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Liver biopsy in the evaluation of patients with chronic hepatitis C who have repeatedly normal or near-normal serum alanine aminotransferase levels
BRIEF OBSERVATION
Liver Biopsy in the Evaluation of Patients with Chronic Hepatitis C Who Have Repeatedly Normal or Near-Normal Serum Alanine Aminotransferase Levels Angela K. Nutt, MD, Hassan A. Hassan, MD, Judy Lindsey, RNP, Laura W. Lamps, MD, Jean-Pierre Raufman, MD
A
s a consequence of the availability of highly sensitive diagnostic tests, the screening of transfusion recipients and former intravenous drug users, and the likelihood that symptomatic patients have already been diagnosed, hepatitis C is being diagnosed more commonly in apparently healthy people who have normal serum alanine aminotransferase levels. Hence, strategies for managing these patients are increasingly important. A recent National Institutes of Health Consensus Conference concluded that treatment of these patients “is not beneficial” but acknowledged “a weak association between alanine aminotransferase levels and severity of the histopathological findings on liver biopsy” (1). Serum alanine aminotransferase levels, however, may fluctuate during the course of the disease, and some patients with normal levels may have advanced liver disease (2– 6), although this has not been seen in all studies (7–10). In some of these studies, the criterion for a normal value and the frequency of serum alanine aminotransferase determinations were not defined, and liver biopsy samples were not evaluated systematically by a pathologist blinded to laboratory values. Moreover, heterogeneity of the hepatitis C virus, including different genotypes and quasispecies, suggests that observations in some parts of the world may not be relevant in the United States. To address these issues, we compared liver biopsy findings in hepatitis C-infected patients who had repeatedly normal serum alanine aminotransferase levels with biopsy results in patients who had elevated levels.
PATIENTS AND METHODS Study Design and Subjects Between 1996 and 1998, we identified 35 consecutive patients with hepatitis C who had two or more normal or near-normal serum alanine aminotransferase levels (ⱕ1.4 times the upper limit of normal of 50 IU/L) during 62
䉷2000 by Excerpta Medica, Inc. All rights reserved.
the 6 months before a liver biopsy was performed. During the same interval, we identified 35 patients who had undergone liver biopsy and who had persistently elevated levels (⬎1.4 times the upper limit of normal) on two or more occasions. Serum alanine aminotransferase levels were measured at the University Hospital of Arkansas or the Little Rock Department of Veterans Affairs Medical Center. All patients were hepatitis C virus RNA-positive by reverse transcriptase-polymerase chain reaction (PCR; National Genetics Institute; Los Angeles, California). Other causes of hepatic disease, including hepatitis B, autoimmune hepatitis, and hereditary liver disease, were excluded. None of the patients were immunosuppressed; all had a negative serological test for infection with the human immunodeficiency virus (HIV). Alcohol use was defined as consumption of more than an occasional drink. Information about risk factors for hepatitis C was obtained directly from patients and by review of medical records.
Liver Biopsy Liver biopsies were performed with standard techniques; there were no complications from the procedure. Specimens were stained with hematoxylin and eosin and Masson’s trichrome and graded by one hepatopathologist (LL) who was unaware of the serum alanine aminotransferase levels. The extent of periportal (with or without bridging) necrosis (scored from 0 to 10), intralobular degeneration and focal necrosis (0 to 4), portal inflammation (0 to 4), and bridging fibrosis or cirrhosis (0 to 4) was scored. The total score (minimum 0, maximum 22) represents the Histological Activity Index (11).
Data Analysis Fisher’s exact test (two-tailed) was used to compare categorical data. Histological Activity Index values were compared using the Wilcoxon rank sum test. We measured the correlation between serum alanine aminotransferase levels and the Histological Activity Index using simple linear regression (Pearson rank correlation).
RESULTS There were no significant differences in age, sex, race, use of alcohol, or risk factors for hepatitis C among the two groups of patients (Table). By design, serum alanine aminotransferase levels in the two groups were significantly different. Mean (⫾ SD) Histological Activity Index scores were 4 ⫾ 2 among patients with normal serum alanine aminotransferase levels and 7 ⫾ 3 among patients with increased serum alanine aminotransferase levels (P ⬍0.001). Sixteen (46%) patients with normal serum alanine aminotransferase levels had a Histological Activity Index ⬎5 compared with 30 (86%) patients with in0002-9343/00/$–see front matter PII S0002-9343(00)00381-8
Liver Biopsy in the Evaluation of Patients with Chronic Hepatitis C/Nutt et al
Table. Characteristics of Patients with Hepatitis C, Stratified by Serum Alanine Aminotransferase Levels Characteristic
Normal Levels* (n ⫽ 35)
Increased Levels (n ⫽ 35)
Number (Percent) or Mean ⫾ SD (Range) Serum alanine aminotransferase level (IU/L) Age (years) Female sex White race† Alcohol use Hepatitis C risk factors Transfusion Intravenous drug use Tattoos Hepatitis C-positive sexual partner None identified
38 ⫾ 13 (7–66) 44 ⫾ 9 (25–69) 7 (20) 22 (63) 13 (37)
140 ⫾ 79 (78–572) 46 ⫾ 9 (30–65) 3 (9) 27 (69) 18 (51)
3 (9) 12 (34) 1 (3) 2 (6) 17 (49)
5 (14) 12 (34) 0 0 18 (51)
* Normal levels indicate two or more values that were ⱕ1.4 times the upper limit of normal. † All other patients were African-American.
creased levels (P ⬍0.05). However, there was considerable overlap in the severity of the biopsy findings (Figure). Among the 35 patients with normal serum alanine aminotransferase levels, 3 (9%) had bridging fibrosis and 4 (11%) had cirrhosis, including 2 patients with repeated serum alanine aminotransferase levels ⬍50 IU/L. All 7 of these patients were men. Among the 35 patients with increased serum alanine aminotransferase levels, 14 (40%) had bridging fibrosis and 7 (20%) had cirrhosis. Of the 28 patients with advanced liver disease seen on biopsy specimens, 3 of the 7 patients with normal serum
Figure. Distribution of Histological Activity Index scores in patients with repeatedly normal (left) and increased (right) serum alanine aminotransferase levels. The higher the index, the more extensive the histological abnormalities.
alanine aminotransferase levels and 9 of the 21 patients with elevated levels reported use of alcohol (P ⫽ 0.6). There was no correlation between mean serum alanine aminotransferase levels and Histological Activity Index.
DISCUSSION Physicians often must make decisions about initiating antiviral therapy in patients with chronic hepatitis C who are asymptomatic and have normal or minimally elevated serum alanine aminotransferase levels. We undertook this study to determine whether the serum alanine aminotransferase level, which is commonly used to judge the degree of liver inflammation, adequately reflects the presence of active, progressive liver disease. Because previous reports indicated that a single normal level does not exclude advanced liver disease or even cirrhosis (2– 6), we included only patients with at least two normal or nearnormal (ⱕ1.4 times the upper limit) levels within 6 months of obtaining a liver biopsy specimen. We found that 20% of these patients had advanced liver disease (extensive fibrosis or cirrhosis). Thus, repeatedly normal serum alanine aminotransferase levels did not exclude histologic findings that might prompt physicians to start patients on antiviral therapy. Previous studies of patients with hepatitis C who had normal or near-normal serum alanine aminotransferase levels were limited by small sample size, lack of definition of the temporal relation of normal levels to performance of the liver biopsy, reliance on only one serum alanine aminotransferase value, lack of PCR confirmation of active hepatitis C infection, or failure to blind the pathologist to the serum alanine aminotransferase levels (2–10). Although we cannot exclude the possibility of undetected July 2000
THE AMERICAN JOURNAL OF MEDICINE威
Volume 109 63
Liver Biopsy in the Evaluation of Patients with Chronic Hepatitis C/Nutt et al
fluctuations in serum alanine aminotransferase levels, our requirement for two or more values during a 6-month interval most likely excluded major elevations. Moreover, because all 7 of the patients with advanced liver disease who had normal levels were men, these levels cannot be ascribed (6) to lower serum alanine aminotransferase levels in women. Even in symptomatic patients with hepatitis C who have elevated serum alanine aminotransferase levels, the long-term value of treatment is not proved (12). Many such patients have slow progression of inflammatory damage and little risk of developing end-stage liver disease. It is uncertain whether surrogate markers of disease, like serum alanine aminotransferase levels or viral titers, have pathophysiologic relevance (12). Currently available treatments are expensive, associated with substantial toxicity, and of limited efficacy. To ensure an appropriate risk:benefit ratio and cost effectiveness, targeting cases likely to progress to cirrhosis is of particular importance. The low cost and relative safety of liver biopsy, the high cost and morbidity of interferon therapy, and our findings of advanced liver disease in 20% of patients with repeatedly normal serum alanine aminotransferase levels suggest that it may be worthwhile to perform liver biopsies in all patients with hepatitis C. This is especially important because histologic results are more important than serum alanine aminotransferase levels in the assessment of treatment response (13–16). Future studies must determine whether antiviral therapy for hepatitis C patients with advanced inflammation or fibrosis, including those with normal serum alanine aminotransferase levels, reduces the incidence of cirrhosis, end-stage liver disease, and hepatocellular carcinoma.
ACKNOWLEDGMENT We thank Trey Spencer, MS, for assistance with statistical analysis of the data.
REFERENCES 1. Management of Hepatitis C. NIH Consensus Statement. 1997;15:1–41. 2. Di Bisceglie AM, Goodman ZD, Ishak KG, et al. Long-term clinical and histopathological follow-up of chronic posttransfusion hepatitis. Hepatology. 1991;14:969 –974.
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3. Esteban JI, Lopez-Talavera JC, Genesca J, et al. High rate of infectivity and liver disease in blood donors with antibodies to hepatitis C virus. Ann Intern Med. 1991;115:443– 449. 4. Alberti A, Morsica G, Chemello L, et al. Hepatitis C viraemia, and liver disease in symptom-free individuals with anti-HCV. Lancet. 1992;340:697– 698. 5. Van Thiel DH, Caraceni P, Molloy PJ, et al. Chronic hepatitis C in patients with normal or near normal alanine aminotransferase levels. The role of interferon ␣2b therapy. J Hepatol. 1995;23:503–508. 6. Gholson CF, Morgan K, Catinis G, et al. Chronic hepatitis C with normal aminotransferase levels. A clinical histologic study. Am J Gastroenterol. 1996;92:1788 –1792. 7. Brillanti S, Foli M, Gaiani S, et al. Persistent hepatitis C viraemia without liver disease. Lancet. 1993;341:464 – 465. 8. Naito M, Norio H, Hagiwara H, et al. Serum hepatitis C virus RNA quantity, and histological features of hepatitis C virus carriers with persistently normal ALT levels. Hepatology. 1994;19:871– 875. 9. Heintges T, Mohr L, Hensel F, et al. Value of liver biopsy prior to interferon therapy for chronic viral hepatitis. Dig Dis Sci. 1998;43: 1562–1565. 10. Mathurin P, Moussalli J, Cadranel JF, et al. Slow progression rate of fibrosis in hepatitis C virus patients with persistently normal alanine aminotransferase activity. Hepatology. 1998;27:868 – 872. 11. Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology. 1981;1:431– 435. 12. Koretz RL. Making end points meet. Gastroenterology. 1999;116: 1266 –1267. 13. Serfaty L, Chazouilleres O, Pawlotsky JM, et al. Interferon alfa therapy in patients with chronic hepatitis C and persistently normal aminotransferase activity. Gastroenterology. 1996;110:291–295. 14. Rossini A, Ravaggi A, Biasi L, et al. Virological response to interferon treatment in hepatitis C virus carriers with normal aminotransferase levels and chronic hepatitis. Hepatology. 1997;26:1012–1017. 15. Sangiovanni A, Morales R, Spinzi GC, et al. Interferon alpha treatment of HCV RNA carriers with persistently normal aminotransferase levels: a pilot randomized controlled study. Hepatology. 1998; 27:853– 856. 16. Silverman AL, Piquette DL, Filipiak CL, et al. Alfa interferon treatment of hepatitis C virus RNA-positive patients with normal or near-normal alanine aminotransferase levels. Am J Gastroenterol. 1997;92:1793–1795. From the Division of Gastroenterology and Hepatology (AKN, HAH, JL, JPR) and Department of Pathology (LWL), University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas. Correspondence should be addressed to Jean-Pierre Raufman, MD, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot 567, Little Rock, Arkansas 72205–7199. Manuscript submitted August 17, 1999, and accepted in revised form March 21, 2000.
Liver Biopsy in the Evaluation of Patients with Chronic Hepatitis C Who Have Repeatedly Normal or Near-Normal Serum Alanine Aminotransferase Levels Angela K. Nutt, MD, Hassan A. Hassan, MD, Judy Lindsey, RNP, Laura W. Lamps, MD, Jean-Pierre Raufman, MD
A
s a consequence of the availability of highly sensitive diagnostic tests, the screening of transfusion recipients and former intravenous drug users, and the likelihood that symptomatic patients have already been diagnosed, hepatitis C is being diagnosed more commonly in apparently healthy people who have normal serum alanine aminotransferase levels. Hence, strategies for managing these patients are increasingly important. A recent National Institutes of Health Consensus Conference concluded that treatment of these patients “is not beneficial” but acknowledged “a weak association between alanine aminotransferase levels and severity of the histopathological findings on liver biopsy” (1). Serum alanine aminotransferase levels, however, may fluctuate during the course of the disease, and some patients with normal levels may have advanced liver disease (2– 6), although this has not been seen in all studies (7–10). In some of these studies, the criterion for a normal value and the frequency of serum alanine aminotransferase determinations were not defined, and liver biopsy samples were not evaluated systematically by a pathologist blinded to laboratory values. Moreover, heterogeneity of the hepatitis C virus, including different genotypes and quasispecies, suggests that observations in some parts of the world may not be relevant in the United States. To address these issues, we compared liver biopsy findings in hepatitis C-infected patients who had repeatedly normal serum alanine aminotransferase levels with biopsy results in patients who had elevated levels.
PATIENTS AND METHODS Study Design and Subjects Between 1996 and 1998, we identified 35 consecutive patients with hepatitis C who had two or more normal or near-normal serum alanine aminotransferase levels (ⱕ1.4 times the upper limit of normal of 50 IU/L) during 62
䉷2000 by Excerpta Medica, Inc. All rights reserved.
the 6 months before a liver biopsy was performed. During the same interval, we identified 35 patients who had undergone liver biopsy and who had persistently elevated levels (⬎1.4 times the upper limit of normal) on two or more occasions. Serum alanine aminotransferase levels were measured at the University Hospital of Arkansas or the Little Rock Department of Veterans Affairs Medical Center. All patients were hepatitis C virus RNA-positive by reverse transcriptase-polymerase chain reaction (PCR; National Genetics Institute; Los Angeles, California). Other causes of hepatic disease, including hepatitis B, autoimmune hepatitis, and hereditary liver disease, were excluded. None of the patients were immunosuppressed; all had a negative serological test for infection with the human immunodeficiency virus (HIV). Alcohol use was defined as consumption of more than an occasional drink. Information about risk factors for hepatitis C was obtained directly from patients and by review of medical records.
Liver Biopsy Liver biopsies were performed with standard techniques; there were no complications from the procedure. Specimens were stained with hematoxylin and eosin and Masson’s trichrome and graded by one hepatopathologist (LL) who was unaware of the serum alanine aminotransferase levels. The extent of periportal (with or without bridging) necrosis (scored from 0 to 10), intralobular degeneration and focal necrosis (0 to 4), portal inflammation (0 to 4), and bridging fibrosis or cirrhosis (0 to 4) was scored. The total score (minimum 0, maximum 22) represents the Histological Activity Index (11).
Data Analysis Fisher’s exact test (two-tailed) was used to compare categorical data. Histological Activity Index values were compared using the Wilcoxon rank sum test. We measured the correlation between serum alanine aminotransferase levels and the Histological Activity Index using simple linear regression (Pearson rank correlation).
RESULTS There were no significant differences in age, sex, race, use of alcohol, or risk factors for hepatitis C among the two groups of patients (Table). By design, serum alanine aminotransferase levels in the two groups were significantly different. Mean (⫾ SD) Histological Activity Index scores were 4 ⫾ 2 among patients with normal serum alanine aminotransferase levels and 7 ⫾ 3 among patients with increased serum alanine aminotransferase levels (P ⬍0.001). Sixteen (46%) patients with normal serum alanine aminotransferase levels had a Histological Activity Index ⬎5 compared with 30 (86%) patients with in0002-9343/00/$–see front matter PII S0002-9343(00)00381-8
Liver Biopsy in the Evaluation of Patients with Chronic Hepatitis C/Nutt et al
Table. Characteristics of Patients with Hepatitis C, Stratified by Serum Alanine Aminotransferase Levels Characteristic
Normal Levels* (n ⫽ 35)
Increased Levels (n ⫽ 35)
Number (Percent) or Mean ⫾ SD (Range) Serum alanine aminotransferase level (IU/L) Age (years) Female sex White race† Alcohol use Hepatitis C risk factors Transfusion Intravenous drug use Tattoos Hepatitis C-positive sexual partner None identified
38 ⫾ 13 (7–66) 44 ⫾ 9 (25–69) 7 (20) 22 (63) 13 (37)
140 ⫾ 79 (78–572) 46 ⫾ 9 (30–65) 3 (9) 27 (69) 18 (51)
3 (9) 12 (34) 1 (3) 2 (6) 17 (49)
5 (14) 12 (34) 0 0 18 (51)
* Normal levels indicate two or more values that were ⱕ1.4 times the upper limit of normal. † All other patients were African-American.
creased levels (P ⬍0.05). However, there was considerable overlap in the severity of the biopsy findings (Figure). Among the 35 patients with normal serum alanine aminotransferase levels, 3 (9%) had bridging fibrosis and 4 (11%) had cirrhosis, including 2 patients with repeated serum alanine aminotransferase levels ⬍50 IU/L. All 7 of these patients were men. Among the 35 patients with increased serum alanine aminotransferase levels, 14 (40%) had bridging fibrosis and 7 (20%) had cirrhosis. Of the 28 patients with advanced liver disease seen on biopsy specimens, 3 of the 7 patients with normal serum
Figure. Distribution of Histological Activity Index scores in patients with repeatedly normal (left) and increased (right) serum alanine aminotransferase levels. The higher the index, the more extensive the histological abnormalities.
alanine aminotransferase levels and 9 of the 21 patients with elevated levels reported use of alcohol (P ⫽ 0.6). There was no correlation between mean serum alanine aminotransferase levels and Histological Activity Index.
DISCUSSION Physicians often must make decisions about initiating antiviral therapy in patients with chronic hepatitis C who are asymptomatic and have normal or minimally elevated serum alanine aminotransferase levels. We undertook this study to determine whether the serum alanine aminotransferase level, which is commonly used to judge the degree of liver inflammation, adequately reflects the presence of active, progressive liver disease. Because previous reports indicated that a single normal level does not exclude advanced liver disease or even cirrhosis (2– 6), we included only patients with at least two normal or nearnormal (ⱕ1.4 times the upper limit) levels within 6 months of obtaining a liver biopsy specimen. We found that 20% of these patients had advanced liver disease (extensive fibrosis or cirrhosis). Thus, repeatedly normal serum alanine aminotransferase levels did not exclude histologic findings that might prompt physicians to start patients on antiviral therapy. Previous studies of patients with hepatitis C who had normal or near-normal serum alanine aminotransferase levels were limited by small sample size, lack of definition of the temporal relation of normal levels to performance of the liver biopsy, reliance on only one serum alanine aminotransferase value, lack of PCR confirmation of active hepatitis C infection, or failure to blind the pathologist to the serum alanine aminotransferase levels (2–10). Although we cannot exclude the possibility of undetected July 2000
THE AMERICAN JOURNAL OF MEDICINE威
Volume 109 63
Liver Biopsy in the Evaluation of Patients with Chronic Hepatitis C/Nutt et al
fluctuations in serum alanine aminotransferase levels, our requirement for two or more values during a 6-month interval most likely excluded major elevations. Moreover, because all 7 of the patients with advanced liver disease who had normal levels were men, these levels cannot be ascribed (6) to lower serum alanine aminotransferase levels in women. Even in symptomatic patients with hepatitis C who have elevated serum alanine aminotransferase levels, the long-term value of treatment is not proved (12). Many such patients have slow progression of inflammatory damage and little risk of developing end-stage liver disease. It is uncertain whether surrogate markers of disease, like serum alanine aminotransferase levels or viral titers, have pathophysiologic relevance (12). Currently available treatments are expensive, associated with substantial toxicity, and of limited efficacy. To ensure an appropriate risk:benefit ratio and cost effectiveness, targeting cases likely to progress to cirrhosis is of particular importance. The low cost and relative safety of liver biopsy, the high cost and morbidity of interferon therapy, and our findings of advanced liver disease in 20% of patients with repeatedly normal serum alanine aminotransferase levels suggest that it may be worthwhile to perform liver biopsies in all patients with hepatitis C. This is especially important because histologic results are more important than serum alanine aminotransferase levels in the assessment of treatment response (13–16). Future studies must determine whether antiviral therapy for hepatitis C patients with advanced inflammation or fibrosis, including those with normal serum alanine aminotransferase levels, reduces the incidence of cirrhosis, end-stage liver disease, and hepatocellular carcinoma.
ACKNOWLEDGMENT We thank Trey Spencer, MS, for assistance with statistical analysis of the data.
REFERENCES 1. Management of Hepatitis C. NIH Consensus Statement. 1997;15:1–41. 2. Di Bisceglie AM, Goodman ZD, Ishak KG, et al. Long-term clinical and histopathological follow-up of chronic posttransfusion hepatitis. Hepatology. 1991;14:969 –974.
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July 2000
THE AMERICAN JOURNAL OF MEDICINE威
Volume 109
3. Esteban JI, Lopez-Talavera JC, Genesca J, et al. High rate of infectivity and liver disease in blood donors with antibodies to hepatitis C virus. Ann Intern Med. 1991;115:443– 449. 4. Alberti A, Morsica G, Chemello L, et al. Hepatitis C viraemia, and liver disease in symptom-free individuals with anti-HCV. Lancet. 1992;340:697– 698. 5. Van Thiel DH, Caraceni P, Molloy PJ, et al. Chronic hepatitis C in patients with normal or near normal alanine aminotransferase levels. The role of interferon ␣2b therapy. J Hepatol. 1995;23:503–508. 6. Gholson CF, Morgan K, Catinis G, et al. Chronic hepatitis C with normal aminotransferase levels. A clinical histologic study. Am J Gastroenterol. 1996;92:1788 –1792. 7. Brillanti S, Foli M, Gaiani S, et al. Persistent hepatitis C viraemia without liver disease. Lancet. 1993;341:464 – 465. 8. Naito M, Norio H, Hagiwara H, et al. Serum hepatitis C virus RNA quantity, and histological features of hepatitis C virus carriers with persistently normal ALT levels. Hepatology. 1994;19:871– 875. 9. Heintges T, Mohr L, Hensel F, et al. Value of liver biopsy prior to interferon therapy for chronic viral hepatitis. Dig Dis Sci. 1998;43: 1562–1565. 10. Mathurin P, Moussalli J, Cadranel JF, et al. Slow progression rate of fibrosis in hepatitis C virus patients with persistently normal alanine aminotransferase activity. Hepatology. 1998;27:868 – 872. 11. Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology. 1981;1:431– 435. 12. Koretz RL. Making end points meet. Gastroenterology. 1999;116: 1266 –1267. 13. Serfaty L, Chazouilleres O, Pawlotsky JM, et al. Interferon alfa therapy in patients with chronic hepatitis C and persistently normal aminotransferase activity. Gastroenterology. 1996;110:291–295. 14. Rossini A, Ravaggi A, Biasi L, et al. Virological response to interferon treatment in hepatitis C virus carriers with normal aminotransferase levels and chronic hepatitis. Hepatology. 1997;26:1012–1017. 15. Sangiovanni A, Morales R, Spinzi GC, et al. Interferon alpha treatment of HCV RNA carriers with persistently normal aminotransferase levels: a pilot randomized controlled study. Hepatology. 1998; 27:853– 856. 16. Silverman AL, Piquette DL, Filipiak CL, et al. Alfa interferon treatment of hepatitis C virus RNA-positive patients with normal or near-normal alanine aminotransferase levels. Am J Gastroenterol. 1997;92:1793–1795. From the Division of Gastroenterology and Hepatology (AKN, HAH, JL, JPR) and Department of Pathology (LWL), University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas. Correspondence should be addressed to Jean-Pierre Raufman, MD, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot 567, Little Rock, Arkansas 72205–7199. Manuscript submitted August 17, 1999, and accepted in revised form March 21, 2000.