Jaundice, or icterus, is a yellowish discoloration of tissue resulting from the deposition of bilirubin. Tissue deposition of bilirubin occurs only in the presence of serum hyperbilirubinemia and is a sign of either liver disease or, less often, a hemolytic disorder. The degree of serum bilirubin elevation can be estimated by physical examination. Slight increases in serum bilirubin are best detected by examining the sclerae which have a particular affinity for bilirubin due to their high elastin content. The presence of scleral icterus indicates a serum bilirubin of at least 3.0 mg/dL. The ability to detect scleral icterus is made more difficult if the examining room has fluorescent lighting. If the examiner suspects scleral icterus, a second place to examine is underneath the tongue. As serum bilirubin levels rise, the skin will eventually become yellow in light-skinned patients and even green if the process is longstanding; the green color is produced by oxidation of bilirubin to biliverdin.
The differential diagnosis for yellowing of the skin is limited. In addition to jaundice, it includes carotenoderma, the use of the drug quinacrine, and excessive exposure to phenols. Carotenoderma is the yellow color imparted to the skin by the presence of carotene; it occurs in healthy individuals who ingest excessive amounts of vegetables and fruits that contain carotene, such as carrots, leafy vegetables, squash, peaches, and oranges. Unlike jaundice, where the yellow coloration of the skin is uniformly distributed over the body, in carotenoderma the pigment is concentrated on the palms, soles, forehead, and nasolabial folds. Carotenoderma can be distinguished from jaundice by the sparing of the sclerae. Quinacrine causes a yellow discoloration of the skin in 4 to 37% of patients treated with it. Unlike carotene, quinacrine can cause discoloration of the sclerae.
Another sensitive indicator of increased serum bilirubin is darkening of the urine, which is due to the renal excretion of conjugated bilirubin. Patients often describe their urine as tea or cola colored. Bilirubinuria indicates an elevation of the direct serum bilirubin fraction and therefore the presence of liver disease.
Increased serum bilirubin levels occur when an imbalance exists between bilirubin production and clearance. A logical evaluation of the patient who is jaundiced requires an understanding of bilirubin production and metabolism.
Production and Metabolism of Bilirubin
Bilirubin, a tetrapyrrole pigment, is a breakdown product of heme (ferroprotoporphyrin IX). About 70 to 80% of the 250 to 300 mg of bilirubin produced each day is derived from the breakdown of hemoglobin in senescent red blood cells. The remainder comes from prematurely destroyed erythroid cells in bone marrow and from the turnover of hemoproteins such as myoglobin and crytochromes found in tissues throughout the body.
The formation of bilirubin occurs in reticuloendothelial cells, primarily in the spleen and liver. The first reaction, catalyzed by the enzyme heme oxygenase, oxidatively cleaves the bridge of the porphyrin group and opens the heme ring. The end products of this reaction are biliverdin, carbon monoxide, and iron. The second reaction, catalyzed by the cytosolic enzyme biliverdin reductase, reduces the central methylene bridge of biliverdin and converts it to bilirubin. Bilirubin formed in the reticuloendothelial cells is virtually insoluble in water. To be transported in blood, it must be solubilized. This is accomplished by its reversible, noncovalent binding to albumin. Unconjugated bilirubin bound to albumin is transported to the liver, where it, but not the albumin, is taken up by hepatocytes via a process that at least partly involves carrier-mediated membrane transport.
In the cytosol of the hepatocyte, unconjugated bilirubin is coupled predominantly to the protein ligandin (formerly called the Y protein). Ligandin was initially thought to be a transport protein facilitating the movement of bilirubin from the sinusodial membrane to the endoplasmic reticulum. It is now thought to slow the cytosolic diffusion of bilirubin and to reduce its efflux back into serum. In the endoplasmic reticulum, bilirubin is solubilized by conjugation to glucuronic acid, forming bilirubin monoglucuronide and diglucuronide. The conjugation of glucuronic acid to bilirubin is catalyzed by bilirubin uridine-diphosphate (UDP) glucuronosyltransferase.
The now hydrophilic bilirubin conjugates diffuse from the endoplasmic reticulum to the canalicular membrane, where bilirubin monoglucuronide and diglucuronide are actively transported into canalicular bile by an energy-dependent mechanism involving the multiple organic ion transport protein/multiple drug resistance protein. The conjugated bilirubin excreted into bile drains into the duodenum and passes unchanged through the proximal small bowel. Conjugated bilirubin is not taken up by the intestinal mucosa. When the conjugated bilirubin reaches the distal ileum and colon, it is hydrolyzed to unconjugated bilirubin by bacterial -glucuronidases. The unconjugated bilirubin is reduced by normal gut bacteria to form a group of colorless tetrapyrroles called urobilinogens. About 80 to 90% of these products are excreted in feces, either unchanged or oxidized to orange derivatives called urobilins. The remaining 10 to 20% of the urobilinogens are passively absorbed, enter the portal venous blood, and are reexcreted by the liver. A small fraction (usually less than 3 mg/dL) escapes hepatic uptake, filters across the renal glomerulus, and is excreted in urine.
Measurement of Serum Bilirubin
The terms direct- and indirect-reacting bilirubin are based on the original van den Bergh reaction. This assay, or a variation of it, is still used in most clinical chemistry laboratories to determine the serum bilirubin level. In this assay, bilirubin is exposed to diazotized sulfanilic acid, splitting into two relatively stable dipyrrylmethene azopigments that absorb maximally at 540 nm, allowing for photometric analysis. The direct fraction is that which reacts with diazotized sulfanilic acid in the absence of an accelerator substance such as alcohol. The direct fraction provides an approximate determination of the conjugated bilirubin in serum. The total serum bilirubin is the amount that reacts after the addition of alcohol. The indirect fraction is the difference between the total and the direct bilirubin and provides an estimate of the unconjugated bilirubin in serum.
With the van den Bergh method, the normal serum bilirubin concentration usually is <1 mg/dL (17 mol/L). Up to 30%, or 0.3 mg/dL (5.1 mol/L), of the total may be direct-reacting (conjugated) bilirubin. Total serum bilirubin concentrations are between 0.2 and 0.9 mg/dL in 95% of a normal population.
Several new techniques, although less convenient to perform, have added considerably to our understanding of bilirubin metabolism. First, they demonstrate that in normal people or those with Gilbert's syndrome, almost 100% of the serum bilirubin is unconjugated; less than 3% is monoconjugated bilirubin. Second, in jaundiced patients with hepatobiliary disease, the total serum bilirubin concentration measured by these new, more accurate methods is lower than the values found with diazo methods. This suggests that there are diazo-positive compounds distinct from bilirubin in the serum of patients with hepatobiliary disease. Third, these studies indicate that in jaundiced patients with hepatobiliary disease, monoglucuronides of bilirubin predominate over the diglucuronides. Fourth, part of the direct-reacting bilirubin fraction includes conjugated bilirubin that is covalently linked to albumin. This albumin-linked bilirubin fraction (delta fraction or biliprotein) represents an important fraction of total serum bilirubin in patients with cholestasis and hepatobiliary disorders. Albumin-bound conjugated bilirubin is formed in serum when hepatic excretion of bilirubin glucuronides is impaired and the glucuronides are present in serum in increasing amounts. By virtue of its tight binding to albumin, the clearance rate of albumin-bound bilirubin from serum approximates the half-life of albumin, 12 to 14 days, rather than the short half-life of bilirubin, about 4 h.
The prolonged half-life of albumin-bound conjugated bilirubin explains two previously unexplained enigmas in jaundiced patients with liver disease: (1) that some patients with conjugated hyperbilirubinemia do not exhibit bilirubinuria during the recovery phase of their disease because the bilirubin is bound to albumin and therefore not filtered by the renal glomeruli and (2) that the elevated serum bilirubin level declines more slowly than expected in some patients who otherwise appear to be recovering satisfactorily. Late in the recovery phase of hepatobiliary disorders, all the conjugated bilirubin may be in the albumin-linked form. Its value in serum falls slowly because of the long half-life of albumin.
Measurement of Urine Bilirubin
Unconjugated bilirubin is always bound to albumin in the serum, is not filtered by the kidney, and is not found in the urine. Conjugated bilirubin is filtered at the glomerulus and the majority is reabsorbed by the proximal tubules; a small fraction is excreted in the urine. Any bilirubin found in the urine is conjugated bilirubin. The presence of bilirubinuria implies the presence of liver disease. A urine dipstick test (Ictotest) gives the same information as fractionation of the serum bilirubin. This test is very accurate. A false-negative test is possible in patients with prolonged cholestasis due to the predominance of conjugated bilirubin covalently bound to albumin.
The Evaluation of Jaundice
The bilirubin present in serum represents a balance between input from production of bilirubin and hepatic/biliary removal of the pigment. Hyperbilirubinemia may result from (1) overproduction of bilirubin; (2) impaired uptake, conjugation, or excretion of bilirubin; or (3) regurgitation of unconjugated or conjugated bilirubin from damaged hepatocytes or bile ducts. An increase in unconjugated bilirubin in serum results from either overproduction, impairment of uptake, or conjugation of bilirubin. An increase in conjugated bilirubin is due to decreased excretion into the bile ductules or backward leakage of the pigment. The initial steps in evaluating the patient with jaundice are to determine (1) whether the hyperbilirubinemia is predominantly conjugated or unconjugated in nature, and (2) whether other biochemical liver tests are abnormal. The thoughtful interpretation of limited data will allow for a rational evaluation of the patient (Fig. 45-1). This discussion will focus solely on the evaluation of the adult patient with jaundice.
Isolated Elevation of Serum Bilirubin
The differential diagnosis of an isolated unconjugated hyperbilirubinemia is limited (Table 45-1). The critical determination is whether the patient is suffering from a hemolytic process resulting in an overproduction of bilirubin (hemolytic disorders and ineffective erythropoiesis) or from impaired hepatic uptake/conjugation of bilirubin (drug effect or genetic disorders).
Hemolytic disorders that cause excessive heme production may be either inherited or acquired. Inherited disorders include spherocytosis, sickle cell anemia, and deficiency of red cell enzymes such as pyruvate kinase and glucose-6-phosphate dehydrogenase. In these conditions, the serum bilirubin rarely exceeds 5 mg/dL. Higher levels may occur when there is coexistent renal or hepatocellular dysfunction, or in acute hemolysis such as a sickle cell crisis. In evaluating jaundice in patients with chronic hemolysis, it is important to remember the high incidence of pigmented (calcium bilirubinate) gallstones found in these patients, which increases the likelihood of choledocholithiasis as an alternative explanation for hyperbilirubinemia.
Acquired hemolytic disorders include microangiopathic hemolytic anemia (e.g., hemolytic-uremic syndrome), paroxysmal nocturnal hemoglobinuria, and immune hemolysis. Ineffective erythropoiesis occurs in cobalamin, folate, and iron deficiencies.
In the absence of hemolysis, the physician should consider a problem with the hepatic uptake or conjugation of bilirubin. Certain drugs, including rifampicin and probenecid, may cause unconjugated hyperbilirubinemia by diminishing hepatic uptake of bilirubin. Impaired bilirubin conjugation occurs in three genetic conditions: Crigler-Najjar syndrome, types I and II, and Gilbert's syndrome. Crigler-Najjar type I is an exceptionally rare condition found in neonates and characterized by severe jaundice (bilirubin > 20 mg/dL) and neurologic impairment due to kernicterus, frequently leading to death in infancy or childhood. These patients have a complete absence of bilirubin UDP glucuronosyltransferase activity, usually due to mutations in the critical 3′ domain of the UDP glucuronosyltransferase gene, and are totally unable to conjugate, hence cannot excrete bilirubin. The only effective treatment is orthotopic liver transplantation. Use of gene therapy and allogeneic hepatocyte infusion are experimental approaches of future promise for this devastating disease.
Crigler-Najjar type II is somewhat more common than type I. Patients live into adulthood with serum bilirubin levels that range from 6 to 25 mg/dL. In these patients, mutations in the bilirubin UDP glucuronosyltransferase gene cause reduced but not completely absent activity of the enzyme. Bilirubin UDP glucuronosyltransferase activity can be induced by the administration of phenobarbital, which can reduce serum bilirubin levels in these patients. Despite marked jaundice, these patients usually survive into adulthood, although they may be susceptible to kernicterus under the stress of intercurrent illness or surgery.
Gilbert's syndrome is also marked by the impaired conjugation of bilirubin due to reduced bilirubin UDP glucuronosyltransferase activity. Molecular analyses show that Gilbert's syndrome is due to reduced expression of UDP glucuronosyltransferase activity caused by lengthening of the TATAA box from A(TA)6 TAA to A(TA)7 TAA in the promoter element of the gene. This results in mild unconjugated hyperbilirubinemia with serum levels almost always less than 6 mg/dL. The serum levels may fluctuate and jaundice is often identified only during periods of fasting. Unlike both Crigler-Najjar syndromes, Gilbert's syndrome is very common. The reported incidence is 3 to 7% of the population with males predominating over females by a ratio of 2-7:1.
Elevated conjugated hyperbilirubinemia is found in two rare inherited conditions: Dubin-Johnson syndrome and Rotor's syndrome (Table 45-1). Patients with both conditions present with asymptomatic jaundice, typically in the second generation of life. The defect in Dubin-Johnson syndrome is a point mutation in the gene for the canalicular multispecific organic anion transporter. These patients have altered excretion of bilirubin into the bile ducts. Rotor's syndrome seems to be a problem with the hepatic storage of bilirubin. Differentiating between these syndromes is possible, but clinically unnecessary, due to their benign nature.
Elevation of Serum Bilirubin with Other Liver Test Abnormalities
The remainder of this chapter will focus on the evaluation of the patient with a conjugated hyperbilirubinemia in the setting of other liver test abnormalities. This group of patients can be divided into those with a primary hepatocellular process and those with intra- or extrahepatic cholestasis. Being able to make this differentiation will guide the physician's evaluation (Fig. 45-1). This differentiation is made on the basis of the history and physical examination as well as the pattern of liver test abnormalities.
A complete medical history is perhaps the single most important part of the evaluation of the patient with unexplained jaundice. Important considerations include the use of or exposure to any chemical or medication, either physician-prescribed or over-the-counter, such as herbal and vitamin preparations and other drugs such as anabolic steroids. The patient should be carefully questioned about possible parenteral exposures, including transfusions, intravenous and intranasal drug use, tattoos, and sexual activity. Other important questions include recent travel history, exposure to people with jaundice, exposure to possibly contaminated foods, occupational exposure to hepatotoxins, alcohol consumption, the duration of jaundice, and the presence of any accompanying symptoms such as arthralgias, myalgias, rash, anorexia, weight loss, abdominal pain, fever, pruritis, and changes in the urine and stool. While none of these latter symptoms are specific for any one condition, they can suggest a particular diagnosis. A history of arthralgias and myalgias predating jaundice suggests hepatitis, either viral or drug-related. Jaundice associated with the sudden onset of severe right upper quadrant pain and shaking chills suggests choledocholithiasis and ascending cholangitis.
The general assessment should include assessment of the patient's nutritional status. Temporal and proximal muscle wasting suggests longstanding diseases such as pancreatic cancer or cirrhosis. Stigmata of chronic liver disease, including spider nevi, palmar erythema, gynecomastia, caput medusae, Dupuytren's contractures, parotid gland enlargement, and testicular atrophy are commonly seen in advanced alcoholic (Laennec's) cirrhosis and occasionally in other types of cirrhosis. An enlarged left supraclavicular node (Virchow's node) or periumbilical nodule (Sister Mary Joseph's nodule) suggest an abdominal malignancy. Jugular venous distention, a sign of right-sided heart failure, suggests hepatic congestion. Right pleural effusion, in the absence of clinically apparent ascites, may be seen in advanced cirrhosis.
The abdominal examination should focus on the size and consistency of the liver, whether the spleen is palpable and hence enlarged, and whether there is ascites present. Patients with cirrhosis may have an enlarged left lobe of the liver which is felt below the xiphoid and an enlarged spleen. A grossly enlarged nodular liver or an obvious abdominal mass suggests malignancy. An enlarged tender liver could be viral or alcoholic hepatitis or, less often, an acutely congested liver secondary to right-sided heart failure. Severe right upper quadrant tenderness with respiratory arrest on inspiration (Murphy's sign) suggests cholecystitis or, occasionally, ascending cholangitis. Ascites in the presence of jaundice suggests either cirrhosis or malignancy with peritoneal spread.
When the physician encounters a patient with unexplained jaundice, there are a battery of tests that are helpful in the initial evaluation. These include total and direct serum bilirubin with fractionation, aminotransferases, alkaline phosphatase, albumin, and prothrombin time tests. Enzyme tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase] are helpful in differentiating between a hepatocellular process and a cholestatic process (see Table 293-1 and Fig. 45-1), a critical step in determining what additional workup is indicated. Patients with a hepatocellular process generally have a disproportionate rise in the aminotransferases compared to the alkaline phosphatase. Patients with a cholestatic process have a disproportionate rise in the alkaline phosphatase compared to the aminotransferases. The bilirubin can be prominently elevated in both hepatocellular and cholestatic conditions and therefore is not necessarily helpful in differentiating between the two.
In addition to the enzyme tests, all jaundiced patients should have additional blood tests, specifically an albumin and a prothrombin time, to assess liver function. A low albumin suggests a chronic process such as cirrhosis or cancer. A normal albumin is suggestive of a more acute process such as viral hepatitis or choledocholithiasis. An elevated prothrombin time indicates either vitamin K deficiency due to prolonged jaundice and malabsorption of vitamin K or significant hepatocellular dysfunction. The failure of the prothrombin time to correct with parenteral administration of vitamin K indicates severe hepatocellular injury.
The results of the bilirubin, enzyme, albumin, and prothrombin time tests will usually indicate whether a jaundiced patient has a hepatocellular or a cholestatic disease. The causes and evaluation of each of these is quite different.
Hepatocellular diseases that can cause jaundice include viral hepatitis, drug or environmental toxicity, alcohol, and end-stage cirrhosis from any cause (Table 45-2). Wilson's disease should be considered in young adults. Autoimmune hepatitis is typically seen in young to middle-aged women, but may affect men and women of any age. Alcoholic hepatitis can be differentiated from viral and toxin-related hepatitis by the pattern of the aminotransferases. Patients with alcoholic hepatitis typically have an AST:ALT ratio of at least 2:1. The AST rarely exceeds 300 U/L. Patients with acute viral hepatitis and toxin-related injury severe enough to produce jaundice typically have aminotransferases greater than 500 U/L, with the ALT greater than or equal to the AST. The degree of aminotransferase elevation can occasionally help in differentiating between hepatocellular and cholestatic processes. While ALT and AST values less than 8 times normal may be seen in either hepatocellular or cholestatic liver disease, values 25 times normal or higher are seen primarily in acute hepatocellular diseases. Patients with jaundice from cirrhosis can have normal or only slight elevations of the aminotransferases.
When the physician determines that the patient has a hepatocellular disease, appropriate testing for acute viral hepatitis includes a hepatitis A IgM antibody, a hepatitis B surface antigen and core IgM antibody, and a hepatitis C viral RNA test. It can take many weeks for the hepatitis C antibody to become detectable, making it an unreliable test if acute hepatitis C is suspected. Depending on circumstances, studies for hepatitis D, E, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) may be indicated. Ceruloplasmin is the initial screening test for Wilson's disease. Testing for autoimmune hepatitis usually includes an antinuclear antibody and measurement of specific immunoglobulins.
Drug-induced hepatocellular injury can be classified either as predictable or unpredictable. Predictable drug reactions are dose-dependent and affect all patients who ingest a toxic dose of the drug in question. The classic example is acetaminophen hepatotoxicity. Unpredictable or idiosyncratic drug reactions are not dose-dependent and occur in a minority of patients. A great number of drugs can cause idiosyncratic hepatic injury. Environmental toxins are also an important cause of hepatocellular injury. Examples include industrial chemicals such as vinyl chloride, herbal preparations containing pyrrolizidine alkaloids (Jamaica bush tea), and the mushrooms Amanita phalloides or verna containing highly hepatotoxic amatoxins.
When the pattern of the liver tests suggests a cholestatic disorder, the next step is to determine whether it is intra- or extrahepatic cholestasis (Fig. 45-1). Distinguishing intrahepatic from extrahepatic cholestasis may be difficult. History, physical examination, and laboratory tests are often not helpful. The next appropriate test is an ultrasound. The ultrasound is inexpensive, does not expose the patient to ionizing radiation, and can detect dilation of the intra- and extrahepatic biliary tree with a high degree of sensitivity and specificity. The absence of biliary dilatation suggests intrahepatic cholestasis, while the presence of biliary dilatation indicates extrahepatic cholestasis. False-negative results occur in patients with partial obstruction of the common bile duct or in patients with cirrhosis or primary sclerosing cholangitis (PSC) where scarring prevents the intrahepatic ducts from dilating.
Although ultrasonography may indicate extrahepatic cholestasis, it rarely identifies the site or cause of obstruction. The distal common bile duct is a particularly difficult area to visualize by ultrasound because of overlying bowel gas. Appropriate next tests include computed tomography (CT) and endoscopic retrograde cholangiopancreatography (ERCP). CT scanning is better than ultrasonography for assessing the head of the pancreas and for identifying choledocholithiasis in the distal common bile duct, particularly when the ducts are not dilated. ERCP is the gold standard for identifying choledocholithiasis. It is performed by introducing a side-viewing endoscope perorally into the duodenum. The ampulla of Vater is visualized and a catheter is advanced through the ampulla. Injection of dye allows for the visualization of the common bile duct and the pancreatic duct. The success rate for cannulation of the common bile duct ranges from 80 to 95%, depending on the operator's experience. Beyond its diagnostic capabilities, ERCP allows for therapeutic interventions, including the removal of common bile duct stones and the placement of stents. In patients in whom ERCP is unsuccessful, transhepatic cholangiography can provide the same information. Magnetic resonance cholangiopancreatography (MRCP) is a rapidly developing, noninvasive technique for imaging the bile and pancreatic ducts; this may replace ERCP as the initial diagnostic test in cases where the need for intervention is felt to be small.
In patients with apparent intrahepatic cholestasis, the diagnosis is often made by serologic testing in combination with percutaneous liver biopsy. The list of possible causes of intrahepatic cholestasis is long and varied (Table 45-3). A number of conditions that typically cause a hepatocellular pattern of injury can also present as a cholestatic variant. Both hepatitis B and C can cause a cholestatic hepatitis (fibrosing cholestatic hepatitis) that has histologic features that mimic large duct obstruction. This disease variant has been reported in patients who have undergone solid organ transplantation. Hepatitis A, alcoholic hepatitis, EBV, and CMV may also present as cholestatic liver disease.
Drugs may cause intrahepatic cholestasis, a variant of drug-induced hepatitis. Drug-induced cholestasis is usually reversible after eliminating the offending drug, although it may take many months for cholestasis to resolve. Drugs most commonly associated with cholestasis are the anabolic and contraceptive steroids. Cholestatic hepatitis has been reported with chlorpromazine, imipramine, tolbutamide, sulindac, cimetidine, and erythromycin estolate. It also occurs in patients taking trimethoprim, sulfamethoxazole, and penicillin-based antibiotics such as ampicillin, dicloxacillin, and clavulinic acid. Rarely, cholestasis may be chronic and associated with progressive fibrosis despite early discontinuation of the drug. Chronic cholestasis has been associated with chlorpromazine and prochlorperazine.
Primary biliary cirrhosis is a disease predominantly of middle-aged women in which there is a progressive destruction of interlobular bile ducts. The diagnosis is made by the presence of the antimitochondrial antibody that is found in 95% of patients. Primary sclerosing cholangitis (PSC) is characterized by the destruction and fibrosis of larger bile ducts. The disease may involve only the intrahepatic ducts and present as intrahepatic cholestasis. However, in 65% of patients with PSC, both intra- and extrahepatic ducts are involved. The diagnosis of PSC is made by ERCP. The pathognomonic findings are multiple strictures of bile ducts with dilatations proximal to the strictures. Approximately 75% of patients with PSC have inflammatory bowel disease.
The vanishing bile duct syndrome and adult bile ductopenia are rare conditions in which there are a decreased number of bile ducts seen in liver biopsy specimens. The histologic picture is similar to that found in primary biliary cirrhosis. This picture is seen in patients who develop chronic rejection after liver transplantation and in those who develop graft-versus-host disease after bone marrow transplantation. Vanishing bile duct syndrome also occurs in rare cases of sarcoidosis, in patients taking certain drugs including chlorpromazine, and idiopathically. There are also familial forms of intrahepatic cholestasis, including the familial intrahepatic cholestatic syndromes, I-III. Benign recurrent cholestasis is an autosomal recessive disease that appears to be due to mutations in a P type ATPase, which probably acts as a bile acid transporter. The disease is marked by recurrent episodes of jaundice and pruritis; the episodes are self-limited but can be debilitating. Cholestasis of pregnancy occurs in the second and third trimesters and resolves after delivery. Its cause is unknown, but the condition is probably inherited and cholestasis can be triggered by estrogen administration.
Other causes of intrahepatic cholestasis include total parenteral nutrition (TPN), nonhepatobiliary sepsis, benign postoperative cholestasis, and a paraneoplastic syndrome associated with a number of different malignancies, including Hodgkin's disease, medullary thyroid cancer, hypernephroma, renal sarcoma, T cell lymphoma, prostate cancer, and several GI malignancies. In patients developing cholestasis in the intensive care unit, the major considerations should be sepsis, shock liver, and TPN jaundice. Jaundice occurring after bone marrow transplantation is most likely due to venoocclusive disease or graft-versus-host disease.
Causes of extrahepatic cholestasis can be split into malignant and benign (Table 45-3). Malignant causes include pancreatic, gallbladder, ampullary, and cholangiocarcinoma. The latter is most commonly associated with PSC and is exceptionally difficult to diagnose because its appearance is often identical to PSC. Pancreatic and gallbladder tumors, as well as cholangiocarcinoma, are rarely resectable and have poor prognoses. Ampullary carcinoma has the highest surgical cure rate of all the tumors that present as painless jaundice. Hilar lymphadenopathy due to metastases from other cancers may cause obstruction of the extrahepatic biliary tree.
Choledocholithiasis is the most common cause of extrahepatic cholestasis. The clinical presentation can range from mild right upper quadrant discomfort with only minimal elevations of the enzyme tests to ascending cholangitis with jaundice, sepsis, and circulatory collapse. PSC may occur with clinically important strictures limited to the extrahepatic biliary tree. In cases where there is a dominant stricture, patients can be effectively managed with serial endoscopic dilatations. Chronic pancreatitis rarely causes strictures of the distal common bile duct, where it passes through the head of the pancreas. AIDS cholangiopathy is a condition, usually due to infection of the bile duct epithelium with CMV or cryptosporidium, which has a cholangiographic appearance similar to PSC. These patients usually present with greatly elevated serum alkaline phosphatase levels, mean of 800 IU/L, but the bilirubin is often near normal. These patients do not typically present with jaundice.
The goal of this chapter is not to provide an encyclopedic review of all of the conditions that can cause jaundice. Rather, it is intended to provide a framework that helps a physician to evaluate the patient with jaundice in a logical way (Fig. 45-1).
Simply stated, the initial step is to obtain appropriate blood tests to determine if the patient has an isolated elevation of serum bilirubin. If so, is the bilirubin elevation due to an increased unconjugated or conjugated fraction? If the hyperbilirubinemia is accompanied by other liver test abnormalities, is the disorder hepatocellular or cholestatic? If cholestatic, is it intra- or extrahepatic? All of these questions can be answered with a thoughtful history, physical examination, and interpretation of laboratory and radiologic tests and procedures.