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Jaundice

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by Steven K. Herrine, MD

Jaundice is a yellowish discoloration of the skin and mucous membranes caused by hyperbilirubinemia. Jaundice becomes visible when the bilirubin level is about 2 to 3 mg/dL (34 to 51 μmol/L).

Pathophysiology

Most bilirubin is produced when 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).

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 (which can lead to GI bleeding).

Etiology

Although hyperbilirubinemia can be classified as predominantly unconjugated or conjugated, many hepatobiliary disorders cause both forms.

Many conditions (see Table: Mechanisms and Some Causes of Jaundice in Adults), including use of certain drugs (see Table: Some Drugs and Toxins That Can Cause Jaundice), can cause jaundice, but the most common causes overall are

  • Inflammatory hepatitis (viral hepatitis, autoimmune hepatitis, toxic hepatic injury)

  • Alcoholic liver disease

  • Biliary obstruction

Mechanisms and Some Causes of Jaundice in Adults

Mechanism

Examples

Suggestive Findings*

Unconjugated hyperbilirubinemia

Increased bilirubin production

Common: Hemolysis

Less common: Resorption of large hematomas, ineffective erythropoiesis

Few or no clinical manifestations of hepatobiliary disease; sometimes anemia, ecchymoses

Serum bilirubin level usually < 3.5 mg/dL (< 59 μmol/L), no bilirubin in urine, normal aminotransferase levels

Decreased hepatic bilirubin uptake

Common: Heart failure

Less common: Drugs, fasting, portosystemic shunts

Decreased hepatic conjugation

Common: Gilbert syndrome

Less common: Ethinyl estradiol, Crigler-Najjar syndrome, hyperthyroidism

Conjugated hyperbilirubinemia

Hepatocellular dysfunction

Common: Drugs, toxins, viral hepatitis

Less common: Alcoholic liver disease, hemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis, steatohepatitis, Wilson disease

Aminotransferase levels usually > 500 U/L

Intrahepatic cholestasis

Common: Alcoholic liver disease, drugs, toxins, viral hepatitis

Less common: Infiltrative disorders (eg, amyloidosis, lymphoma, sarcoidosis, TB), pregnancy, primary biliary cirrhosis, steatohepatitis

Gradual onset of jaundice, sometimes pruritus

If severe, clay-colored stools, steatorrhea

If long-standing, weight loss

Alkaline phosphatase and GGT usually > 3 times normal

Aminotransferase levels < 200 U/L

Extrahepatic cholestasis

Common: Common bile duct stone, pancreatic cancer

Less common: Acute cholangitis, pancreatic pseudocyst, primary sclerosing cholangitis, common duct strictures caused by previous surgery, other tumors

Depending on cause, manifestations possibly similar to those of intrahepatic cholestasis or a more acute disorder (eg, abdominal pain or vomiting due to a common bile duct stone or acute pancreatitis)

Alkaline phosphatase and GGT usually > 3 times normal

Aminotransferase levels < 200 U/L

Other, less common mechanisms

Hereditary disorders (mainly Dubin-Johnson syndrome and Rotor syndrome)

Normal liver enzymes

*Symptoms and signs of the causative disorder may be present.

Bilirubin is present in urine.

GGT =γ-glutamyltransferase.

Some Drugs and Toxins That Can Cause Jaundice

Mechanism

Drugs or Toxins

Increased bilirubin production

Drugs that cause hemolysis (common among patients with G6PD deficiency), such as sulfa drugs and nitrofurantoin

Decreased hepatic uptake

Chloramphenicol, probenecid, rifampin

Decreased conjugation

Ethinyl estradiol

Hepatocellular dysfunction

Acetaminophen (high dose or overdose), amiodarone, isoniazid, NSAIDs, statins, many others, many drug combinations

Amanita phalloides mushrooms, carbon tetrachloride, phosphorus

Intrahepatic cholestasis

Amoxicillin/clavulanate, anabolic steroids, chlorpromazine, pyrrolizidine alkaloids (eg, in herbal preparations), oral contraceptives, phenothiazines

Evaluation

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 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, G6PD deficiency); and disorders associated with liver or biliary disease, including inflammatory bowel disease, infiltrative disorders (eg, amyloidosis, lymphoma, sarcoidosis, TB), 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.

Some Risk Factors for Hepatitis

Type of Hepatitis

Risk Factors

A

Day care attendance or employment

Residence or employment in a closed institution

Travel to an endemic area

Oral-anal sex

Ingestion of raw shellfish

B

Injection drug use

Hemodialysis

Sharing of razor blades or toothbrushes

Tattooing

Body piercing

Absence of vaccination in health care workers

High-risk sexual activity

Birth in areas of high endemicity

C

Blood transfusion before 1992

Injection drug use

Hemodialysis

Exposure during health care work or sexual activity

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. 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 μmol/L). Breath odor should be noted (eg, for fetor hepaticus).

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.

The skin is examined for jaundice, palmar erythema, needle tracks, vascular spiders, excoriations, xanthomas (consistent with primary biliary cirrhosis), 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

  • 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 (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 alcoholic 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 elderly 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).

Findings Suggesting a Cause of Jaundice

Finding

Possible Causes

Risk factors

Alcohol use (heavy)

Alcoholic liver disease, including alcoholic hepatitis and cirrhosis

GI cancer

Extrahepatic biliary obstruction

Hypercoagulable state

Hepatic vein thrombosis (Budd-Chiari syndrome)

Inflammatory bowel disease

Primary sclerosing cholangitis

Pregnancy

Intrahepatic cholestasis, steatohepatitis (acute fatty liver due to pregnancy)

Previous cholecystectomy

Biliary stricture

Retained or recurrent common duct stone

Recent surgery

Ischemic hepatitis

Benign postoperative intrahepatic cholestasis

Lengthy cardiac bypass surgery

Symptoms

Colicky right upper quadrant, right shoulder, or subscapular pain (current or previous)

Choledocholithiasis

Constant right upper quadrant pain

Acute alcoholic or viral hepatitis, acute cholangitis

Dark urine

Conjugated hyperbilirubinemia

Joint pain, swelling, or both

Hepatitis (autoimmune or viral)

Hemochromatosis

Primary sclerosing cholangitis

Sarcoidosis

Nausea or vomiting before jaundice

Acute hepatitis

Common bile duct obstruction by a stone (particularly if accompanied by abdominal pain or rigors)

Pruritus and clay-colored stools

Intrahepatic or extrahepatic cholestasis, possibly severe if stools are clay-colored

Viral prodrome (eg, fever, malaise, myalgias)

Acute viral hepatitis

Physical examination

Abdominal collateral vasculature, ascites, and splenomegaly

Portal hypertension (eg, due to cirrhosis)

Cachexia in a patient with a hard, lumpy liver

Metastases (common)

Cirrhosis (less often)

Diffuse lymphadenopathy in a patient with acute jaundice

Infectious mononucleosis

Diffuse lymphadenopathy in a patient with chronic jaundice

Lymphoma, leukemia

Dupuytren contractures, palmar erythema, paucity of axillary and pubic hair, and vascular spiders

Alcoholic liver disease

Gynecomastia and testicular atrophy

Alcoholic liver disease, anabolic steroid use

Hyperpigmentation

Hemochromatosis, primary biliary cirrhosis

Kayser-Fleischer rings

Wilson disease

Needle marks

Hepatitis B or C

Resolving hematoma

Extravasation of blood into tissues

Xanthomas

Primary biliary cirrhosis

Testing

The following are done:

  • Blood tests (bilirubin, aminotransferase, alkaline phosphatase)

  • Usually imaging

  • Sometimes biopsy or laparoscopy

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) and moderate alkaline phosphatase elevation (< 3 times normal)

  • Cholestasis: Moderate aminotransferase elevation (< 200 U/L) and marked alkaline phosphatase elevation (> 3 times normal)

  • Hyperbilirubinemia without hepatobiliary dysfunction: Mild hyperbilirubinemia (eg, < 3.5 mg/dL [< 59 μmol/L]) with normal aminotransferase and alkaline phosphatase levels

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 GI bleeding: Coagulation profile (PT/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: CBC 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 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.

Treatment

The cause and any complications are treated. Jaundice itself requires no treatment in adults (unlike in neonates—see Metabolic, Electrolyte, and Toxic Disorders in Neonates). Itching, if bothersome, may be relieved with cholestyramine 2 to 8 g po bid. However, cholestyramine is ineffective in patients with complete biliary obstruction.

Geriatrics Essentials

Symptoms may be attenuated or missed in the elderly; eg, abdominal pain may be mild or absent in acute viral hepatitis. A sleep disturbance or mild confusion resulting from portosystemic encephalopathy 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 elderly 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.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • FURADANTIN, MACROBID, MACRODANTIN
  • No US brand name
  • RIFADIN, RIMACTANE
  • LANIAZID
  • AMOXIL
  • CORDARONE
  • TYLENOL
  • ESTRADERM, ESTROGEL, VIVELLE

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