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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)

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 (which can lead to gastrointestinal bleeding).

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 or viral hepatitis, hemochromatosis, primary sclerosing cholangitis, sarcoidosis); and missed menses (pregnancy).

Past medical history should identify known causative disorders, such as hepatobiliary disease (eg, gallstones, hepatitis, cirrhosis); disorders that can cause hemolysis (eg, hemoglobinopathy, glucose-6-phosphate dehydrogenase [G6PD] deficiency); and disorders associated with liver or biliary disease, including inflammatory bowel disease, infiltrative disorders (eg, amyloidosis, lymphoma, sarcoidosis, tuberculosis), and HIV infection or AIDS.

Drug history should include questions about use of drugs or exposure to toxins known to affect the liver (see table Some Drugs and Toxins That Can Cause Jaundice) 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.

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 (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).

Jaundice

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The abdomen is inspected for collateral vasculature, ascites, 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.

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), paucity of axillary and pubic hair, hyperpigmentation, ecchymoses, petechiae, and purpura.

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

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 (eg, abdominal collateral vasculature, ascites, splenomegaly). Massive upper GI bleeding suggests variceal bleeding due to portal hypertension (and possibly coagulopathy).

Ascending cholangitis is suggested by fever and marked, continuous right upper quadrant abdominal pain; acute pancreatitis with biliary obstruction (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, particularly when a viral prodrome, risk factors, or both are present; however, acetaminophen overdose 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, 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.

• 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 Findings Suggesting a Cause of Jaundice).

The following are done:

• Blood tests (bilirubin, aminotransferase, alkaline phosphatase)

• Usually imaging

• Sometimes biopsy (percutaneous or transjugular approaches)

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 or hemolysis (unconjugated) vs Dubin-Johnson syndrome or Rotor syndrome (conjugated).

Other blood tests are done based on clinical suspicion and initial test findings, as for the following:

• Signs of hepatic insufficiency (eg, encephalopathy, ascites, ecchymoses) or gastrointestinal (GI) bleeding: Coagulation profile (prothrombin time [PT]/partial thromboplastin time [PTT])

• Hepatitis risk factors (see table Some Risk Factors for Hepatitis) or a hepatocellular mechanism suggested by blood test results: Hepatitis viral and autoimmune serologic tests

• Fever, abdominal pain, and tenderness: Complete blood count and, if patients appear ill, blood cultures

Suspicion of hemolysis 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, 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, cirrhosis).

If ultrasonography shows extrahepatic cholestasis, other tests may be necessary to determine the cause; usually, magnetic resonance cholangiopancreatography (MRCP), endoscopic ultrasonography (EUS), or endoscopic retrograde cholangiopancreatography (ERCP) is used. ERCP is more invasive but allows treatment of some obstructive lesions (eg, stone removal, stenting of strictures).

Liver biopsy 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, hemochromatosis, Wilson disease). 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.