CHOLESTASIS AND ALCOHOLIC LIVER DISEASE

CHOLESTASIS

1089-3261/99 $8.00

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CHOLESTASIS AND ALCOHOLIC LIVER DISEASE Bruce Y. Tung, MD, and Robert L. Carithers, Jr, MD

Patients with alcoholic liver disease frequently manifest clinical or histologic evidence of cholestasis. Although cholestasis is defined as an impairment of bile excretion, it is a term frequently used by pathologists to describe the retention of bile in hepatocytes, canaliculi, or bile ducts leading to microscopically visible bile thrombi. Cholestasis usually presents clinically as jaundice or elevation in serum bilirubin, although histologic cholestasis and clinical jaundice do not always co-exist. True cholestasis is therefore more properly defined as increased bile salt retention and elevated serum alkaline phosphatase; only a minority of such patients have jaundice. This article reviews the prevalence and prognostic significance of cholestasis in alcoholic liver disease. Although the precise mechanisms by which alcohol intake leads to intrahepatic cholestasis are not well understood, the available data are examined, and the differential diagnosis and clinical evaluation of jaundice in patients with alcoholic liver disease are discussed. MECHANISMS OF ALCOHOL-INDUCED CHOLESTASIS

In contrast with the well-described effects of ethanol on mitochondrial structure and function, fatty acid metabolism, lipid peroxidation, and oxidant-antioxidant balance, the effects of ethanol intake on bile secretion are poorly understood. In the rat model, ethanol can have both stimulatory and inhibitory effects on bile acid secretion, depending on From the Department of Medicine, Division of Gastroenterology, Section of Hepatology, University of Washington School of Medicine, Seattle, Washington

CLINICS IN LIVER DISEASE VOLUME 3 NUMBER 3 * AUGUST 1999

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the ethanol concentration and the duration of intake.41Early studies proposed that alcohol-associated cholestasis may be caused by hepatocyte necrosis with swelling and compression of intrahepatic biliary radic a l or ~ ~ by~increased permeability of bile d u c t ~ l e sMore . ~ ~ recent work suggests that ethanol may affect bile acid uptake and secretion at several different levels, including the hepatocyte basolateral membrane and within the intracellular compartment.26 At the hepatocyte basolateral membrane, the Na+,K+-ATPase plays an essential role in maintaining steady-state transmembrane ion gradients and the resting transmembrane electric potential.s0Ethanol has been shown to inhibit the function of the Na+,K+-ATPase pump in a variety 64 In addition, direct alterations of tissues, including intact hepat~cytes.~~, in plasma membrane assembly and fluidity may alter membrane permeability and disrupt the transmembrane ion and electric gradient^.^", 57, 82 These gradients are crucial in driving Na+-dependent bile salt uptake by hepatocytes, which is necessary for normal biliary secretion. In this way, ethanol may inhibit hepatocyte bile acid uptake and disrupt an important step in bile secretion. Ethanol may also have important toxic effects on intracellular processes that are essential for normal bile formation. Among the best studied of these processes is microtubule assembly, which forms an integral part of the cytoskeleton and which plays an important role in intracellular vesicle trafficking. The role of the microtubule system in normal bile secretion remains somewhat controversial. In a rat model, inhibition of microtubule function by colchicine or vinblastine significantly reduces biliary lipid secretion. Bile acid secretion and bile flow are also reduced, but to a lesser extent.27Microtubules appear to be more important in the augmentation of bile flow than in the maintenance of basal bile flow rates. In rats, administration of colchicine does not affect basal bile flow rates. However, the augmentation of bile flow that is 17, 52 In addiseen with taurocholate infusion is inhibited by c~lchicine.'~, tion, co-administration of colchicine and phalloidin, an inhibitor of microfilament function, further blunts the choleretic action of taurocholate.I7,52 This finding suggests the existence of an important synergistic relationship between the microtubule system and microfilament cytoskeleton in the physiologic augmentation of normal bile secretion. but not a11O ' studies, ethanol administration has been In shown to decrease microtubule polymerization and to induce morphologic alterations in microtubule structure. Ethanol-induced interference with microtubule function is thought to be mediated through its oxidative metabolite, acetaldehyde. The protein tubulin, which polymerizes to form microtubules, has striking acetaldehyde-binding properties, and acetaldehyde binding leads to impairment of microtubule assembly.83 Recently, ethanol has been shown to directly reduce the intracellular vesicle movement that is dependent on microtubule-associated motor enzymes such as d ~ n a m i nIn . ~an ~ isolated perfused rat liver model, the methyl donor S-adenosyl-L-methionine has been shown to counteract the inhibitory action of ethanol on bile salt secretion but not through

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effects on vesicular exocyt~sis.~ In summary, indirect evidence suggests that alcohol-induced cholestasis may occur, in part, through impairment of microtubule function by acetaldehyde binding. From available data, this mechanism is more likely to affect bile salt-dependent bile flow, which is more affected by microtubule function than is bile saltindependent bile flow. BILE ACIDS AND ALCOHOLIC LIVER DISEASE

In patients with alcoholic liver disease, serum concentrations of the primary bile acids, cholic acid and chenodeoxycholic acid, are often 29, 78, 81 Increases in serum bile acid concentrations strikingly ele~ated.~, are seen despite an overall reduction in bile acid pool size and synthesis rate; the increased concentrations probably reflect decreased hepatic uptake of bile acids.” Total serum bile acid concentrations are elevated in patients with alcoholic hepatitis, severe steatosis, and cirrhosis when compared with controls or persons with only mild alcoholic steato~is.~~, In fact, elevations of total serum bile acid concentrations may actually correlate better with histologic progression of alcoholic liver disease than 78, 81 The correlation between serum do standard serum bio~hemistries.~, bile acid concentrations and histologic cholestasis is less clear. In patients with alcoholic hepatitis or cirrhosis, total serum bile acid concentrations correlate with histologic inflammatory scores and serum bilirubin concentrations but not with histologic cholestasis scores.3,81 By contrast, mosP2,81 but not all19 studies show serum and biliary concentrations of secondary bile acids such as deoxycholic acid to be markedly reduced or absent. Low deoxycholic acid concentrations appear to be caused by a decrease in 7a-dehydroxylase activity of fecal bacteria in alcoholic cirrhotics, and not by deoxycholate malabsorption or rehydroxylation to cholic The significance of elevated serum bile acid concentrations in patients with alcoholic liver disease is unclear. At high concentrations, endogenous bile acids, especially the dihydroxy bile acids chenodeoxycholic acid and deoxycholic acid, may be hepatotoxic in h ~ m a n s . 3En~ dogenous bile acids could, in part, mediate the hepatotoxicity of alcohol, as they are thought to do in chronic cholestatic diseases.59Preliminary studies have investigated the role of ursodeoxycholic acid in the treatment of alcoholic liver disease. In vitro, ursodeoxycholic acid and tauroursodeoxycholic acid protect against ethanol-induced injury in a hepatoblastoma cell line.48 In vivo, ursodeoxycholic acid administration decreases ethanol-induced steatosis and lipid peroxidation and stabilizes liver plasma membranes in rats.51In the only published study in humans, ursodeoxycholic acid has been shown to improve serum bilirubin, y-glutamyl transpeptidase and alanine aminotransferase (ALT) concentrations in patients with alcoholic cirrhosis after 4 weeks of treatment.56 Ursodeoxycholic acid also has shown some promise in improving biochemical and histologic parameters in patients with nonalcoholic steato-

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hepatitis.34It remains to be seen whether these findings will be confirmed in larger randomized trials and whether the therapeutic effect applies also to patients with alcoholic liver disease. JAUNDICE AND HISTOLOGIC CHOLESTASIS IN ALCOHOLIC LIVER DISEASE

The spectrum of alcoholic liver disease may be broadly divided into three major clinicopathologic categories: alcoholic steatosis (fatty liver), alcoholic hepatitis (steatonecrosis), and alcoholic cirrhosis. Although each is a distinct entity, they often present with overlapping clinical and histologic features. Both histologic cholestasis and jaundice may occur across the entire spectrum of alcoholic liver disease and in some cases may be seen independent of significant steatosis, hepatitis, or cirrhosis (Fig. 1). ALCOHOLIC STEATOSIS

Hepatic fatty accumulation is the most common histologic feature of alcoholic liver disease and may occur in as many as 80% of alcoholics.I8 In fact, steatosis can be easily induced by only moderate alcohol intake.65In the classic form of macrovesicular steatosis, a single large intracellular fat globule displaces the nucleus and cytoplasm to the periphery of the cell. Macrovesicular steatosis is seen most prominently in a pericentral location (zone 3). Microvesicular steatosis (alcoholic foamy degeneration) is a pattern of multiple small intracellular fat droplets around a centrally placed nucleus. This pattern is much less common but may carry a worse prognosis.75Patients with alcoholic steatosis generally have clinically mild disease, with nonspecific symptoms of fatigue, anorexia and nausea, or asymptomatic hepatomegaly and serum aminotransferase elevations. In rare instances, patients with alcoholic steatosis have severe chole-

Figure 1. Overlapping syndromes of alcoholic liver disease. (Adapted from Finlayson NDC: Clinical features of alcoholic liver disease. Bailliere’s Clinical Gastroenterology 7:627,1993; with permission.)

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stasis. Ballard et a17 described five patients with alcoholic steatosis presenting with jaundice. Liver biopsy in all five patients showed severe steatosis and marked cholestasis with little hepatic fibrosis. Obstructive jaundice was considered in all cases; two patients underwent oral cholecystography and one patient had exploratory laparotomy to rule out extrahepatic biliary obstruction. All five patients improved with supportive care and abstinence. Morgan et a147described three similar patients who presented with steatosis and severe cholestasis. In all three patients, a mixture of macrovesicular and microvesicular steatosis was noted. Hepatic failure characterized by progressive encephalopathy and coagulopathy developed and led to death in two of the patients. An unusual association between alcoholic steatosis and jaundice, hypercholesterolemia, and hemolytic anemia also has been described.87 Despite the previously noted cases, significant cholestasis is relatively rare in patients with isolated alcoholic steatosis. In a large cooperative study of alcoholic liver disease conducted by the Department of Veteran Affairs (VA) histologic cholestasis was seen in only 19% of the patients who had alcoholic steatosis. Jaundice was more common, however, occurring in 31% of these patients.I4 Although the prognosis of hepatic steatosis is generally favorable, there is a small risk of progression to cirrhosis, especially if alcohol intake continues. Sorensen et al7I evaluated 258 alcoholic men admitted to the hospital with no evidence of cirrhosis on initial liver biopsy. After 10 to 13 years of follow-up, 21% of the men who had moderate to severe steatosis but no alcoholic hepatitis on initial biopsy had developed cirrhosis. In a similar study, Teli et a175followed 88 patients with histologically identified alcoholic steatosis for 8 to 16 years and found that 10% developed evidence of cirrhosis. The presence of histologic cholestasis in association with alcoholic steatosis did not appear to be of prognostic significance in determining the risk of progression to cirrhosis in these studies.71 ALCOHOLIC HEPATITIS

Alcoholic hepatitis is a clinically more severe condition than steatosis. In its milder forms, patients often have nonspecific symptoms such as anorexia, nausea, vomiting, and diarrhea, or may have asymptomatic hepatomegaly and serum aminotransferase elevations. In its more severe form, patients with alcoholic hepatitis present with jaundice, fever, right upper quadrant pain, and occasionally with confusion. Alcoholic hepatitis usually develops in patients with a long duration of alcohol abuse and typically follows a period of especially heavy alcohol intake. Histologically, alcoholic hepatitis is characterized by hepatocyte ballooning degeneration and necrosis, often accompanied by the presence of Mallory’s bodies. A variable number of inflammatory cells are always present, with neutrophils predominating. Pericellular and perivenular (centrilobular) fibrosis are also characteristic lesions. Bile stasis

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and bile ductular proliferation are sometimes seen, as are giant mitochondria and acidophilic bodies (Fig. 2).21,23 The association between cholestasis and alcoholic hepatitis was first described by Phillips and D a v i d s ~ n ?who ~ noted the accumulation of bile pigment in chronic alcoholics with acute decompensation. These authors subsequently described four illustrative cases in alcoholic patients of severe and prolonged jaundice that simulated extrahepatic biliary ob~truction.~~ The clinical features were so suggestive of biliary obstruction that exploratory laparotomy was performed in two patients. In the other two patients, liver biopsy confirmed the characteristic findings of alcoholic hepatitis with severe cholestasis. The prevalence of histologic cholestasis in alcoholic hepatitis varies greatly among studies, depending on patient selection criteria (Table 1). In an early report from Beckett et a1,8 five of six patients (83%) with alcoholic hepatitis for whom liver biopsies were available showed significant bile stasis and associated bile ductular proliferation. Birschbach et all1 prospectively biopsied 100 consecutive patients with alcoholic hepatitis and found that 45% had histologic evidence of cholestasis; however, the cholestasis was moderate or severe in only 12%. In a large VA cooperative study, histologic cholestasis was seen in only 25% of 217 patients with alcoholic hepatitis.14Moderate to severe tissue cholestasis is seen in as many as 43% of patients with very severe alcoholic hepati-

Figure 2. Alcoholic hepatitis with cholestasis. There is ballooning degeneration of hepatocytes with Malloty's hyaline (arrow) and accompanying inflammatory cells, including neutrophils. A canalicular bile plug (arrowhead) also is present (hematoxylin-eosin, original magnification x 466). (Courtesy of S. L. Taylor, MD, Seattle, WA.)

1961

1971

1972 1974 1991

8

28

23 11 14

42

Beckett

Harinasuta

Galambos Birschbach Chedid

Mathurin

122

76 100 217

257

7

No.

Prospective

Retrospective Prospective Prospective

Retrospective

Case series

Study Design

NR

NR 38 55

47

100 NR

32 NR 12 NR 43

21 45 25 NR

95

20 56 51

37

67

NR

83

Cirrhosis

("/.I

("/.I

(%I

Cholestasis ModerateSevere (%)

Cholestasis*

Jaundice

Cholestasis seen in 32% of cirrhotic but only in 18% of noncirrhotic patients DF >32 or encephalopathy in all patients

Liver histology not available in 1 patient No difference in mortality in patients with or without Mallory bodies

Comments

Tholestasis is defined as histologic evidence of bile thrombi and is graded on a scale using none, mild, moderate, or severe histologic cholestasis NR = not reported; DF = discriminant function

1996

Year

Author

~~

Reference

~

Table 1. PREVALENCE OF JAUNDICE AND HISTOLOGIC CHOLESTASIS IN PATIENTS WITH ALCOHOLIC HEPATITIS

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& CARITHERS

tis." The degree of histologic cholestasis, therefore, clearly reflects the underlying severity of disease. The finding of histologic cholestasis does not always coincide with the presence of jaundice. Harinasuta and Zimmerman2*found that only 32% of patients with alcoholic hepatitis had histologic cholestasis, although 47% were clinically jaundiced. In the VA cooperative study,14 55% of patients with alcoholic hepatitis were jaundiced, but only 25% had histologic cholestasis. Conversely, in 67 patients with alcoholic hepatitis and moderate to severe cholestasis, only 61% had significant jaundice.50Nevertheless, the presence of elevated serum alkaline phosphatase generally correlates well with serum bilirubin elevation and tissue cholestasis in patients with alcoholic hepatitis.53 The presence of cholestasis clearly has prognostic significance in patients with alcoholic hepatitis. The inclusion of serum bilirubin in the discriminant function [prothrombin time - control (seconds)]

+ serum bilirubin (mg/dL)

underscores its role in distinguishing patients with mild alcoholic hepatitis from those with more severe disease.4O Patients with alcoholic hepatitis and a discriminant function greater than 32 have a 28-day mortality rate of 35% and a 90-day mortality rate of 55?'0.'~, 63 By contrast, mortality in patients with alcoholic hepatitis and serum bilirubin less than or equal to 5 mg/dL is only 2% at 6 m0nths.2~ Nissenbaum et a150 closely examined the prognostic significance of moderate to severe histologic cholestasis in patients with alcoholic hepatitis. Patients with cholestatic alcoholic hepatitis had clinically more severe disease than those without cholestasis, demonstrated by significantly more ascites, encephalopathy, malnutrition, and higher discriminant function. Histologically, tissue cholestasis was correlated with more fibrosis, parenchymal necrosis, bile duct proliferation, portal inflammation, and overall histologic severity score. On survival analysis, histologic cholestasis was associated with increased mortality; after 5 years, only 22% of patients with cholestatic alcoholic hepatitis were alive, compared with 54% of patients without cholestasis. ACUTE ALCOHOLIC CHOLESTASIS

Glover et alZ4coined the term acute aZcoholic cholestasis to describe patients with alcohol-associated jaundice and severe cholestasis on liver biopsy but without histologic evidence of steatosis or alcoholic hepatitis. The three patients in this report all recovered spontaneously, although two had associated fibrosis. Isolated alcohol-induced cholestasis is rare, and most cases are associated with steatosis or alcoholic hepatitis.45 Afshani et a12described a subgroup of alcoholic patients with microscopic cholangitis characterized by peri- and intraductal polymorphonuclear leukocytes. None of these patients had extrahepatic biliary obstruction, and most also had associated alcoholic steatosis or hepatitis. Thus,

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the presence of microscopic cholangitis was thought to characterize a subgroup of patients with severe cholestasis from alcoholic liver disease. CHOLESTASIS AND ALCOHOLIC PANCREATITIS Long-term alcohol abuse can result in acute or chronic pancreatitis. The association between chronic pancreatitis and obstruction of the common bile duct has long been rec~gnized.~ The advent of percutaneous and endoscopic cholangiography has renewed interest in this association. The wide range of incidence of biliary obstruction in patients with chronic pancreatitis, as reported in available studies, results from differences in patient selection, severity of pancreatitis studied, and variable diagnostic criteria.38,66, 68, 70, 85, 86 Scott et aF8 performed cholangiography in 38 patients with chronic pancreatitis and found that 11 of the 38 patients (29%) had common bile duct stenosis. By contrast, common bile duct stenosis was seen in 62% of a highly selected group of patients with chronic pancreatitis undergoing surgical intervention.86 The clinical course of jaundice in patients with chronic pancreatitis is also quite variable. Segal et al" emphasized that cholestasis associated with pancreatitis can be divided into three groups: transient, which is thought to be caused by common bile duct compression from edema of the pancreatic head; recurrent, which may be caused by recurrent exacerbations of pancreatitis; and prolonged, which is caused by fibrosis and scarring of the intrapancreatic portion of the bile duct (Fig. 3). Sarles et aP7 found that jaundice is observed in approximately one third of patients with chronic calcific pancreatitis and is typically transient in nature. In this series, prolonged jaundice (longer than 1 month in duration) occurred in only 3% of patients. In contrast, Littenberg et a138 retrospectively evaluated 47 patients admitted with pancreatitis and significant elevations in alkaline phosphatase; 31 patients (65%) had transient jaundice, but 16 patients (35%)had prolonged jaundice lasting more than 1 month. Fifteen of the 16 patients (94%) with prolonged jaundice had radiologically proven common bile duct stenosis, compared with only 2 (Wo) of the 31 patients with transient jaundice. In some patients, common bile duct stenosis complicating chronic pancreatitis may not be clinically evident; Kalvaria et a131 found 17% of patients with radiologically significant common bile duct stenoses caused by pancreatitis had no history of jaundice or abdominal pain. Biliary obstruction from chronic pancreatitis may induce many changes in hepatic histology. Initially, portal edema, portal fibrosis, ductular proliferation, and microscopic cholangitis with varying degrees of intrahepatic cholestasis are seen.l, 35, 86 With prolonged obstruction, secondary sclerosing ~holangitis~~, 86 and secondary biliary cirrhomay develop. The risk of progression to biliary cirrhosis has sis', 35, 38, been a subject of controversy. In a large study from France, no cases of biliary cirrhosis were seen in more than 300 patients with chronic pancreatitis.66Other studies have suggested a 6% incidence of biliary

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Figure 3. Tight distal common bile duct stricture from chronic pancreatitis (arrows). Significant dilation of the common bile duct is seen upstream of the stricture. (Courtesy of C. A. Rohrmann, Jr, MD, Seattle, WA.)

cirrhosis in patients with chronic pancreatitis and common bile duct stenoses.', 35 On liver biopsy, histologic evidence of extrahepatic obstruction is common in patients with chronic pancreatitis, but features of alcoholic liver disease are surprisingly uncommon. Alcoholic steatosis, hepatitis, and cirrhosis do not frequently coincide with obstructive features in patients with chronic alcoholic pancreatitis.', 35, 38, 68,86 Lesur et a135studied 48 patients with chronic alcoholic pancreatitis and common bile duct stenosis. Liver biopsy findings were consistent with extrahepatic obstruction in 33 patients (69%) and with changes of alcoholic liver disease in 9 patients (19y0).Three of these 9 patients had biliary cirrhosis, 5 had alcoholic cirrhosis, and 2 had alcoholic hepatitis. No differences in clinical, biochemical, or radiological findings distinguished those with obstructive features from those with features of alcoholic liver disease. In summary, jaundice and extrahepatic biliary obstruction are not uncommon in patients with pancreatitis and may be transient, recurrent, or prolonged. Patients with prolonged jaundice typically have fixed stenoses of the distal common bile duct. Progression to secondary sclerosing cholangitis and secondary biliary cirrhosis may occur; thus, a

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diagnosis of common bile duct obstruction should be considered in all chronic alcoholics presenting with jaundice. CHOLELlTHlASlS AND ALCOHOLIC LIVER DISEASE

The association between alcohol and the formation of gallstones has been debated. Early studies from post mortem evaluations found that cholelithiasis was very common in patients with alcoholic cirrhosis, occurring in more than 30% of cirrhotic patients compared with 16% of Pigmented calcium bilirubinate stones were especially common and were postulated to be caused by chronic hemolysis from hypersplenism. By contrast, several case control and large cohort studies have shown a protective effect of alcohol against the development of gallstones.39,69 The apparent protective effect seen in these studies has been attributed by some to selection bias, because patients with symptomatic gallstones may decrease their alcohol intake.76However, moderate alcohol use has been shown to decrease bile lithogenicity by reducing biliary cholesterol c~ncentration.~~ A recent study suggests a paradoxical relationship: in patients with mild liver disease, alcohol use may protect against the development of cholelithiasis, but the risk of gallstone formation is elevated once cirrhosis develops.61In general, complications of gallstones represent an unusual cause of jaundice in the alcoholic patient." EVALUATION OF JAUNDICE IN THE ALCOHOLIC PATIENT

Many different conditions may lead to the development of jaundice in the alcoholic patient: Acetaminophen toxicity Acute alcoholic cholestasis Alcoholic steatosis Alcoholic hepatitis* Alcoholic cirrhosis* Acute viral hepatitis Drug reaction Hemolysis Biliary obstruction Acute pancreatitis Chronic pancreatitis* Pancreatic carcinoma Pancreatic pseudocyst Choledocholithiasis Acute cholecystitis *Represents the most common diagnoses.

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Of these, alcoholic hepatitis, alcoholic cirrhosis, and biliary obstruction from chronic pancreatitis are the most common. Usually, these conditions can be easily differentiated on clinical grounds with the aid of biochemical and radiologic data. In certain situations, however, more invasive procedures may be required for an accurate diagnosis. In jaundiced alcoholics with heavy recent alcohol intake, malaise, fever, tender hepatomegaly, leukocytosis, and serum aspartate aminotransferase (AST) greater than serum ALT concentration (but neither greater than 400 IU/L), a diagnosis of alcoholic hepatitis can easily be made. However, the full syndrome occurs in only a minority of patients with alcoholic liver disease.I2,36 The serum alkaline phosphatase concentration is also quite useful, because it is usually strikingly elevated in patients with biliary obstruction. Some patients with alcoholic liver disease alone, however, may also have significant elevations of alkaline pho~phatase.~~ Plain abdominal radiographs demonstrating pancreatic calcification or abdominal ultrasonography showing dilated bile ducts should raise the suspicion of biliary obstruction from chronic pancreatitis. The precise role of liver biopsy in the alcoholic patient is still controversial. Liver biopsy may confirm a clinical diagnosis of alcoholic liver disease, exclude other unsuspected causes of liver disease, assess extent of liver disease, and define prognosis. However, a prebiopsy clinical diagnosis of alcoholic liver disease is both highly sensitive and highly specific for the diagnosis of alcoholic liver disease.74,84 Because therapeutic options for most patients with alcoholic liver disease are limited to supportive measures, some clinicians prefer not to incur the small but finite risk of liver biopsy6A simple biochemical index has been proposed that accurately predicts the presence or absence of cirrhosis in alcoholics without the need for liver biopsy.60Others, however, have found that nonalcoholic diagnoses may be identified in as many as 20% of liver biopsies from patients with suspected alcoholic liver disease.37 In addition, histologic features can be used to identify patients with alcoholic liver disease who are more likely to respond to corticosteroid therapy42 or who are at increased risk for progression to ~ i r r h o s i sIn .~~ summary, liver biopsy is indicated when the diagnosis of alcoholic liver disease is uncertain. In patients for whom there is a strong clinical suspicion of alcoholic liver disease, liver biopsy may be necessary only if prognostic information is desired or treatment decisions will be affected. Endoscopic retrograde cholangiopancreatography (ERCP) is indicated to evaluate suspected extrahepatic biliary obstruction in patients with alcoholic liver disease. An early study reported that ERCP identified biliary obstruction in 20% of seriously ill alcoholics with hyperbilirubinemia or markedly elevated alkaline phosphatase.22The safety of performing ERCP with or without biliary sphincterotomy in patients with alcoholic hepatitis has not been studied. The presence of cirrhosis, however, is an independent risk factor for complications following endoscopic biliary sphincterotomy.20Overall, the absolute risk of complications after sphincterotomy in patients with cirrhosis is approximately

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20%; the risk of significant hemorrhage is 4% to ~ Y o . ~ O 62, In case series, mortality rates in cirrhotic patients who undergo biliary sphincterotomy 62, 73 These rates for choledocholithiasis can be as high as 6% to 149'0.~~. compare favorably, however, to complications of surgical treatment in these high-risk patients5*46, 62, 73 Endoscopic biliary stenting can be more safely performed and is effective in treating the biliary obstruction that may complicate chronic pancreatitis.16 SUMMARY

Histologic cholestasis and clinical jaundice may be seen in all stages of alcoholic liver disease. In rare cases, isolated cholestasis without significant steatosis, hepatitis, or cirrhosis is identified in an alcoholic patient. The mechanisms of ethanol-induced cholestasis are not well studied but may involve compression of intrahepatic biliary radicals or interference with basolateral uptake and intracellular transport of bile acids. In the evaluation of the jaundiced alcoholic patient, clinical, biochemical, and radiologic data are usually sufficient to distinguish alcohol-induced liver disease from extrahepatic biliary obstruction. In cases where the diagnosis is not readily apparent, more invasive studies such as liver biopsy or ERCP may be necessary. The risk of these invasive studies is directly related to the degree of underlying hepatic dysfunction. References 1. Afroudakis A, Kaplowitz N: Liver histopathology in chronic common bile duct stenosis due to chronic alcoholic pancreatitis. Hepatology 1:65-72, 1981 2. Afshani P, Littenberg G, Wollman J, et al: Significance of microscopic cholangitis in alcoholic liver disease. Gastroenterology 75:1045-1050, 1978 3. Alm R, Carlson J, Eriksson S: Fasting serum bile acids in liver disease. Scand J Gastroenterol 17213-218, 1982 4. Alvaro D, Gigliozzi A, Piat C, et al: Effect of S-adenosyl-L-methionine on ethanol cholestasis and hepatotoxicity in isolated perfused rat liver. Dig Dis Sci 40:1592-1600, 1995 5. Aranha GV, Sontag SJ, Greenlee HB: Cholecystectomy in cirrhotic patients: A formidable operation. Am J Surg 143:60, 1982 6. Atterbury CE: Should we routinely perform liver biopsy in suspected alcoholic liver disease? J Clin Gastroenterol 10:605-607, 1988 7. Ballard H, Bernstein M, Farrar JT Fatty liver presenting as obstructive jaundice. Am J Med 30:196-201, 1961 8. Beckett AG, Livingstone AV, Hill KR Acute alcoholic hepatitis. BMJ 21113-1119, 1961 9. Behrend M, Behrend A Chronic pancreatitis causing complete and incomplete obstruction of the common bile duct. Arch Surg 5751-61, 1948 10. Berman WJ, Gil J, Jennett RB, et al: Ethanol, hepatocellular organelles, and microtubules. Lab Invest 48760-767,1983 11. Birschbach HR, Harinasuta U, Zimmerman HJ: Alcoholic steatonecrosis: Prospective study of prevalence of Mallory bodies in biopsy specimens and comparison of severity of hepatic disease in patients with and without this histological feature. Gastroenterology 66~1195-1202,1974

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12. Bruguera M, Bordas JM, Rodes J: Asymptomatic liver disease in alcoholics. Arch Pathol Lab Med 101:644-647, 1977 13. Carithers RL Jr, Herlong HF, Diehl AM, et al: Methylprednisolone therapy in patients with severe alcoholic hepatitis. Ann Intern Med 110:685-690, 1989 14. Chedid A, Mendenhall C, Gartside P, et al: Prognostic factors in alcoholic liver disease. Am J Gastroenterol86:210-216, 1991 15. Crawford JM, Berken CA, Gollan JL: Role of the hepatocyte microtubular system in the excretion of bile salts and biliary lipid: Implications for intracellular vesicular transport. J Lipid Res 29:144-156, 1988 16. Deviere J, Devaere S, Baize M, et al: Endoscopic biliary drainage in chronic pancreatitis. Gastrointest Endosc 36:96-100, 1990 17. Dubin M, Maurice M, Feldmann G, et al: Influence of colchicine and phalloidin on bile secretion and hepatic ultrastructure in the rat. Gastroenterology 79:646-654, 1980 18. Edmondson HA, Peters RL, Frankel HH, et al: The early stage of liver injury in the alcoholic. Medicine (Baltimore) 46:119-129, 1967 19. Einarsson K, Angelin B, Bjorkhem I, et al: The diagnostic value of fasting individual serum bile acids in anicteric alcoholic liver disease: Relation to liver morphology. Hepatology 5:108-111, 1985 20. Freeman ML, Nelson DB, Sherman S, et al: Complications of endoscopic biliary sphincterotomy. N Engl J Med 335:909-918, 1996 21. French SW, Nash J, Shitabata P, et al: Pathology of alcoholic liver disease. Semin Liver Dis 13:154-169, 1993 22. Friedman MS, Falkenstein DB, Zimmon DS: Bile duct obstruction in alcoholic liver disease: The role of ERCP [abstract]. Gastroenterology 79:1017, 1980 23. Galambos JT: Natural history of alcoholic hepatitis: Histological changes. Gastroenterology 63:1026-1035, 1972 24. Glover SC, Brunt PW, McPhie J L Cholestasis in acute alcoholic liver disease. Lancet 2:1305-1306, 1977 25. Goldberg S, Mendenhall C, Anderson S, et al: VA cooperative study on alcoholic hepatitis: IV. The significance of clinically mild alcoholic hepatitis-describing the population with minimal hyperbilirubinemia. Am J Gastroenterol 81:1029-1034, 1986 26. Green RM, Crawford JM: Hepatocellular cholestasis: Pathobiology and histological outcome. Semin Liver Dis 15:372-389, 1995 27. Gregory DH, Vlahcevic ZR, Prugh MF, et al: Mechanism of secretion of biliary lipids: Role of a microtubular system in hepatocellular transport of biliary lipids in the rat. Gastroenterology 74:93-100, 1978 28. Harinasuta U, Zimmerman HJ: Alcoholic steatonecrosis: Relationship between severity of hepatic disease and presence of Mallory bodies in the liver. Gastroenterology 60:1036-1046, 1971 29. Jonsson G, Hedenborg G, Wisen 0, et a1 Serum concentrations and excretion of bile acids in cirrhosis. Scand J Clin Lab Invest 52:599-605, 1992 30. Kalant H, Mons W, Mahon MA: Acute effects of ethanol on tissue electrolytes in the rat. Can J Physiol Pharmacol44:l-12, 1966 31. Kalvaria I, Bornman PC, Marks IN, et al: The spectrum and natural history of common bile duct stenosis in chronic alcohol-induced pancreatitis. Ann Surg 210:608413, 1989 32. Knodell RG, Kinsey MD, Boedeker EC, et al: Deoxycholate metabolism in alcoholic cirrhosis. Gastroenterology 71:196-201, 1976 33. LaRusso NF, Szczepanik PA, Hoffmann AF: Effect of deoxycholic acid ingestion on bile acid metabolism and biliary lipid secretion in normal subjects. Gastroenterology 72:132-140, 1977 34. Laurin J, Lindor KD, Crippin JS, et a1 Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: A pilot study. Hepatology 23314641467, 1996 35. Lesur G, Levy P, Flejou J-F, et al: Factors predictive of liver histopathological appearance in chronic alcoholic pancreatitis with common bile duct stenosis and increased serum alkaline phosphatase. Hepatology 18:1078-1081, 1993

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