominantly unconjugated or conjugated, many hepatobiliary disorders cause both forms.
Many conditions (see table ), including use of certain drugs (see table ), can cause jaundice, but the most common causes overall are
Inflammatory hepatitis Causes of Hepatitis Hepatitis is inflammation of the liver characterized by diffuse or patchy necrosis. Hepatitis may be acute or chronic (usually defined as lasting > 6 months). Most cases of acute viral hepatitis... read more (viral hepatitis, autoimmune hepatitis, toxic hepatic injury)
Biliary obstruction
Evaluation of Jaundice
History
History of present illness should include onset and duration of jaundice. Hyperbilirubinemia can cause urine to darken before jaundice is visible. Therefore, the onset of dark urine indicates onset of hyperbilirubinemia more accurately than onset of jaundice. Important associated symptoms include fever, prodromal symptoms (eg, fever, malaise, myalgias) before jaundice, changes in stool color, pruritus, steatorrhea, and abdominal pain (including location, severity, duration, and radiation). Important symptoms suggesting severe disease include nausea and vomiting, weight loss, and possible symptoms of coagulopathy (eg, easy bruising or bleeding, tarry or bloody stools).
Review of systems should seek symptoms of possible causes, including weight loss and abdominal pain (cancer); joint pain and swelling (autoimmune Overview of Chronic Hepatitis Chronic hepatitis is hepatitis that lasts > 6 months. Common causes include hepatitis B and C viruses, nonalcoholic steatohepatitis (NASH), alcohol-related liver disease, and autoimmune liver... read more or viral hepatitis Overview of Acute Viral Hepatitis Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A nonspecific viral prodrome is followed... read more , hemochromatosis Hereditary Hemochromatosis Hereditary hemochromatosis is a genetic disorder characterized by excessive iron (Fe) accumulation that results in tissue damage. Manifestations can include systemic symptoms, liver disorders... read more , primary sclerosing cholangitis Primary Sclerosing Cholangitis (PSC) Primary sclerosing cholangitis (PSC) is patchy inflammation, fibrosis, and strictures of the bile ducts that has no known cause. However, 80% of patients with PSC also have inflammatory bowel... read more , sarcoidosis Sarcoidosis Sarcoidosis is an inflammatory disorder resulting in noncaseating granulomas in one or more organs and tissues; etiology is unknown. The lungs and lymphatic system are most often affected, but... read more
); and missed menses (pregnancy).
Past medical history should identify known causative disorders, such as hepatobiliary disease (eg, gallstones Cholelithiasis Cholelithiasis is the presence of one or more calculi (gallstones) in the gallbladder. Gallstones tend to be asymptomatic. The most common symptom is biliary colic; gallstones do not cause dyspepsia... read more , hepatitis Causes of Hepatitis Hepatitis is inflammation of the liver characterized by diffuse or patchy necrosis. Hepatitis may be acute or chronic (usually defined as lasting > 6 months). Most cases of acute viral hepatitis... read more , cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more ); disorders that can cause hemolysis Overview of Hemolytic Anemia At the end of their normal life span (about 120 days), red blood cells (RBCs) are removed from the circulation. Hemolysis is defined as premature destruction and hence a shortened RBC life span... read more
(eg, hemoglobinopathy Overview of Hemoglobinopathies Hemoglobinopathies are genetic disorders affecting the structure or production of the hemoglobin molecule. Hemoglobin molecules consist of polypeptide chains whose chemical structure is genetically... read more , glucose-6-phosphate dehydrogenase [G6PD] deficiency Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzymatic defect common in people with African ancestry that can result in hemolysis after acute illnesses or intake of oxidant... read more
); and disorders associated with liver or biliary disease, including inflammatory bowel disease Overview of Inflammatory Bowel Disease Inflammatory bowel disease (IBD), which includes Crohn disease and ulcerative colitis, is a relapsing and remitting condition characterized by chronic inflammation at various sites in the gastrointestinal... read more , infiltrative disorders (eg, amyloidosis Amyloidosis Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more
, lymphoma Overview of Lymphoma Lymphomas are a heterogeneous group of tumors arising in the reticuloendothelial and lymphatic systems. The major types are Hodgkin lymphoma Non-Hodgkin lymphoma See table Comparison of Hodgkin... read more , sarcoidosis Sarcoidosis Sarcoidosis is an inflammatory disorder resulting in noncaseating granulomas in one or more organs and tissues; etiology is unknown. The lungs and lymphatic system are most often affected, but... read more
, tuberculosis Tuberculosis (TB) Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more
), and HIV infection or AIDS Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more
.
Drug history should include questions about use of drugs or exposure to toxins known to affect the liver (see table ) and about vaccination against hepatitis.
Surgical history should include questions about previous surgery on the biliary tract (a potential cause of strictures).
Social history should include questions about risk factors for hepatitis (see table Some Risk Factors for Hepatitis), amount and duration of alcohol use, injection drug use, and sexual history.
Family history should include questions about recurrent, mild jaundice in family members and diagnosed hereditary liver disorders. The patient’s history of recreational drug and alcohol use should be corroborated by friends or family members when possible.
Physical examination
Vital signs are reviewed for fever and signs of systemic toxicity (eg, hypotension, tachycardia).
General appearance is noted, particularly for cachexia and lethargy.
Head and neck examination includes inspection of the sclerae and tongue for icterus and the eyes for Kayser-Fleischer rings Kayser-Fleischer rings Wilson disease results in accumulation of copper in the liver and other organs. Hepatic or neurologic symptoms develop. Diagnosis is based on a low serum ceruloplasmin level, high urinary excretion... read more (best seen with slit lamp). Mild jaundice is best seen by examining the sclerae in natural light; it is usually detectable when serum bilirubin reaches 2 to 2.5 mg/dL (34 to 43 micromol/L). Breath odor should be noted (eg, for fetor hepaticus).
The abdomen is inspected for collateral vasculature, ascites Ascites Ascites is free fluid in the peritoneal cavity. The most common cause is portal hypertension. Symptoms usually result from abdominal distention. Diagnosis is based on physical examination and... read more , and surgical scars. The liver is palpated for hepatomegaly, masses, nodularity, and tenderness. The spleen is palpated for splenomegaly. The abdomen is examined for umbilical hernia, shifting dullness, fluid wave, masses, and tenderness. The rectum is examined for gross or occult blood.
Men are checked for testicular atrophy and gynecomastia.
The upper extremities are examined for Dupuytren contractures Dupuytren Contracture Dupuytren contracture is progressive contracture of the palmar fascial bands, causing flexion deformities of the fingers. Treatment is with corticosteroid injection, surgery, or injections of... read more .
Neurologic examination includes mental status assessment and evaluation for asterixis (a characteristic flapping tremor of the hands).
The skin is examined for jaundice, palmar erythema, needle tracks, vascular spiders, excoriations, xanthomas (consistent with primary biliary cholangitis Primary Biliary Cholangitis (PBC) Primary biliary cholangitis (PBC; formerly known as primary biliary cirrhosis) is an autoimmune liver disorder characterized by the progressive destruction of intrahepatic bile ducts, leading... read more ), paucity of axillary and pubic hair, hyperpigmentation, ecchymoses, petechiae, and purpura.
Red flags
The following findings are of particular concern:
Marked abdominal pain and tenderness
Altered mental status
Gastrointestinal (GI) bleeding (occult or gross)
Ecchymoses, petechiae, or purpura
Interpretation of findings
Severity of illness is indicated mainly by the degree (if any) of hepatic dysfunction. Ascending cholangitis is a concern because it requires emergency treatment.
Severe hepatic dysfunction is indicated by encephalopathy (eg, mental status change, asterixis) or coagulopathy (eg, easy bleeding, purpura, tarry or heme-positive stool), particularly in patients with signs of portal hypertension Portal Hypertension Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in North America), schistosomiasis (in endemic areas), or hepatic vascular abnormalities. Consequences... read more (eg, abdominal collateral vasculature, ascites, splenomegaly). Massive upper GI bleeding suggests variceal bleeding Varices Varices are dilated veins in the distal esophagus or proximal stomach caused by elevated pressure in the portal venous system, typically from cirrhosis. They may bleed massively but cause no... read more due to portal hypertension (and possibly coagulopathy).
Ascending cholangitis is suggested by fever and marked, continuous right upper quadrant abdominal pain; acute pancreatitis Acute Pancreatitis Acute pancreatitis is acute inflammation of the pancreas (and, sometimes, adjacent tissues). The most common triggers are gallstones and alcohol intake. The severity of acute pancreatitis is... read more with biliary obstruction Choledocholithiasis and Cholangitis Choledocholithiasis is the presence of stones in bile ducts; the stones can form in the gallbladder or in the ducts themselves. These stones cause biliary colic, biliary obstruction, gallstone... read more (eg, due to a common duct stone or pancreatic pseudocyst) may manifest similarly.
Cause of jaundice may be suggested by the following:
Acute jaundice in the young and healthy suggests acute viral hepatitis Overview of Acute Viral Hepatitis Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A nonspecific viral prodrome is followed... read more , particularly when a viral prodrome, risk factors, or both are present; however, acetaminophen overdose Acetaminophen Poisoning Acetaminophen poisoning can cause gastroenteritis within hours and hepatotoxicity 1 to 3 days after ingestion. Severity of hepatotoxicity after a single acute overdose is predicted by serum... read more is also common.
Acute jaundice after acute drug or toxin exposure in healthy patients is likely to be due to that substance.
A long history of heavy alcohol use suggests alcohol-related liver disease Alcohol-Related Liver Disease Alcohol consumption is high in most Western countries. According to a survey using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of alcohol... read more
, particularly when typical stigmata are present.
A personal or family history of recurrent, mild jaundice without findings of hepatobiliary dysfunction suggests a hereditary disorder, usually Gilbert syndrome Gilbert Syndrome Hereditary or inborn metabolic disorders may cause unconjugated or conjugated hyperbilirubinemia (see Overview of bilirubin metabolism). Unconjugated hyperbilirubinemia: Crigler-Najjar syndrome... read more .
Gradual onset of jaundice with pruritus, weight loss, and clay-colored stools suggests intrahepatic or extrahepatic cholestasis.
Painless jaundice in older patients with weight loss and a mass but with minimal pruritus suggests biliary obstruction caused by cancer.
Other examination findings can also be helpful (see table ).
Testing
The following are done:
Blood tests Laboratory Tests of the Liver and Gallbladder Laboratory tests are generally effective for the following: Detecting hepatic dysfunction Assessing the severity of liver injury Monitoring the course of liver diseases and the response to treatment... read more (bilirubin, aminotransferase, alkaline phosphatase)
Usually imaging
Blood tests include measurement of total and direct bilirubin, aminotransferase, and alkaline phosphatase levels in all patients. Results help differentiate cholestasis from hepatocellular dysfunction (important because patients with cholestasis usually require imaging tests):
Hepatocellular dysfunction: Marked aminotransferase elevation (> 500 U/L [8.35 microkat/L]) and moderate alkaline phosphatase elevation (< 3 times normal)
Cholestasis: Moderate aminotransferase elevation (< 200 U/L [3.34 microkat/L]) and marked alkaline phosphatase elevation (> 3 times normal)
Also, patients with hepatocellular dysfunction or cholestasis have dark urine due to bilirubinuria because conjugated bilirubin is excreted in urine; unconjugated bilirubin is not. Bilirubin fractionation also differentiates conjugated from unconjugated forms. When aminotransferase and alkaline phosphatase levels are normal, fractionation of bilirubin can help suggest causes, such as Gilbert syndrome Gilbert Syndrome Hereditary or inborn metabolic disorders may cause unconjugated or conjugated hyperbilirubinemia (see Overview of bilirubin metabolism). Unconjugated hyperbilirubinemia: Crigler-Najjar syndrome... read more or hemolysis Overview of Hemolytic Anemia At the end of their normal life span (about 120 days), red blood cells (RBCs) are removed from the circulation. Hemolysis is defined as premature destruction and hence a shortened RBC life span... read more (unconjugated) vs Dubin-Johnson syndrome Dubin-Johnson Syndrome and Rotor Syndrome Hereditary or inborn metabolic disorders may cause unconjugated or conjugated hyperbilirubinemia (see Overview of bilirubin metabolism). Unconjugated hyperbilirubinemia: Crigler-Najjar syndrome... read more or Rotor syndrome Dubin-Johnson Syndrome and Rotor Syndrome Hereditary or inborn metabolic disorders may cause unconjugated or conjugated hyperbilirubinemia (see Overview of bilirubin metabolism). Unconjugated hyperbilirubinemia: Crigler-Najjar syndrome... read more (conjugated).
Other blood tests are done based on clinical suspicion and initial test findings, as for the following:
Signs of hepatic insufficiency (eg, encephalopathy Portosystemic Encephalopathy Portosystemic encephalopathy is a neuropsychiatric syndrome that can develop in patients with liver disease. It most often results from high gut protein or acute metabolic stress (eg, gastrointestinal... read more , ascites Ascites Ascites is free fluid in the peritoneal cavity. The most common cause is portal hypertension. Symptoms usually result from abdominal distention. Diagnosis is based on physical examination and... read more , ecchymoses) or gastrointestinal (GI) bleeding: Coagulation profile (prothrombin time [PT]/partial thromboplastin time [PTT])
Hepatitis risk factors (see table Some Risk Factors for Hepatitis Some Risk Factors for Hepatitis
) or a hepatocellular mechanism suggested by blood test results: Hepatitis viral and autoimmune serologic tests Serology Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A nonspecific viral prodrome is followed... read more
Fever, abdominal pain, and tenderness: Complete blood count and, if patients appear ill, blood cultures
Suspicion of hemolysis Overview of Hemolytic Anemia At the end of their normal life span (about 120 days), red blood cells (RBCs) are removed from the circulation. Hemolysis is defined as premature destruction and hence a shortened RBC life span... read more can be confirmed by a peripheral blood smear.
Imaging is done if pain suggests extrahepatic obstruction or cholangitis or if blood test results suggest cholestasis.
Abdominal ultrasonography is usually done first; usually, it is highly accurate in detecting extrahepatic obstruction. CT and MRI are alternatives. Ultrasonography is usually more accurate for gallstones Cholelithiasis Cholelithiasis is the presence of one or more calculi (gallstones) in the gallbladder. Gallstones tend to be asymptomatic. The most common symptom is biliary colic; gallstones do not cause dyspepsia... read more , and CT is more accurate for pancreatic lesions. All these tests can detect abnormalities in the biliary tree and focal liver lesions but are less accurate in detecting diffuse hepatocellular disorders (eg, hepatitis Overview of Acute Viral Hepatitis Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A nonspecific viral prodrome is followed... read more , cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more ).
If ultrasonography shows extrahepatic cholestasis, other tests may be necessary to determine the cause; usually, magnetic resonance cholangiopancreatography (MRCP) Magnetic resonance imaging (MRI) , endoscopic ultrasonography (EUS), or endoscopic retrograde cholangiopancreatography (ERCP) Endoscopic retrograde cholangiopancreatography (ERCP) Imaging is essential for accurately diagnosing biliary tract disorders and is important for detecting focal liver lesions (eg, abscess, tumor). It is limited in detecting and diagnosing diffuse... read more
is used. ERCP is more invasive but allows treatment of some obstructive lesions (eg, stone removal, stenting of strictures).
Liver biopsy Liver Biopsy Liver biopsy provides histologic information about liver structure and evidence of liver injury (type and degree, any fibrosis); this information can be essential not only to diagnosis but also... read more is not commonly required but can help diagnose certain disorders (eg, disorders causing intrahepatic cholestasis, some kinds of hepatitis, some infiltrative disorders, Dubin-Johnson syndrome Dubin-Johnson Syndrome and Rotor Syndrome Hereditary or inborn metabolic disorders may cause unconjugated or conjugated hyperbilirubinemia (see Overview of bilirubin metabolism). Unconjugated hyperbilirubinemia: Crigler-Najjar syndrome... read more , hemochromatosis Hereditary Hemochromatosis Hereditary hemochromatosis is a genetic disorder characterized by excessive iron (Fe) accumulation that results in tissue damage. Manifestations can include systemic symptoms, liver disorders... read more , Wilson disease Wilson Disease Wilson disease results in accumulation of copper in the liver and other organs. Hepatic or neurologic symptoms develop. Diagnosis is based on a low serum ceruloplasmin level, high urinary excretion... read more
). Biopsy can also help when liver enzyme abnormalities are unexplained by other tests.
Laparoscopy (peritoneoscopy) allows direct inspection of the liver and gallbladder without the trauma of a full laparotomy. Unexplained cholestatic jaundice warrants laparoscopy occasionally and diagnostic laparotomy rarely.
Treatment of Jaundice
Treatment of causes and complications
The cause and any complications are treated. Jaundice itself requires no treatment in adults (unlike in neonates—see Neonatal Hyperbilirubinemia Neonatal Hyperbilirubinemia Jaundice is a yellow discoloration of the skin and eyes caused by hyperbilirubinemia (elevated serum bilirubin concentration). The serum bilirubin level required to cause jaundice varies with... read more ). Itching, if bothersome, may be relieved with cholestyramine 2 to 8 g orally twice a day. However, cholestyramine is ineffective in patients with complete biliary obstruction.
Geriatrics Essentials: Jaundice
Symptoms may be attenuated or missed in the older patient; eg, abdominal pain may be mild or absent in acute viral hepatitis Overview of Acute Viral Hepatitis Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A nonspecific viral prodrome is followed... read more . A sleep disturbance or mild confusion resulting from portosystemic encephalopathy Portosystemic Encephalopathy Portosystemic encephalopathy is a neuropsychiatric syndrome that can develop in patients with liver disease. It most often results from high gut protein or acute metabolic stress (eg, gastrointestinal... read more may be misattributed to dementia.
Key Points
Suspect acute viral hepatitis in patients, particularly young and healthy patients, who have acute jaundice, particularly with a viral prodrome.
Suspect biliary obstruction due to cancer in older patients with painless jaundice, weight loss, an abdominal mass, and minimal pruritus.
Suspect hepatocellular dysfunction if aminotransferase levels are > 500 U/L and alkaline phosphatase elevation is < 3 times normal.
Suspect cholestasis if aminotransferase levels are < 200 U/L and alkaline phosphatase elevation is > 3 times normal.
Hepatic dysfunction is significant if mental status is altered and coagulopathy is present.
Drugs Mentioned In This Article
Drug Name | Select Trade |
---|---|
acetaminophen |
7T Gummy ES, Acephen, Aceta, Actamin, Adult Pain Relief, Anacin Aspirin Free, Apra, Children's Acetaminophen, Children's Pain & Fever , Comtrex Sore Throat Relief, ED-APAP, ElixSure Fever/Pain, Feverall, Genapap, Genebs, Goody's Back & Body Pain, Infantaire, Infants' Acetaminophen, LIQUID PAIN RELIEF, Little Fevers, Little Remedies Infant Fever + Pain Reliever, Mapap, Mapap Arthritis Pain, Mapap Infants, Mapap Junior, M-PAP, Nortemp, Ofirmev, Pain & Fever , Pain and Fever , PAIN RELIEF , PAIN RELIEF Extra Strength, Panadol, PediaCare Children's Fever Reducer/Pain Reliever, PediaCare Children's Smooth Metls Fever Reducer/Pain Reliever, PediaCare Infant's Fever Reducer/Pain Reliever, Pediaphen, PHARBETOL, Plus PHARMA, Q-Pap, Q-Pap Extra Strength, Silapap, Triaminic Fever Reducer and Pain Reliever, Triaminic Infant Fever Reducer and Pain Reliever, Tylenol, Tylenol 8 Hour, Tylenol 8 Hour Arthritis Pain, Tylenol 8 Hour Muscle Aches & Pain, Tylenol Arthritis Pain, Tylenol Children's, Tylenol Children's Pain+Fever, Tylenol CrushableTablet, Tylenol Extra Strength, Tylenol Infants', Tylenol Infants Pain + Fever, Tylenol Junior Strength, Tylenol Pain + Fever, Tylenol Regular Strength, Tylenol Sore Throat, XS No Aspirin, XS Pain Reliever |
cholestyramine |
Locholest , Locholest Light, Prevalite , Questran, Questran Light |