45 - 52 Jaundice

52 Jaundice

and costs. Patients with high-risk endoscopic findings (e.g., varices, ulcers with active bleeding or a visible vessel) benefit from hemo­ static therapy at endoscopy. EVALUATION AND MANAGEMENT OF LGIB (FIG. 51-2) Patients with hematochezia and hemodynamic instability should have upper endoscopy to rule out an upper GI source before evalua­ tion of the lower GI tract. Colonoscopy after an oral lavage solution is the procedure of choice in most patients admitted with LGIB. If ongoing hemody­ namically significant hematochezia precludes bowel preparation and colonoscopy, computed tomography (CT) angiography is sug­ gested. If extravasation is seen, angiography is performed, allowing treatment with transcatheter arterial embolization. If no extravasa­ tion is seen, colonoscopy is subsequently performed. PART 2 Cardinal Manifestations and Presentation of Diseases EVALUATION AND MANAGEMENT OF SMALL-INTESTINAL OR OBSCURE GIB In patients with severe bleeding suspected to be from the small intestine, CT angiography or angiography is the initial test. For others, video capsule endoscopy is generally the next diagnostic test suggested, although repeat upper and lower endoscopy may be considered because second-look procedures in some observational studies identify a source in up to ~25% of cases (a push enteros­ copy, usually performed with a pediatric colonoscope to inspect the entire duodenum and proximal jejunum, may be substituted for a repeat standard upper endoscopy). Systematic reviews report a diagnostic yield with capsule endoscopy of ~55%. Limitations of capsule endoscopy include the inability to fully visualize the small intestinal mucosa, sample tissue, or apply therapy. If capsule endoscopy is positive, management is dictated by the finding. If capsule endoscopy is negative, clinically stable patients may be observed and treated with iron if iron deficiency is present. In those with further bleeding (e.g., need for transfusions), additional testing is performed. A second capsule endoscopy may be considered because some observational studies report it identifies a source in up to 50% or more of cases. CT enterography also may follow a negative capsule endoscopy, given its higher sensitivity for small-intestinal masses (CT enterography also may be used initially instead of video capsule in patients with concern for small bowel narrowing [e.g., stricture, prior surgery or radiation, Crohn’s disease]). “Deep” enteroscopy (double-balloon, single-balloon, or spiral enteroscopy) is commonly the next test after capsule endoscopy for clinically important GIB documented or suspected to be from the small intestine because it allows the endoscopist to examine, obtain specimens from, and provide therapy to much or all of the small intestine. Other imaging techniques sometimes used in evaluation of obscure GIB include CT angiography, angiography, 99mTc-labeled red-blood-cell scintigraphy, and 99mTc-pertechnetate scintigraphy for Meckel’s diverticulum (especially in young patients). If all tests are unrevealing, intraoperative endoscopy is indicated in patients with severe recurrent or persistent bleeding requiring repeated transfusions. POSITIVE FECAL OCCULT BLOOD TEST Fecal occult blood testing is recommended only for colorectal can­ cer screening, beginning at age 45 years in average-risk adults. A positive test necessitates colonoscopy. If evaluation of the colon is negative, further workup is not recommended unless iron-deficiency anemia or GI symptoms are present. ■ ■FURTHER READING Chen H et al: Thalidomide for recurrent bleeding due to small-intestinal angiodysplasia. N Engl J Med 389:1649, 2023. Kaplan DE et al: AASLD practice guidance on risk stratification and management of portal hypertension and varices in cirrhosis. Hepatology 79:1180, 2024. Karuppasamy K et al: ACR Appropriateness criteria® radiologic man­ agement of lower gastrointestinal tract bleeding: 2021 update. J Am Coll Radiol 18:S139, 2021.

Laine L et al: ACG clinical guideline: Upper gastrointestinal and ulcer bleeding. Am J Gastroenterol 116:899, 2021. Lau JYW et al: Timing of endoscopy for acute upper gastrointestinal bleeding. N Engl J Med 382:1299, 2020. Pennazio M et al: Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: European Society of Gastrointestinal Endoscopy (ESGE) guideline— update 2022. Endoscopy 55:58, 2023. Sengupta N et al: Management of patients with acute lower gastro­ intestinal bleeding: An updated ACG guideline. Am J Gastroenterol 118:208, 2023. Villaneuva C et al: Transfusion strategies for acute upper gastrointes­ tinal bleeding. N Engl J Med 368:11, 2013. Ye Z et al: Gastrointestinal bleeding prophylaxis for critically ill patients: A clinical practice guideline. BMJ 368:16722, 2020. Savio John, Daniel S. Pratt

Jaundice Jaundice is a yellowish discoloration of body tissues 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 dis­ ease or, less often, a hemolytic disorder or disorder of bilirubin metabo­ lism. The degree of serum bilirubin elevation can be estimated by physical examination. Slight increases in serum bilirubin level are best detected by examining the sclerae for icterus. Sclerae have a particular affinity for bilirubin due to their high elastin content, and the presence of scleral icterus indicates a serum bilirubin level of at least 51 μmol/L (3 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 site 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 long-standing; 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 drugs including quinacrine, sunitinib, and sorafenib; and excessive exposure to phenols. Carotenoderma, a yellow coloring of the skin, is associ­ ated with diabetes, hypothyroidism, and anorexia nervosa, but most commonly, it is caused by the ingestion of an excessive amount of vegetables and fruits such as carrots, leafy vegetables, squash, peaches, and oranges that contain carotene. In jaundice, the yellow coloration of the skin is uniformly distributed over the body, whereas in caroteno­ derma, 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 4–37% of patients treated with it. It has also been reported with the use of the tyrosine kinase inhibitors sunitinib and sorafenib. Another sensitive indicator of increased serum bilirubin is dark­ ening 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 frac­ tion and, therefore, the presence of liver or biliary disease. Serum bilirubin levels increase 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 (See Chap. 349) Bilirubin, a tetrapyrrole pigment, is a breakdown product of heme (ferroprotoporphyrin IX). About 80–85% of the

4 mg/kg body weight 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 cytochromes 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 microsomal enzyme heme oxygenase, oxidatively cleaves the α bridge of the porphyrin group and opens the heme ring. The end products of this reaction are biliverdin, carbon monoxide, and iron. The sec­ ond 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 due to tight internal hydrogen bonding between the water-soluble moieties of bilirubin—that is, the bonding of the propionic acid carboxyl groups of one dipyrrolic half of the molecule with the imino and lactam groups of the opposite half. This configura­ tion blocks solvent access to the polar residues of bilirubin and places the hydrophobic residues on the outside. To be transported in blood, bilirubin must be solubilized. Solubilization is accomplished by the reversible, noncovalent binding of bilirubin to albumin. Unconjugated bilirubin bound to albumin is transported to the liver. There, the bilirubin—but not the albumin—is taken up by hepatocytes via a pro­ cess that at least partly involves carrier-mediated membrane transport. Remarkably, a full understanding of this process remains elusive as no specific bilirubin transporter has yet been identified (Chap. 349, Fig. 349-1). After entering the hepatocyte, unconjugated bilirubin is bound in the cytosol to several proteins including proteins in the glutathione-S-

transferase superfamily. These proteins serve both to reduce efflux of bilirubin back into the serum and to present the bilirubin for conjuga­ tion. In the endoplasmic reticulum, bilirubin is made aqueous soluble by conjugation to glucuronic acid, a process that disrupts the hydro­ phobic internal hydrogen bonds and yields bilirubin monoglucuronide and diglucuronide. The conjugation of glucuronic acid to bilirubin is catalyzed by bilirubin uridine diphosphate-glucuronosyl transferase (UDPGT). 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 mul­ tidrug resistance–associated protein 2 (MRP2). A portion of bilirubin glucuronides is transported into the sinusoids and portal circulation by MRP3 and is subjected to reuptake into the hepatocyte by the sinu­ soidal organic anion transport protein 1B1 (OATP1B1) and OATP1B3. The conjugated bilirubin excreted into bile drains into the duodenum and passes unchanged through the proximal small bowel. Conjugated bilirubin is not reabsorbed by the intestinal mucosa due to its hydro­ philicity and increased molecular size. When the conjugated bilirubin reaches the distal ileum and colon, it is hydrolyzed to unconjugated bilirubin by bacterial β-glucuronidases. The unconjugated bilirubin is reduced by normal gut bacteria to form a group of colorless tetrapyr­ roles called urobilinogens and other products, the nature and relative amounts of which depend on the bacterial flora. About 80–90% of these products are excreted in feces, either unchanged or oxidized to orange derivatives called urobilins. The remaining 10–20% of the urobilinogens undergo enterohepatic cycling. A small fraction (usually <3 mg/dL) escapes hepatic uptake, filters across the renal glomerulus, and is excreted in urine. Increased urinary excretion of urobilinogen can be due to increased bilirubin production, increased hepatic reab­ sorption of urobilinogen from the colon, or decreased hepatic clear­ ance of urobilinogen. ■ ■MEASUREMENT OF SERUM BILIRUBIN The terms direct and indirect bilirubin—that is, conjugated and unconjugated bilirubin, respectively—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 and splits into two relatively stable dipyrrylmethene azopigments that absorb

maximally at 540 nm, allowing photometric analysis. The direct frac­ tion is that which reacts with diazotized sulfanilic acid in the absence of an accelerator substance such as alcohol. The direct fraction provides an approximation of the conjugated bilirubin level in serum. The total serum bilirubin is the amount that reacts after the addition of alcohol to allow the release of unconjugated bilirubin from albumin binding sites. The indirect fraction is the difference between the total and the direct bilirubin levels and provides an estimate of the unconjugated bilirubin in serum. Unconjugated bilirubin also reacts with diazo reagents, albeit slowly, even when the accelerator is absent. Thus, the calculated indirect bilirubin may underestimate the true amount of unconjugated bilirubin in circulation.

Jaundice CHAPTER 52 With the van den Bergh method, the normal serum bilirubin con­ centration usually is between 17 and 26 μmol/L (1 and 1.5 mg/dL). Total serum bilirubin concentrations are between 3.4 and 15.4 μmol/L (0.2 and 0.9 mg/dL) in 95% of a normal population. Unconjugated hyperbilirubinemia is present when the direct fraction is <15% of the total serum bilirubin. The presence of even limited amounts of true conjugated bilirubin in serum suggests significant hepatobiliary pathology. As conjugated hyperbilirubinemia is always associated with bilirubinuria (except in the presence of delta bilirubin in prolonged cholestasis when jaundice is overt), detection of bilirubin in urine via dipstick test is extremely helpful to confirm the presence of conjugated hyperbilirubinemia in a patient with a mildly elevated direct fraction. Other techniques, although less convenient to perform, have added considerably to our understanding of bilirubin metabolism. First, studies using these methods demonstrate that, in normal persons or those with Gilbert’s syndrome, almost 100% of the serum bilirubin is unconjugated; <3% is monoconjugated bilirubin. Second, in jaundiced patients with hepatobiliary disease, the total serum bilirubin concen­ tration measured by these more accurate methods is lower than the values found with diazo methods. This finding 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 diglucuronides. Fourth, part of the directreacting bilirubin fraction includes conjugated bilirubin that is cova­ lently linked to albumin. This albumin-linked fraction of conjugated bilirubin (delta fraction, delta bilirubin, or biliprotein) represents an important fraction of total serum bilirubin in patients with cholestasis and hepatobiliary disorders. The delta bilirubin is formed in serum when hepatic excretion of bilirubin glucuronides is impaired and the glucuronides accumulate in serum. By virtue of its tight binding to albumin, the clearance rate of delta bilirubin from serum approximates the longer half-life of albumin (18–20 days) rather than the short halflife of bilirubin (about 4 h). The prolonged half-life of albumin-bound conjugated bilirubin accounts for two previously unexplained enigmas in jaundiced patients with liver disease: (1) that some patients with conjugated hyperbiliru­ binemia do not exhibit bilirubinuria during the recovery phase of their disease because the delta bilirubin, although conjugated, is covalently 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. ■ ■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 on urine dipstick test (Ictotest) indicates an elevation of the conjugated bilirubin fraction that cannot be excreted from the liver and implies the presence of hepatobiliary disease. A false-negative result is possible in patients with prolonged cholestasis due to the predomi­ nance of delta bilirubin, which is covalently bound to albumin and therefore not filtered by the renal glomeruli.

APPROACH TO THE PATIENT Jaundice The goal of this chapter is not to provide an encyclopedic review of every condition that causes jaundice. Rather, the chapter is intended to offer a framework that helps a physician to evaluate the patient with jaundice in a logical way (Fig. 52-1). The initial step is to perform appropriate blood tests in order to determine whether 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 the cause intra- or extrahepatic? These questions can all be answered with a thought­ ful history, physical examination, and interpretation of appropriate laboratory and radiologic tests and procedures. PART 2 Cardinal Manifestations and Presentation of Diseases The bilirubin present in serum represents a balance between input from the 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. History (focus on medication/drug exposure) Physical examination Lab tests: Bilirubin with fractionation, ALT, AST, alkaline phosphatase, prothrombin time, and albumin Isolated elevation of the bilirubin Direct hyperbilirubinemia (direct >15%) See Table 52-1 Inherited disorders Dubin-Johnson syndrome Rotor syndrome Indirect hyperbilirubinemia (direct <15%) See Table 52-1 Drugs Rifampicin Probenecid Results negative Additional virologic testing CMV DNA, EBV capsid antigen Hepatitis D antibody (if indicated) Hepatitis E IgM (if indicated)
Inherited disorders Gilbert’s syndrome Crigler-Najjar syndromes Hemolytic disorders Ineffective erythropoiesis Results negative Results negative FIGURE 52-1  Evaluation of the patient with jaundice. ALT, alanine aminotransferase; AMA, antimitochondrial antibody; ANA, antinuclear antibody; AST, aspartate aminotransferase; CMV, cytomegalovirus; EBV, Epstein-Barr virus; ERCP, endoscopic retrograde cholangiopancreatography; LKM, liver-kidney microsomal antibody; MRCP, magnetic resonance cholangiopancreatography; SMA, smooth-muscle antibody; SPEP, serum protein electrophoresis.

An increase in unconjugated bilirubin in serum results from overproduction, impaired 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 permits a rational evaluation of the patient (Fig. 52-1). The fol­ lowing discussion will focus solely on the evaluation of the adult patient with jaundice. ISOLATED ELEVATION OF SERUM BILIRUBIN Unconjugated Hyperbilirubinemia  The differential diagnosis of isolated unconjugated hyperbilirubinemia is limited (Table 52-1). The critical determination is whether the patient is suffering from a hemolytic process resulting in an overproduction of biliru­ bin (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 Bilirubin and other liver tests elevated Hepatocellular pattern: ALT/AST elevated out of proportion to alkaline phosphatase See Table 52-2 Cholestatic pattern: Alkaline phosphatase out of proportion ALT/AST See Table 52-3 Ultrasound

1. Viral serologies Hepatitis A IgM Hepatitis B surface antigen and core antibody (IgM) Hepatitis C RNA
2. Toxicology screen Acetaminophen level
3. Ceruloplasmin (if patient <40 years of age)
4. ANA, SMA, SPEP Dilated ducts Extrahepatic cholestasis CT/MRCP/ERCP Ducts not dilated Intrahepatic cholestasis Serologic testing AMA Hepatitis serologies Hepatitis A, CMV, EBV Review drugs (see Table 52-3) AMA positive Liver biopsy MRCP/Liver biopsy Liver biopsy

TABLE 52-1  Causes of Isolated Hyperbilirubinemia I. Indirect hyperbilirubinemia A. Hemolytic disorders B. Ineffective erythropoiesis C. Increased bilirubin production

1. Massive blood transfusion
2. Resorption of hematoma D. Drugs
3. Rifampin
4. Probenecid
5. Atazanavir
6. Antibiotics—cephalosporins and penicillins E. Inherited conditions
7. Crigler-Najjar types I and II
8. Gilbert’s syndrome II. Direct hyperbilirubinemia (inherited conditions) A. Dubin-Johnson syndrome B. Rotor syndrome spherocytosis, sickle cell anemia, thalassemia, and deficiency of red cell enzymes such as pyruvate kinase and glucose-6-phosphate dehydrogenase. In these conditions, the serum bilirubin level rarely exceeds 86 μmol/L (5 mg/dL). Higher levels may occur when there is coexistent renal or hepatocellular dysfunction or in acute hemo­ lysis, such as a sickle cell crisis. In evaluating jaundice in patients with chronic hemolysis, it is important to remember the high inci­ dence 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 hemo­ lytic anemia (e.g., hemolytic-uremic syndrome), paroxysmal nocturnal hemoglobinuria, spur cell anemia, immune hemolysis, and parasitic infections (e.g., malaria and babesiosis). Ineffective erythropoiesis occurs in cobalamin, folate, and iron deficiencies. Resorption of hematomas and massive blood transfusions both can result in increased hemoglobin release and overproduction of bilirubin. In the absence of hemolysis, the physician should consider a problem with the hepatic uptake or conjugation of bilirubin. Cer­ tain drugs, including rifampin and probenecid, may cause uncon­ jugated 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

342 μmol/L [>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 UDPGT activ­ ity; are totally unable to conjugate bilirubin; and hence cannot excrete it. Crigler-Najjar type II is somewhat more common than type I. Patients live into adulthood with serum bilirubin levels of 103–428 μmol/L (6–25 mg/dL). In these patients, mutations in the bilirubin UDPGT gene cause the reduction—typically ≤10%—of the enzyme’s activity. Bilirubin UDPGT 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 concurrent illness or surgery. Gilbert’s syndrome is also marked by the impaired conjugation of bilirubin due to reduced bilirubin UDPGT activity (typically 10–35% of normal). Patients with Gilbert’s syndrome have mild unconjugated hyperbilirubinemia, with serum levels almost always <103 μmol/L (6 mg/dL). The serum levels may fluctuate, and

jaundice is often identified only during periods of stress, concur­ rent illness, alcohol use, or fasting. Unlike both Crigler-Najjar syndromes, Gilbert’s syndrome is very common. The reported inci­ dence is 3–7% of the population, with males predominating over females by a ratio of 1.5–7:1. The mildly elevated indirect serum hyperbilirubinemia seen in Gilbert’s syndrome is generally of no clinical consequence and may actually have protective effects. Conjugated Hyperbilirubinemia  Elevated conjugated hyperbiliru­ binemia is found in two rare inherited conditions: Dubin-Johnson syndrome and Rotor syndrome (Table 52-1). Patients with either condition present with asymptomatic jaundice. The defect in Dubin-Johnson syndrome is the presence of mutations in the gene for MRP2. These patients have altered excretion of bilirubin into the bile ducts. Rotor syndrome is caused by a deficiency of the major hepatic drug reuptake transporters OATP1B1 and OATP1B3. Differentiating between these syndromes is possible but is clinically unnecessary due to their benign nature. Jaundice CHAPTER 52 ELEVATION OF SERUM BILIRUBIN WITH OTHER

LIVER TEST ABNORMALITIES The remainder of this chapter will focus on the evaluation of patients with 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. This distinction, which is based on the history and physical examination as well as the pattern of liver test abnormalities, guides the clinician’s evaluation (Fig. 52-1). History  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, whether physician-prescribed, overthe-counter, complementary, or alternative medicines (e.g., herbal and vitamin preparations) or other drugs such as anabolic steroids. The patient should be carefully questioned about possible paren­ teral exposures, including transfusions, intravenous and intranasal drug use, tattooing, and sexual activity. Other important points 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 signs and symptoms, such as arthralgias, myalgias, rash, anorexia, weight loss, abdominal pain, fever, pruritus, and changes in the urine and stool. While none of the latter manifestations is specific for any one condition, any of them can suggest a 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-upperquadrant pain and shaking chills suggests choledocholithiasis and ascending cholangitis. Physical Examination  The general assessment should include evaluation of the patient’s nutritional status. Temporal and proximal muscle wasting suggests long-standing disease 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 alcohol-related cirrhosis and occasionally in other types of cirrhosis. An enlarged left supra­ clavicular node (Virchow’s node) or a periumbilical nodule (Sister Mary Joseph’s nodule) suggests an abdominal malignancy. Jugular venous distention, a sign of right-sided heart failure, and/or a pulsa­ tile liver suggest hepatic congestion. Right pleural effusion even in the absence of clinically apparent ascites may be seen in advanced cirrhosis. The abdominal examination should focus on the size and con­ sistency of the liver, on whether the spleen is palpable and hence enlarged, and on whether ascites is 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 signify viral or alcoholic hepatitis; an infiltrative process such as amyloidosis; 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. Ascites in the presence of jaundice suggests either cirrhosis or malignancy with peritoneal spread. Laboratory Tests  A battery of tests are helpful in the initial evaluation of a patient with unexplained jaundice. These include total and direct serum bilirubin measurement; determination of serum aminotransferase, alkaline phosphatase, and albumin con­ centrations; and prothrombin time tests. Enzyme tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase [ALP]) are helpful in differentiating between a hepatocellular process and a cholestatic process (Table 348-1; Fig. 52-1)—a critical step in determining what additional workup is indicated. Patients with a hepatocellular process generally have a rise in the aminotransferases that is disproportionate to that in ALP, whereas patients with a cholestatic process have a rise in ALP that is disproportionate to that of the aminotransferases. The serum bilirubin can be prominently elevated in both hepatocellular and cholestatic conditions and therefore is not necessarily helpful in differentiating between the two. PART 2 Cardinal Manifestations and Presentation of Diseases In addition to enzyme tests, all jaundiced patients should have additional blood tests—specifically, an albumin level and a pro­ thrombin time—to assess liver function. A low albumin level suggests a chronic process such as cirrhosis or cancer. A normal albumin level 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 dysfunc­ tion. 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 and offer some indication of the duration and severity of the disease. The causes and evaluations of hepatocellular and cholestatic diseases are quite different. Hepatocellular Conditions  Hepatocellular diseases that can cause jaundice include viral hepatitis, drug or environmental tox­ icity, alcohol, and end-stage cirrhosis from any cause (Table 52-2). Wilson’s disease occurs primarily in young adults and usually between the ages of 3 and 55. Autoimmune hepatitis is typically seen in young to middle-aged women but may affect men and TABLE 52-2  Hepatocellular Conditions That May Produce Jaundice Viral hepatitis   Hepatitis A, B, C, D, and E   Epstein-Barr virus   Cytomegalovirus   Herpes simplex virus Alcoholic hepatitis Chronic liver disease and cirrhosis Drug toxicity   Predictable, dose-dependent (e.g., acetaminophen)   Unpredictable, idiosyncratic (e.g., isoniazid) Environmental toxins   Vinyl chloride   Jamaica bush tea—pyrrolizidine alkaloids   Kava kava   Wild mushrooms—Amanita phalloides, A. verna Wilson’s disease Autoimmune hepatitis

women of any age. Alcoholic hepatitis can be differentiated from viral and toxin-related hepatitis by the pattern of the aminotrans­ ferases: patients with alcoholic hepatitis typically have an AST-toALT ratio of at least 2:1, and the AST level rarely exceeds 300 U/L. Patients with acute viral hepatitis and toxin-related injury severe enough to produce jaundice typically have aminotransferase levels

500 U/L, with the ALT greater than or equal to the AST. While ALT and AST values <8 times normal may be seen in either hepa­ tocellular 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 slightly elevated aminotransferase levels. When the clinician determines that a patient has a hepatocellular disease, appropriate testing for acute viral hepatitis includes a hepa­ titis A IgM antibody assay, a hepatitis B surface antigen and core IgM antibody assay, a hepatitis C viral RNA test, and, depending on the circumstances, a hepatitis E IgM antibody assay. The hepatitis C

antibody can take up to 6 weeks to become detectable, making it an unreliable test if acute hepatitis C is suspected. Studies for hepatitis D, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) may also be indicated. Ceruloplasmin is the initial screening test for Wilson’s disease. Testing for autoimmune hepatitis usually includes antinuclear antibody and anti–smooth muscle antibody assays and measurement of specific immunoglobulins. Drug-induced hepatocellular injury can be classified as either predictable or unpredictable. Predictable drug reactions are dosedependent 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) or kava, and the mushrooms Amanita phalloides and A. verna, which contain highly hepatotoxic amatoxins. Cholestatic Conditions  When the pattern of the liver tests sug­ gests a cholestatic disorder, the first step is to determine whether it is intra- or extrahepatic cholestasis (Fig. 52-1). Distinguishing intrahepatic from extrahepatic cholestasis may be difficult. His­ tory, physical examination, and laboratory tests often are not helpful. The next appropriate test is an ultrasound. The ultra­ sound 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 dilation suggests intrahepatic cholestasis, while its presence 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 chol­ angitis (PSC), in which scarring prevents the intrahepatic ducts from dilating. Although ultrasonography may indicate extrahepatic cholesta­ sis, 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), magnetic resonance cholan­ giopancreatography (MRCP), endoscopic retrograde cholangiopan­ creatography (ERCP), percutaneous transhepatic cholangiography (PTC), and endoscopic ultrasound (EUS). CT and MRCP are 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. Beyond its diagnostic capabilities, ERCP allows therapeutic interventions, including the removal of common bile duct stones and the placement of stents. PTC can provide the same information as ERCP and also allows for intervention in patients in whom ERCP is unsuccessful due to

proximal biliary obstruction or altered gastrointestinal anatomy. MRCP has replaced ERCP as the initial diagnostic test in most cases. EUS displays sensitivity and specificity comparable to that of MRCP in the detection of bile duct obstruction and allows biopsy of suspected malignant lesions. In patients with apparent intrahepatic cholestasis, the diagnosis is often made by serologic testing in combination with a liver biopsy. The list of possible causes of intrahepatic cholestasis is long and varied (Table 52-3). A number of conditions that typically cause a hepatocellular pattern of injury can also present as a cholestatic variant. Both hepatitis B and C viruses can cause cholestatic hepa­ titis (fibrosing cholestatic hepatitis). This disease variant has been TABLE 52-3  Cholestatic Conditions That May Produce Jaundice I. Intrahepatic A. Viral hepatitis

1. Fibrosing cholestatic hepatitis—hepatitis B and C
2. Hepatitis A, Epstein-Barr virus infection, cytomegalovirus infection B. Alcoholic hepatitis C. Drug toxicity
3. Pure cholestasis—anabolic and contraceptive steroids
4. Cholestatic hepatitis—chlorpromazine, erythromycin estolate
5. Chronic cholestasis—chlorpromazine and prochlorperazine D. Primary biliary cholangitis E. Sclerosing cholangitis, primary and secondary F. Vanishing bile duct syndrome
6. Chronic rejection of liver transplants
7. Sarcoidosis
8. Drugs G. Congestive hepatopathy and ischemic hepatitis H. Inherited conditions
9. Progressive familial intrahepatic cholestasis
10. Benign recurrent intrahepatic cholestasis I. Cholestasis of pregnancy J. Total parenteral nutrition K. Nonhepatobiliary sepsis L. Benign postoperative cholestasis M. Paraneoplastic syndrome N. Veno-occlusive disease O. Graft-versus-host disease P. Infiltrative disease
11. Tuberculosis
12. Lymphoma
13. Amyloidosis Q. Infections
14. Malaria
15. Leptospirosis II. Extrahepatic A. Malignant
16. Cholangiocarcinoma
17. Pancreatic cancer
18. Gallbladder cancer
19. Ampullary cancer
20. Malignant involvement of the porta hepatis lymph nodes B. Benign
21. Choledocholithiasis
22. Postoperative biliary strictures
23. Primary sclerosing cholangitis
24. Chronic pancreatitis
25. AIDS cholangiopathy
26. Mirizzi’s syndrome
27. Parasitic disease (ascariasis)

reported in patients who have undergone solid organ transplanta­ tion. The availability of direct-acting antiviral drugs has reduced the incidence of this condition. Hepatitis A and E, alcoholic hepatitis, and EBV or CMV infections may also present as cholestatic liver disease. Drugs may cause intrahepatic cholestasis that is usually revers­ ible after discontinuation of the offending agent, although it may take many months for cholestasis to resolve. Drugs most commonly associated with cholestasis are the anabolic and con­ traceptive steroids. Cholestatic hepatitis has been reported with chlorpromazine, imipramine, tolbutamide, sulindac, cimetidine, and erythromycin estolate. It also occurs in patients taking trim­ ethoprim; sulfamethoxazole; and penicillin-based antibiotics such as ampicillin, dicloxacillin, and clavulanic acid. Rarely, cholestasis may be chronic and associated with progressive fibrosis despite early discontinuation of the offending drug. Chronic cholestasis has been associated with chlorpromazine and prochlorperazine. Jaundice CHAPTER 52 Primary biliary cholangitis is an autoimmune disease predomi­ nantly affecting women and characterized by progressive destruc­ tion of interlobular bile ducts. The diagnosis is made by the detection of antimitochondrial antibody, which is found in 95% of patients. PSC is characterized by the destruction and fibrosis of larger bile ducts. The diagnosis of PSC is made with cholangiogra­ phy (MRCP), which demonstrates the pathognomonic segmental strictures. Approximately 75% of patients with PSC also have inflammatory bowel disease. The vanishing bile duct syndrome and adult bile ductopenia are rare conditions in which a decreased number of bile ducts are seen in liver biopsy specimens. This histologic picture is also seen in patients who develop chronic rejection after liver transplantation and in those who develop graft-versus-host disease after bone mar­ row 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. The familial intrahepatic cholestatic syndromes include progressive familial intrahepatic cholestasis (PFIC) types 1–3 and benign recur­ rent intrahepatic cholestasis (BRIC) types 1 and 2. BRIC is charac­ terized by episodic attacks of pruritus, cholestasis, and jaundice beginning at any age, which can be debilitating but do not lead to chronic liver disease. Serum bile acids are elevated during episodes, but serum γ-glutamyltransferase (γ-GT) activity is normal. PFIC disorders begin at childhood and are progressive in nature. All three types of PFIC are associated with progressive cholestasis, elevated levels of serum bile acids, and similar phenotypes but different genetic mutations. Only type 3 PFIC is associated with high levels of γ-GT. Cholestasis of pregnancy occurs in the second and third tri­ mesters and resolves after delivery. Its cause remains 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, renal cell cancer, renal sarcoma, T-cell lymphoma, prostate cancer, and several gastrointestinal malig­ nancies. In patients developing cholestasis in the intensive care unit, the major considerations should be sepsis, ischemic hepatitis (“shock liver”), and TPN-related jaundice. Jaundice occurring after bone marrow transplantation is most likely due to veno-occlusive disease (also called sinusoidal obstruction syndrome) or graftversus-host disease. In addition to hemolysis, sickle cell disease may cause intrahepatic and extrahepatic cholestasis. Jaundice is a late finding in heart failure caused by hepatic congestion and hepatocellular hypoxia. Ischemic hepatitis is a distinct entity of acute hypoperfusion characterized by an acute and dramatic elevation in the serum aminotransferases followed by a gradual peak in serum bilirubin.