Jaundice, or icterus, is yellowish discoloration of the skin, mucous membranes, sclerae, and body fluids resulting from excess accumulation and deposition of bilirubin in the body in the presence of serum hyperbilirubinemia. The yellow hue may be mimicked by carotenemia, but in the latter condition, no scleral icterus is present and bilirubin levels are normal.1 To appreciate the differential diagnosis of jaundice requires an understanding of the fundamental metabolism of bilirubin; the risk factors, epidemiology, and pathophysiology of common causes of jaundice; and the available serologic and imaging studies used in the workup of jaundiced patients. This article focuses on assessment of the adult patient with new-onset jaundice, reviews guidelines for selecting appropriate tests, and discusses interpretation of results.
NORMAL BILIRUBIN METABOLISM
Bilirubin is a breakdown product of hemoglobin in RBCs (Figure 1). Approximately 80% of bilirubin is formed from the breakdown of heme in reticuloendothelial cells, primarily the spleen and liver. The remainder comes from heme molecules in other proteins, such as myoglobin. Heme is converted to biliverdin by heme oxygenase and then to bilirubin by biliverdin reductase. The bilirubin formed by these enzymatic reactions is unconjugated or indirect and is highly insoluble in water. It is transported in the blood tightly but reversibly bound to albumin, escaping kidney filtration and readily taken up by the liver for conjugation. Normally, 90% to 95% of circulating bilirubin is unconjugated. Hypoalbuminemia, displacement of bilirubin from the albumin molecules by various medications, and/or elevated levels of unconjugated bilirubin in the blood may cause diffusion of bilirubin across the blood-brain barrier. When unconjugated bilirubin levels in the blood reach 15 to 20 mg/dL, bilirubin encephalopathy or kernicterus may occur.
Hepatic uptake of unconjugated bilirubin across the sinusoidal membrane occurs, and within the hepatocyte, bilirubin is conjugated by microsomal uridine diphosphoglucuronyl transferase (UDPGT) to a direct, water-soluble form facilitating its excretion into bile. Bilirubin that spills into the urine therefore is conjugated bilirubin. Biliary excretion is mediated by an ATP-dependent canalicular multispecific organic anion transporter. This process is highly efficient under normal conditions, so plasma unconjugated bilirubin concentrations remain low.2 Normal serum values for total bilirubin are 0.2 to 1.0 mg/dL; for conjugated bilirubin, 0.1 to 0.3 mg/dL; and for unconjugated bilirubin, 0.2 to 0.8 mg/dL.
The first manifestation of conjugated hyperbilirubinemia is commonly tea-colored urine; scleral icterus may be present but usually reflects unconjugated bilirubin, which binds more easily to tissues.2 Conjugated bilirubin is excreted in bile into the duodenum and then metabolized by gut bacteria into urobilinogen. Some of this product is excreted in the feces as oxidized stercobilin (which gives feces a brown color), and some is reabsorbed, entering the portal venous circulation to be re-excreted by the liver. A small amount escapes hepatic uptake, passes into systemic circulation, and is excreted in urine as urobilinogen (normal levels of urobilinogen in urine are 0 to 0.2 mg/dL).
Two clues to bilirubin dysfunction can be gathered from simple urine and stool analysis. First, increased conjugated bilirubin may spill into the urine, rendering it tea-colored, which indicates a problem past the UDPGT conjugation. Second, the stool may appear acholic and light gray in cases of biliary obstruction or stasis in the absence of stercobilin.2
PATHOPHYSIOLOGY OF HYPERBILIRUBINEMIA
Jaundice is detectable when serum bilirubin levels are greater than 2.5 to 3.0 mg/dL. Clinical evidence of jaundice lags behind the increase in serum bilirubin levels by several days, reflecting the time required for bilirubin to permeate the skin and mucous membranes; thus, darkening of the urine and light-colored stools may precede the development of jaundice.1 Jaundice may result from an increase in unconjugated or conjugated bilirubin levels. In general, unconjugated hyperbilirubinemia results from overproduction, impaired uptake, or conjugation of bilirubin, whereas conjugated hyperbilirubinemia is due to dysfunction of hepatocytes, impaired excretion into the bile ducts, or backward leakage of the pigment with reflux of conjugates into the plasma. This classification system highlights the predominant rise in either conjugated or unconjugated bilirubin levels; but even in purely hemolytic states, a small increase in conjugated bilirubin may occur as well.
“The differential diagnosis for jaundice is based on whether the disease responsible is prehepatic, hepatic, or posthepatic.”
Significant levels of conjugated bilirubin may be observed with hemolysis in the presence of underlying liver disease, sepsis, drug toxicity, or when the amount of bilirubin generated exceeds conjugating and excreting capacities (in acute hemolytic crises or after massive blood transfusions).3 Similarly in liver disease, although conjugated bilirubin predominates, one may see a slighter increase in the unconjugated form.
EVALUATION OF THE JAUNDICED PATIENT
The initial steps in evaluating the jaundiced patient are to determine whether the hyperbilirubinemia is predominantly conjugated or unconjugated; whether the disease process responsible for jaundice is likely to be hemolytic, hepatocellular, or cholestatic; and whether other biochemical liver test results are abnormal. The diagnostic possibilities can be narrowed considerably, and many clues to the etiology of hyperbilirubinemia and the presence of liver pathology can be ascertained from a carefully performed history and physical examination, basic laboratory test results, and biochemical and serological markers. Thus, the differential diagnosis for jaundice is based on whether the disease responsible for jaundice is prehepatic (primarily unconjugated hyperbiliru-binemia), hepatic (mixed hyperbilirubinemia), or posthepatic (conjugated hyperbilirubinemia).
Risk factors for toxic or viral hepatitis should be carefully evaluated (Table 1). Carefully document the duration of jaundice, and perform a review of systems for pertinent causes: arthralgias, myalgias, rash, fatigue, anorexia, weight loss, steatorrhea, abdominal pain, fever and chills, nausea and vomiting, pruritus, and/or changes in the urine and stool. Abdominal pain is the most common presenting symptom in pancreatic and biliary tract malignancy; other symptoms suggesting malignancy include hepatosplenomegaly, palpable gallbladder (Courvoisier sign: cancer of the common bile duct), mass lesions, weight loss, and evidence of Virchow node or Sister Mary Joseph nodule. Colicky right upper quadrant pain radiating to the back or shoulder with fever suggests gallstone disease, particularly if the history includes cholelithiasis, biliary surgeries, and/or inflammatory bowel disease. In patients with severe concurrent illness, consider sepsis, hepatic ischemia, and opportunistic infections.2 Pruritus and clay-colored stools suggest intrahepatic or extrahepatic cholestasis.
A thorough evaluation of the patient’s medical history should identify known causative disorders: hepatobiliary disease (gallstones, hepatitis), hemolysis (hemoglobinopathy), and disorders associated with liver disease (inflammatory bowel disease, infiltrative disorders, HIV infection or immunodeficiency). Review the medications for potential hepatotoxicity, and inquire about vaccination status against hepatitis A and B. Consider context when looking for metabolic causes: Reye syndrome in young patients with flulike symptoms and aspirin consumption, infectious mononucleosis in patients with considerable fatigue, or preeclampsia in pregnant women.
Initial laboratory evaluation of jaundice includes measuring the total and fractionated bilirubin levels and ordering a prothrombin time (PT) and basic liver function tests (LFTs): albumin, alanine (ALT) and aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), 5′-nucleotidase (5NT), and alkaline phosphatase (ALP). Additional serology is ordered based on clinical suspicion and may include a CBC to screen for hemolysis, viral hepatitis serology, and blood toxicology screening. The pattern of liver chemistry abnormalities is useful in differentiating hepatocellular from cholestatic injury.
ALT and AST are released from hepatocytes in response to injury; ALT is more sensitive and specific for liver damage, whereas AST also rises in other GI, myocardial, or skeletal muscle injury. In cirrhosis and chronic liver disease, aminotransferase enzymes may be normal as there are markedly decreased numbers of functioning hepatocytes to release enzymes. Elevated LFTs in a patient with jaundice points to primary hepatobiliary disease. Hepatocellular dysfunction causes marked aminotransferase elevation (greater than 500 U/L) and moderate ALP elevation (less than 3 times normal).4 AST and ALT levels usually rise in similar amounts, except in alcoholic hepatitis when the rise in AST level is greater (2:1 ratio). Severely elevated aminotransferase levels (greater than 10,000 U/L) suggest ischemia, severe viral hepatitis, or acetaminophen toxicity. Marked increases in ALP level (greater than 4 to 5 times normal), GGT, and 5NT with lower elevations of AST and ALT (less than 200 U/L) are typically seen in cholestatic disorders.4,5 If the alkaline phosphatase level is normal, extrahepatic obstruction is unlikely. Low albumin levels and prolongation of PT are seen in advanced liver disease, as the liver’s synthetic capacity is lost. Significant hepatic dysfunction is indicated by altered mental status and coagulopathy.4
The first-line imaging study for jaundice is ultrasonography (US), which is inexpensive, noninvasive, and does not require use of contrast or ionizing radiation. US is useful for identifying biliary duct dilation, is more accurate for diagnosis of gallstones and for determining the location of the obstruction (in 90% of patients),1,6 and can evaluate the liver parenchyma for cirrhosis, tumor, steatosis, or congestion.6 Nondilated biliary ducts caused by early, intermittent, or incomplete biliary obstruction, tumor encasement of ducts, sclerosing cholangitis, or cirrhosis may produce falsenegative results. Endoscopic ultrasonography is more invasive but allows excellent visualization of the ductal system while avoiding problems of overlying bowel gas and obese habitus.
CT with intravenous contrast provides better resolution, allowing evaluation of the anatomy; is less operatordependent; and provides information about pancreatic abnormality, lymph node involvement, and tumor extent in malignancy.6 CT offers additional information following an abnormal US or may be the initial imaging modality in some cases.2 Magnetic resonance cholangiopancreatography (MRCP) is a relatively new noninvasive procedure that allows visualization of the biliary ductal system without exposure to ionizing radiation (making it safe during pregnancy). Studies show that MRCP determines the cause and level of obstruction with a sensitivity of 95% and specificity of 94% and will assess tumor anatomy, vascular involvement, and staging parameters.6
Direct visualization of the biliary tree with either endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous cholangiography (PTC) provides diagnostic and therapeutic options, including sphincterotomy, stone extraction, stent placement, or balloon dilation and biopsy. ERCP is particularly useful when biliary obstruction is strongly suspected, is the test of choice for choledocholithiasis, and is useful for diagnosing pancreatic cancer.2 ERCP involves catheter insertion through the ampulla of Vater with contrast; there is a 3% complication rate, including pancreatitis, duodenal perforation, and bleeding.6 PTC involves a transhepatic route and may allow visualization of anatomy above the level of obstruction in patients with complete biliary obstruction.6
- To appreciate the differential diagnosis of jaundice requires an understanding of the fundamental metabolism of bilirubin; the risk factors, epidemiology, and pathophysiology of common causes of jaundice; and the available serologic and imaging studies used in the workup of jaundiced patients.
- The diagnostic possibilities can be narrowed considerably, and many clues to the etiology of hyperbilirubinemia and the presence of liver pathology can be ascertained from a carefully performed history and physical examination, basic laboratory test results, and biochemical and serological markers.
- The differential diagnosis for jaundice is based on whether the disease responsible for jaundice is prehepatic (primarily unconjugated hyperbilirubinemia), hepatic (mixed hyperbilirubinemia), or posthepatic (conjugated hyperbilirubinemia).
- The PA plays an essential role in the evaluation of adult patients with new-onset jaundice and should be able to recognize risk factors, perform an appropriate workup, and provide initial management and referral.
In patients with unconjugated hyperbilirubinemia diseases, as much as 85% of total serum bilirubin is the unconjugated form. Increased RBC destruction in disorders associated with ineffective erythropoiesis and hemolysis increase unconjugated bilirubin levels by 1 to 4 mg/dL3(Table 2). A CBC, reticulocyte count, and peripheral blood smear analysis are useful in the diagnosis of hemolytic processes; liver function test results are normal in hemolytic settings. Reductions in hepatic blood flow due to heart failure or to surgical or naturally occurring shunts impair the delivery and uptake of bilirubin to hepatocytes.1,3 Large hematoma formation caused by trauma may also increase unconjugated bilirubin.
Two inherited autosomal recessive diseases, Gilbert syndrome and Crigler-Najjar syndrome, cause unconjugated hyperbilirubinemia resulting from reduced activity of UDPGT, which impairs conjugation of bilirubin; LFT, ALP, albumin, and PT results are normal in these settings, and no bilirubin spills into the urine. Gilbert syndrome affects 4% to 13% of the population, with a male predominance, and has a reported 10% to 35% UDPGT enzyme activity causing intermittent, self-resolving jaundice in the absence of hemolysis or underlying liver disease.3
Unconjugated levels can reach up to 6 mg/dL with stress (dehydration, fatigue, alcohol use, reduced caloric intake). Crigler-Najjar type II (Arias) syndrome has approximately 10% UDPGT enzyme activity resulting in unconjugated bilirubin levels of 6 to 20 mg/dL; affected patients are susceptible to but rarely experience kernicterus, and UDPGT activity can be induced with phenobarbital therapy.3 Crigler-Najjar type I syndrome is the neonatal condition characterized by complete absence of UDPGT enzyme activity and results in severe jaundice with unconjugated bilirubin levels reaching 20 to 50 mg/dL. Neurologic impairment due to kernicterus frequently leads to death in infancy as bilirubin pigment deposits in the brain and spinal cord, causing cerebral palsy, mental retardation, hearing deficits, paralysis, and opisthotonos. Emergent treatment with plasmapheresis and/or phototherapy can be life-sustaining in these infants until liver transplantation can be arranged.
MIXED AND CONJUGATED HYPERBILIRUBINEMIA
Mixed and conjugated hyperbilirubinemia can occur in a wide spectrum of hepatobiliary diseases, including acute or chronic liver injury, extrahepatic biliary obstruction, and familial disorders of bilirubin excretion (Table 3). Viral hepatitis results in a clinical syndrome where the patient presents with laboratory evidence of liver cell necrosis caused by immune-mediated hepatocyte injury preceded or accompanied by malaise, fever, and jaundice. Viral hepatitis can be caused by A, B, C, D or E viruses; but the liver can also be involved in the course of infection of other organs with secondary pathogens such as Epstein-Barr virus (EBV), herpes simplex virus (HSV), and HIV, particularly in immunocompromised patients. Clinical manifestations range from asymptomatic infection to acute or fulminant hepatitis. Uncomplicated cases require rest, a high-calorie diet, and avoidance of hepatotoxic agents, including alcohol. Hepatic tenderness and hepatomegaly are common; aminotransferases may reach dramatic levels except in cases of hepatitis C and alcoholic hepatitis, in which the rise is no more than five times normal.5 The ALP level rises modestly up to two to four times greater than baseline.
Alcoholic hepatitis caused by chronic, excessive alcohol consumption is one of the major causes of liver disease in the United States. Metabolism of alcohol by the hepatocyte initiates immunologic activity and cytokine release that damage the liver. Complete abstinence from alcohol is the cornerstone of treatment, with supportive care for withdrawal symptoms and nutritional and psychological counseling.
Heavy metal accumulation and deposition in the liver also results in liver disease and jaundice. Hemochromatosis is an autosomal recessive disease where the small intestine absorbs excessive iron and stores it in glands and muscle, including the liver, pancreas, heart, joints, skin, and gonads. Unexplained darkening of the skin, diabetes, and heart failure suggest hemochromatosis.2 Treatment includes removal of excess iron by repeated phlebotomy or iron chelation with deferoxamine (Desferal, generics).
Wilson disease caused by an abnormality of chromosome 13 causes toxic accumulation of copper in the brain, liver, skin, and joints. Of note, Kayser-Fleischer rings are caused by corneal copper deposits, and neurologic manifestations may predominate. Treatment involves copper chelation with D-penicillamine, zinc therapy, and elimination of copper-rich foods from the diet.
Cholestasis, or impaired bile formation, can be categorized as intrahepatic (defect at the level of the hepatocyte) or extrahepatic (obstruction of bile flow within the biliary tract) (Table 4). Cholestasis produces a mixed hyperbilirubinemia with a predominance of conjugated bilirubin; bilirubin spilling into the urine renders it tea-colored. The liver is large, smooth, and nontender; splenomegaly is unlikely except if associated with primary biliary cirrhosis, stools are pale, and steatorrhea may develop in severe cases.4 Intrahepatic disorders often manifest with pruritus, whereas extrahepatic disorders may cause signs of cholangitis: fever, right upper quadrant pain, leukocytosis, and hypotension. Benign cholestasis causes recurrent gradual attacks of pruritus and jaundice with intermittent complete resolution; the condition is considered benign in that it does not lead to cirrhosis or end-stage liver disease. The aminotransferase levels in cholestasis are mildly elevated with marked alkaline phosphate elevation. When hepatitis causes a cholestatic process, the biochemical abnormalities may be indistinguishable from those in extrahepatic obstruction. In this situation, ultrasound with normal findings may be sufficient to permit a conservative “watch and wait approach”; CT-guided biopsy is utilized to rule out tumors. The most common cause of obstructive jaundice is choledocholithiasis, but malignant neoplasms should be suspected in older patients presenting with painless jaundice.6 Progressive anorexia, weight loss, deterioration in performance, and/or vague abdominal pain should prompt suspicion of a malignant etiology.
Primary biliary cirrhosis is a chronic autoimmune, nonsuppurative destructive cholangitis most common among women in the 6th or 7th decade of life. It predominantly causes pruritus, fatigue, and conjugated hyperbilirubinemia. Autoimmune hepatitis also has a female predilection and induces cell-mediated chronic hepatocellular necrosis and inflammation leading to fibrosis, cirrhosis, and liver failure. Primary sclerosing cholangitis is a chronic progressive inflammatory disorder, associated with ulcerative colitis, which affects the intrahepatic and extrahepatic bile ducts and leads to fibrosis and stricture formation. The goals of treatment for both of these autoimmune diseases are to slow the progression rate of the disease and to alleviate symptoms. Ursodeoxycholic acid (UDCA) has been shown to slow progression and delay need for liver transplant but is most effective in early stages of disease. Immunosuppressant agents and/or corticosteroids are used in management. Prognosis is poor, and end-stage liver disease requiring liver transplantation usually results.
“Although the cause of jaundice can often be anticipated through a focused history and examination, confirmatory testing is needed.”
Cholestasis is a common feature of drug-induced liver injury and may also be associated with minimal biochemical findings of hepatic inflammation in patients receiving longterm total parenteral nutrition, in those with gram-negative sepsis, and in patients with postoperative hepatocellular dysfunction from surgical anesthetics.1 Two autosomal recessive diseases, Dubin-Johnson syndrome and Rotor syndrome, manifest as benign, asymptomatic jaundice in early adulthood. Both are caused by mutations to canalicular systems with altered bilirubin excretion into the bile ducts. Total bilirubin levels rarely exceed 5 mg/dL in either of these disorders. Table 5 provides other diagnostic hints in jaundice evaluation.
The PA plays an essential role in the evaluation of adult patients with new-onset jaundice and should be able to recognize risk factors, perform an appropriate workup, and provide initial management and referral. The differential diagnosis of jaundice is vast, and the condition is seen in a variety of medical and surgical specialties. The cause of jaundice can often be correctly anticipated through a focused history and physical examination, but confirmatory diagnostic evaluation is nevertheless required.