- Email: [email protected]
Alcohol abuse and liver disease: True, true, but not necessarily related
SELECTED SUMMARIES
December 1991
should have been deferred for more convincing evidence of effectiveness of the same procedure by open laparotomy. On the other hand, it can be argued, as these authors do, that the laparoscopist’s fine instruments and magnified images allow more precise dissection and promise better results. It thus follows that the place of laparoscopic surgery in the treatment of duodenal ulcers must be determined by its own risks and recurrence rates. Cure of duodenal ulcers requires complete separation of all parietal cells from vagal innervation. Any technique that leaves even a small patch of innervated parietal cells will allow some ulcers to behave as if they had never been treated. Variations in vagal anatomy have always frustrated surgeons, especially in performing parietal cell vagotomy, in which beginners experience ulcer recurrence rates of up to 30% (Br J Surg 1987;74:1056-1059). Failures were attributed to dissecting too little esophagus, missing the posterior “criminal nerve,” and leaving the first antral branch in the vascular “crow’s foot.” None of these errors were avoided with certainty in the present study. Moreover, one must worry that parietal cells medial to the lesser curve seromyotomy remain innervated and responsive to vagal stimulation. Having cited these reservations, however, we must acknowledge that equally rational reservations were once held about other treatments that have subsequently proved to be effective. Thus, surgeons who are well trained in laparoscopic techniques should be encouraged to test this procedure in a controlled comparison with its proven counterpart, parietal cell vagotomy. Such a trial might yield one of three possible conclusions. One possibility is that laparoscopic vagotomy’s effect is no more sustained than medical therapy, in which case the operation should be abandoned. The second possibility is that it is as effective and innocuous as parietal cell vagotomy, in which case it should become the elective operation of choice for duodenal ulcers. The third possibility is somewhere in between, i.e., that it is not quite as effective as parietal cell vagotomy but cures 70%-80% of duodenal ulcers. What shall we do with that conclusion? Should the contest between drugs and procedures be won by novelty, charm, or profitability of laparoscopy? America’s leading manufacturer of laparoscopic equipment, charged with falsifying orders and securities law violations, has a 650-person sales force committed to answering such questions in favor of profit by selling laparoscopy to the public as well as to surgeons (Wall Street Journal, April 16, 1991). Might this be the “trend of thought” presaged by the present study? Laparoscopic anterior lesser curve seromyotomy plus posterior truncal vagotomy is certainly an interesting procedure for the treatment of duodenal ulcer; its efficacy remains to be proven. Guidelines and safeguards clarifying the indications, safety, efficacy, and training for this procedure must be developed. It is imperative that this new procedure be at first restricted to carefully controlled prospective randomized trials in which patients are followed for at least 5 years. H. H. McGUIRE,JR., M.D. M. L. SCHUBERT, M.D.
Reply. Kurt Semm of Kiel, Germany, performed the first laparoscopic appendectomy in 1982, and Philippe Mouret of Lyon, France, performed the first laparoscopic cholecystectomy in 1987. They opened a new era in abdominal surgery, and the fact that “600,000 patients are being considered candidates for laparoscopic cholecystectomy” is not frightening; it simply shows that there is a large consensus among surgeons on how to give the best possible treatment to their patients. Indeed, if “commercial profiteering” existed in the beginning, it was condemned by the majority of surgeons. Currently, many papers published in recognized scientific journals clearly show the benefit of laparoscopic treatment,
1745
placing ethical constraints on the planning of randomized controlled trials (Br J Surg 1991;78:150-154). Regarding the posterior vagotomg and anterior lesser curve seromyotomy by videocoelioscopy, the whole of the posterior gastric wall is denervated by the division of the posterior vagus trunk. There is no need, therefore, to worry about Grassi’s “criminal branch,” accused of being responsible for the recurrence in duodenal ulcer surgery by incomplete vagotomy. The technique we propose is the same one we have performed in open surgery for years with good long-term results, and different publications have shown its effectiveness and safety in the treatment of chronic duodenal ulcer. However, the laparoscopy procedure is not easy and must be considered an advanced technique requiring thorough experimental practice, and we insist on this point in our conclusion in the published study. We also point out that this study was an initial one, and long-term results will be the subject of another publication. Finally, we believe the traditional books of abdominal or general surgery need to be rewritten. The “trend of thought” must be distinguished from the “material trend”: it represents a new philosophy of operation, resulting in a shorter and more comfortable hospital stay for patients and a financial savings for health care institutions. N. KATKHOUDA.
M.D.
ALCOHOL ABUSE AND LIVER DISEASE: TRUE, TRUE, BUT NOT NECESSARILY RELATED Takase S, Takada N, Enomoto N, et al. (Division of Gastroenterology, Department of Internal Medicine, Kanazawa Medical University, Uchinada, Ishikawa, Japan). Different types of chronic hepatitis in alcoholic patients: does chronic hepatitis induced by alcohol exist? Hepatology 1991;13:876881 (May). The authors selected 27 patients from their alcoholic patient population because each showed histological evidence of chronic active hepatitis (CAH) and each had sera available for retrospective analysis of viral markers. The number of alcohol-abusing patients from which these cases are selected is not stated. Two with CAH who did not have sera available are not included in the study. The cases were divided into groups based on the serological findings: the AL group (7 cases; 26%) had no markers for either hepatitis C virus (HCV) or hepatitis B virus (HBV); the HB group (4 cases; 15%) were positive for hepatitis B surface antigen (HBsAg); the HCl group (7 cases; 26%) were positive for anti-HCV but negative for HCV RNA genome by a polymerase chain reaction (PCR); and. the HC2 group (9 cases; 33%) had both anti-HCV and the HCV genome. A history of blood transfusions was obtained in 2 of 7 patients in the AL group, in 6 of 16 with evidence of HCV (HCl and HC2), and in 0 of 4 in the HB group. There were no significant differences between groups in results of initial conventional liver tests. Serum aspartate aminotransferase and alanine aminotransferase levels declined during 4 weeks of abstinence in most patients in the AL and HCl groups but not in the HB or HC2 groups. Serum desialotransferrin and alcohol liver membrane antibodies were detected more frequently in the sera of patients in the AL and HCl groups. There was a trend [not statistically significant) toward increased frequency of centrilobular ballooning in the AL group. The
1746
SELECTED SUMMARIES
GASTROENTEROLOGY Vol. 101, No. 6
authors conclude that CAH in the AL group, in whom there were no markers for HBV or HCV, may be caused by alcohol. They further conclude that patients who had anti-HCV but not the HCV genome (group HCl) may represent cases in which both alcohol and HCV are involved.
colleagues. The data presented support the concept that alcohol can produce CAH but do not address the issue of mechanism. It further emphasizes that not all liver disease seen in alcoholics is related to that drug.
Comment. There is ample evidence to incriminate alcohol as a hepatotoxin. Heavy intake may lead to an acute hepatitis with a mixed inflammatory infiltrate that is predominantly polymorphonuclear (PMN). With abstinence, the acute cellular necrosis resolves. The PMN infiltrates disappear before the mononuclear so that after several weeks the biopsy appearance is histologically difficult to distinguish from injury unrelated to alcohol and indistinguishable from CAH of other causes. If the biopsy is performed after a variable period of freedom from alcohol, it is therefore common to find a histological picture quite compatible with CAH in alcoholic patients without incriminating other causes. With continued abstinence and without residual fibrosis, the liver in the majority becomes histologically normal. However, it has been recognized for some time that approximately 10% have continued chronic hepatitis without further alcohol injury [see review by Mezey (Prog Liver Dis 1982;6:555-572)]. The specific role of immunity in this continued process is not clear. The question addressed in this paper is whether CAH is in fact related to the alcohol abuse that brought it to our attention, perhaps perpetuated by immunologic mechanisms, or is caused by unrecognized superimposed viral infection. There is no logical reason to believe that in this case, as in others, several etiologies are mutually exclusive. With the recent availability of serological tests for HCV exposure, alcoholics around the world have been found to be positive for anti-HCV in surprisingly high numbers. For example, 38.7% were positive in Spain (Lancet 1989;2:1004-1006), and 54% were positive in France [J Hepatol 1990;11:393 (letter)]. Obviously, not all alcoholics have the same risk factors. A careful prospective study of these patients and their risks compared with an appropriate control group has not been performed. In the small sample of alcoholics reported here, selected because they had CAH on biopsy, 52% (14/27) had evidence of exposure to HCV. Serological tests could not incriminate any etiology other than alcohol in 26% (7/27) of the cases. A control group from the population without CAH is not reported, and the data are difficult to evaluate. The incidence of anti-HCV appears to be similar to that reported in alcoholics without selection for CAH. The selection bias is difficult to escape but would tend to increase the frequency of cases positive for anti-HCV if, in fact, most cases of CAH in alcoholics were related to the hepatitis viruses. All of the patients selected for study had similar levels of alcohol intake. We are not told if they were abstinent or for how long, information that would also be helpful. Because the level of desialiated transferrin is related to recent alcohol ingestion, I am confused by the differences found between the groups. Further, this protein is independent of liver disease (Hepatology 1991;13:455-459), as are alcohol liver membrane antibodies, and there should therefore be no differences in these values between the groups. Similarly, why should there be a trend toward an increased frequency of centrilobular ballooning of hepatocytes in those alcoholics without evidence of viral disease? Surely viral infection does not protect the liver from this alcohol-associated damage. The differences are not statistically significant, and we cannot draw conclusions. The number of patients in each group is too small to allow more than the speculation of the authors. Taking the numbers at face value, one could equally well conclude (probably quite erroneously) that the combination of the chemical injury of alcohol and the injury of viral infection is not particularly more damaging than either alone. We must have a much larger prospective and appropriately controlled trials to answer the provocative questions raised by Dr. Takase and
Reply.
J. L. ACHORD,M.D. Thank you for the comments of Dr. Achord. A histological
feature compatible
with CAH in patients
with alcoholic
hepatitis
who had abstained from alcohol was first described by Galambos (Gastroenterology 1972;63:1026-1035). We have already pointed out that there are two types of CAH in heavy drinkers (Dig Dis Sci 1983;28:207-215): one type is similar to the cases reported by Galambos or described by Dr. Achord, in which the patient has stopped drinking but the liver changes persist and progress: in the other type, the clinical and histological changes improve quickly after the patient stops drinking. These problems were discussed in an international conference, the proceedings of which were published
in Gasfroenterologia Japonica (Volume 25, Suppl. 1, May 1990). The features of the former type are similar to those of the HCl or HC2 group of the present paper, suggesting that this type of CAH may be caused by HCV or by the combination of both etiologies, alcohol and HCV. This type of CAH has very high risk for developing hepatocellular carcinoma (HCC). Prevalences of HCV markers in alcoholics were high, as pointed out in the comment. However, the differences in diagnostic criteria for alcoholic liver disease must be considered to evaluate these results. In some reports, HCV marker (antibodies to C-100-3
protein) was detected in patients with liver disease of alcoholics, in whom the evidence of alcoholic liver disease was documented poorly. The prevalence was quite different depending on the type of alcoholic liver disease. In our own series, all HCV markers (HCV RNA, antibody to C-100-3 protein, antibody to clone 14 protein) were scarcely found in patients with alcoholic fibrosis and alcoholic hepatitis. Clone-14 antibody was positive in only I of 30 patients with alcoholic fibrosis or hepatitis. On the other hand, the prevalence of HCV markers was about 37% in 41 patients with alcoholic cirrhosis and about 80% in 15 alcoholic patients with HCC. These data were reported in the last IASL meeting in 1990, and the abstract was published in Hepotology (Volume 12, No. 2). The prevalence of HCV markers in CAH was 16 of 23 (69.6%) when HBV-related patients were excluded in the present study. This prevalence was quite different from that of alcoholic fibrosis and alcoholic hepatitis and was similar to that of HCC. We cannot understand the number of patients (14) in the comment who had evidence of exposure to HCV. This may be miscounting; HCV RNA was detected in 29 of 31 nonalcoholic patients with non-A, non-B chronic hepatitis (Gastroenterol Jpn 1991;26:42-46), and the remaining 2 patients were positive for C-100-3 antibodies, The prevalence of HCV markers in chronic hepatitis was clearly higher in nonalcoholics than in alcoholics. Some of these results were mentioned briefly in the discussion of the paper. From these results, we believe the high incidence of HCV markers in CAH of heavy drinkers is not attributable to selection bias. Follow-up study of alcoholic liver disease showed that liver cirrhosis developed with shorter duration and higher frequency in CAD than alcoholic fibrosis, and HCC developed with very high frequency in CAH patients with HCV markers but in very few patients with the other types of alcoholic liver disease (Alcohol, Immunity and Cancer. CRC Press, 1991, in press). These results may be related to the high prevalences of HCV markers in alcoholic cirrhosis and HCC and suggest that HCV-marker positive CAH and cirrhotic patients may be a high-risk group for the development of HCC if they continue drinking. Fletcher et al. (Hepatology 1991;13:455-459) have reported that desialotransferrin is a very useful marker for differentiation of
December 1991
should have been deferred for more convincing evidence of effectiveness of the same procedure by open laparotomy. On the other hand, it can be argued, as these authors do, that the laparoscopist’s fine instruments and magnified images allow more precise dissection and promise better results. It thus follows that the place of laparoscopic surgery in the treatment of duodenal ulcers must be determined by its own risks and recurrence rates. Cure of duodenal ulcers requires complete separation of all parietal cells from vagal innervation. Any technique that leaves even a small patch of innervated parietal cells will allow some ulcers to behave as if they had never been treated. Variations in vagal anatomy have always frustrated surgeons, especially in performing parietal cell vagotomy, in which beginners experience ulcer recurrence rates of up to 30% (Br J Surg 1987;74:1056-1059). Failures were attributed to dissecting too little esophagus, missing the posterior “criminal nerve,” and leaving the first antral branch in the vascular “crow’s foot.” None of these errors were avoided with certainty in the present study. Moreover, one must worry that parietal cells medial to the lesser curve seromyotomy remain innervated and responsive to vagal stimulation. Having cited these reservations, however, we must acknowledge that equally rational reservations were once held about other treatments that have subsequently proved to be effective. Thus, surgeons who are well trained in laparoscopic techniques should be encouraged to test this procedure in a controlled comparison with its proven counterpart, parietal cell vagotomy. Such a trial might yield one of three possible conclusions. One possibility is that laparoscopic vagotomy’s effect is no more sustained than medical therapy, in which case the operation should be abandoned. The second possibility is that it is as effective and innocuous as parietal cell vagotomy, in which case it should become the elective operation of choice for duodenal ulcers. The third possibility is somewhere in between, i.e., that it is not quite as effective as parietal cell vagotomy but cures 70%-80% of duodenal ulcers. What shall we do with that conclusion? Should the contest between drugs and procedures be won by novelty, charm, or profitability of laparoscopy? America’s leading manufacturer of laparoscopic equipment, charged with falsifying orders and securities law violations, has a 650-person sales force committed to answering such questions in favor of profit by selling laparoscopy to the public as well as to surgeons (Wall Street Journal, April 16, 1991). Might this be the “trend of thought” presaged by the present study? Laparoscopic anterior lesser curve seromyotomy plus posterior truncal vagotomy is certainly an interesting procedure for the treatment of duodenal ulcer; its efficacy remains to be proven. Guidelines and safeguards clarifying the indications, safety, efficacy, and training for this procedure must be developed. It is imperative that this new procedure be at first restricted to carefully controlled prospective randomized trials in which patients are followed for at least 5 years. H. H. McGUIRE,JR., M.D. M. L. SCHUBERT, M.D.
Reply. Kurt Semm of Kiel, Germany, performed the first laparoscopic appendectomy in 1982, and Philippe Mouret of Lyon, France, performed the first laparoscopic cholecystectomy in 1987. They opened a new era in abdominal surgery, and the fact that “600,000 patients are being considered candidates for laparoscopic cholecystectomy” is not frightening; it simply shows that there is a large consensus among surgeons on how to give the best possible treatment to their patients. Indeed, if “commercial profiteering” existed in the beginning, it was condemned by the majority of surgeons. Currently, many papers published in recognized scientific journals clearly show the benefit of laparoscopic treatment,
1745
placing ethical constraints on the planning of randomized controlled trials (Br J Surg 1991;78:150-154). Regarding the posterior vagotomg and anterior lesser curve seromyotomy by videocoelioscopy, the whole of the posterior gastric wall is denervated by the division of the posterior vagus trunk. There is no need, therefore, to worry about Grassi’s “criminal branch,” accused of being responsible for the recurrence in duodenal ulcer surgery by incomplete vagotomy. The technique we propose is the same one we have performed in open surgery for years with good long-term results, and different publications have shown its effectiveness and safety in the treatment of chronic duodenal ulcer. However, the laparoscopy procedure is not easy and must be considered an advanced technique requiring thorough experimental practice, and we insist on this point in our conclusion in the published study. We also point out that this study was an initial one, and long-term results will be the subject of another publication. Finally, we believe the traditional books of abdominal or general surgery need to be rewritten. The “trend of thought” must be distinguished from the “material trend”: it represents a new philosophy of operation, resulting in a shorter and more comfortable hospital stay for patients and a financial savings for health care institutions. N. KATKHOUDA.
M.D.
ALCOHOL ABUSE AND LIVER DISEASE: TRUE, TRUE, BUT NOT NECESSARILY RELATED Takase S, Takada N, Enomoto N, et al. (Division of Gastroenterology, Department of Internal Medicine, Kanazawa Medical University, Uchinada, Ishikawa, Japan). Different types of chronic hepatitis in alcoholic patients: does chronic hepatitis induced by alcohol exist? Hepatology 1991;13:876881 (May). The authors selected 27 patients from their alcoholic patient population because each showed histological evidence of chronic active hepatitis (CAH) and each had sera available for retrospective analysis of viral markers. The number of alcohol-abusing patients from which these cases are selected is not stated. Two with CAH who did not have sera available are not included in the study. The cases were divided into groups based on the serological findings: the AL group (7 cases; 26%) had no markers for either hepatitis C virus (HCV) or hepatitis B virus (HBV); the HB group (4 cases; 15%) were positive for hepatitis B surface antigen (HBsAg); the HCl group (7 cases; 26%) were positive for anti-HCV but negative for HCV RNA genome by a polymerase chain reaction (PCR); and. the HC2 group (9 cases; 33%) had both anti-HCV and the HCV genome. A history of blood transfusions was obtained in 2 of 7 patients in the AL group, in 6 of 16 with evidence of HCV (HCl and HC2), and in 0 of 4 in the HB group. There were no significant differences between groups in results of initial conventional liver tests. Serum aspartate aminotransferase and alanine aminotransferase levels declined during 4 weeks of abstinence in most patients in the AL and HCl groups but not in the HB or HC2 groups. Serum desialotransferrin and alcohol liver membrane antibodies were detected more frequently in the sera of patients in the AL and HCl groups. There was a trend [not statistically significant) toward increased frequency of centrilobular ballooning in the AL group. The
1746
SELECTED SUMMARIES
GASTROENTEROLOGY Vol. 101, No. 6
authors conclude that CAH in the AL group, in whom there were no markers for HBV or HCV, may be caused by alcohol. They further conclude that patients who had anti-HCV but not the HCV genome (group HCl) may represent cases in which both alcohol and HCV are involved.
colleagues. The data presented support the concept that alcohol can produce CAH but do not address the issue of mechanism. It further emphasizes that not all liver disease seen in alcoholics is related to that drug.
Comment. There is ample evidence to incriminate alcohol as a hepatotoxin. Heavy intake may lead to an acute hepatitis with a mixed inflammatory infiltrate that is predominantly polymorphonuclear (PMN). With abstinence, the acute cellular necrosis resolves. The PMN infiltrates disappear before the mononuclear so that after several weeks the biopsy appearance is histologically difficult to distinguish from injury unrelated to alcohol and indistinguishable from CAH of other causes. If the biopsy is performed after a variable period of freedom from alcohol, it is therefore common to find a histological picture quite compatible with CAH in alcoholic patients without incriminating other causes. With continued abstinence and without residual fibrosis, the liver in the majority becomes histologically normal. However, it has been recognized for some time that approximately 10% have continued chronic hepatitis without further alcohol injury [see review by Mezey (Prog Liver Dis 1982;6:555-572)]. The specific role of immunity in this continued process is not clear. The question addressed in this paper is whether CAH is in fact related to the alcohol abuse that brought it to our attention, perhaps perpetuated by immunologic mechanisms, or is caused by unrecognized superimposed viral infection. There is no logical reason to believe that in this case, as in others, several etiologies are mutually exclusive. With the recent availability of serological tests for HCV exposure, alcoholics around the world have been found to be positive for anti-HCV in surprisingly high numbers. For example, 38.7% were positive in Spain (Lancet 1989;2:1004-1006), and 54% were positive in France [J Hepatol 1990;11:393 (letter)]. Obviously, not all alcoholics have the same risk factors. A careful prospective study of these patients and their risks compared with an appropriate control group has not been performed. In the small sample of alcoholics reported here, selected because they had CAH on biopsy, 52% (14/27) had evidence of exposure to HCV. Serological tests could not incriminate any etiology other than alcohol in 26% (7/27) of the cases. A control group from the population without CAH is not reported, and the data are difficult to evaluate. The incidence of anti-HCV appears to be similar to that reported in alcoholics without selection for CAH. The selection bias is difficult to escape but would tend to increase the frequency of cases positive for anti-HCV if, in fact, most cases of CAH in alcoholics were related to the hepatitis viruses. All of the patients selected for study had similar levels of alcohol intake. We are not told if they were abstinent or for how long, information that would also be helpful. Because the level of desialiated transferrin is related to recent alcohol ingestion, I am confused by the differences found between the groups. Further, this protein is independent of liver disease (Hepatology 1991;13:455-459), as are alcohol liver membrane antibodies, and there should therefore be no differences in these values between the groups. Similarly, why should there be a trend toward an increased frequency of centrilobular ballooning of hepatocytes in those alcoholics without evidence of viral disease? Surely viral infection does not protect the liver from this alcohol-associated damage. The differences are not statistically significant, and we cannot draw conclusions. The number of patients in each group is too small to allow more than the speculation of the authors. Taking the numbers at face value, one could equally well conclude (probably quite erroneously) that the combination of the chemical injury of alcohol and the injury of viral infection is not particularly more damaging than either alone. We must have a much larger prospective and appropriately controlled trials to answer the provocative questions raised by Dr. Takase and
Reply.
J. L. ACHORD,M.D. Thank you for the comments of Dr. Achord. A histological
feature compatible
with CAH in patients
with alcoholic
hepatitis
who had abstained from alcohol was first described by Galambos (Gastroenterology 1972;63:1026-1035). We have already pointed out that there are two types of CAH in heavy drinkers (Dig Dis Sci 1983;28:207-215): one type is similar to the cases reported by Galambos or described by Dr. Achord, in which the patient has stopped drinking but the liver changes persist and progress: in the other type, the clinical and histological changes improve quickly after the patient stops drinking. These problems were discussed in an international conference, the proceedings of which were published
in Gasfroenterologia Japonica (Volume 25, Suppl. 1, May 1990). The features of the former type are similar to those of the HCl or HC2 group of the present paper, suggesting that this type of CAH may be caused by HCV or by the combination of both etiologies, alcohol and HCV. This type of CAH has very high risk for developing hepatocellular carcinoma (HCC). Prevalences of HCV markers in alcoholics were high, as pointed out in the comment. However, the differences in diagnostic criteria for alcoholic liver disease must be considered to evaluate these results. In some reports, HCV marker (antibodies to C-100-3
protein) was detected in patients with liver disease of alcoholics, in whom the evidence of alcoholic liver disease was documented poorly. The prevalence was quite different depending on the type of alcoholic liver disease. In our own series, all HCV markers (HCV RNA, antibody to C-100-3 protein, antibody to clone 14 protein) were scarcely found in patients with alcoholic fibrosis and alcoholic hepatitis. Clone-14 antibody was positive in only I of 30 patients with alcoholic fibrosis or hepatitis. On the other hand, the prevalence of HCV markers was about 37% in 41 patients with alcoholic cirrhosis and about 80% in 15 alcoholic patients with HCC. These data were reported in the last IASL meeting in 1990, and the abstract was published in Hepotology (Volume 12, No. 2). The prevalence of HCV markers in CAH was 16 of 23 (69.6%) when HBV-related patients were excluded in the present study. This prevalence was quite different from that of alcoholic fibrosis and alcoholic hepatitis and was similar to that of HCC. We cannot understand the number of patients (14) in the comment who had evidence of exposure to HCV. This may be miscounting; HCV RNA was detected in 29 of 31 nonalcoholic patients with non-A, non-B chronic hepatitis (Gastroenterol Jpn 1991;26:42-46), and the remaining 2 patients were positive for C-100-3 antibodies, The prevalence of HCV markers in chronic hepatitis was clearly higher in nonalcoholics than in alcoholics. Some of these results were mentioned briefly in the discussion of the paper. From these results, we believe the high incidence of HCV markers in CAH of heavy drinkers is not attributable to selection bias. Follow-up study of alcoholic liver disease showed that liver cirrhosis developed with shorter duration and higher frequency in CAD than alcoholic fibrosis, and HCC developed with very high frequency in CAH patients with HCV markers but in very few patients with the other types of alcoholic liver disease (Alcohol, Immunity and Cancer. CRC Press, 1991, in press). These results may be related to the high prevalences of HCV markers in alcoholic cirrhosis and HCC and suggest that HCV-marker positive CAH and cirrhotic patients may be a high-risk group for the development of HCC if they continue drinking. Fletcher et al. (Hepatology 1991;13:455-459) have reported that desialotransferrin is a very useful marker for differentiation of