Alcohol and Alcoholism Vol. 35, No. 3, pp. 286-295, 2000
© 2000 Medical Council on Alcoholism
EFFECT OF ALCOHOL CONSUMPTION ON THE PROGRESSION OF HEPATITIS C VIRUS INFECTION AND RISK OF HEPATOCELLULAR CARCINOMA IN JAPANESE PATIENTS
Institute for Clinical Research, Nagasaki Chuo National Hospital, WHO Collaborating Center for Reference and Research on Viral Hepatitis, 2-1001-1 Kubara, Omura City, Nagasaki 856, Japan
Received 3 August 1999; first review notified 7 December 1999; accepted 4 January 1999
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ABSTRACT |
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 TOPFOOTNOTES ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Chronic hepatitis C virus (HCV) infection is associated with a spectrum of liver diseases and a proportion of chronic cases progress through cirrhosis to hepatocellular carcinoma (HCC). The viral and host factors that are important in the clinical and histological progression of HCV infection are unclear. We investigated the effect of moderate (<80 g/day) and heavy (>80 g/day) alcohol intake on the histological and clinical progression of HCV infection and their associated risk of hepatic cancer in a group of Japanese patients. A number of other variables were assessed to evaluate their impact on disease progression. We recruited 120 patients with HCV infection and categorized them into four groups, based on alcohol consumption pattern. All clinical and biochemical profiles were collected from recorded files. Liver biopsies were analysed for the degree of fibrosis, presence of cirrhosis and histological activity of necroinflammation. Hepatic tumours were detected by the follow-up imaging analysis. There was no difference in the age, length of exposure to HCV infection and HCV RNA serum levels in the alcohol and alcohol-free groups. The histological grading of necroinflammation, serum levels of alanine aminotransferase and HCV RNA did not have any correlation with each other in the alcohol and alcohol-free group. There was a 1.5–2.5-fold greater risk of liver cirrhosis and hepatocellular carcinoma in the alcohol intake group compared to the alcohol-free group. Kruskal–Wallis analysis among four groups demonstrated a significant transition to fibrosis (P < 0.05) for alcoholics with HCV infection. The increased risk of liver cancer in the alcohol group is independent of size and growth of tumours. The clinical manifestations of gastro-oesophageal variceal bleeding, ascites, and encephalopathy were also higher in the alcohol intake group. Alcohol consumption is an important risk factor in the histological and clinical progression of HCV infection and has no relation with HCV replication. Chronic HCV carriers should avoid excessive alcohol intake to reduce the acceleration of liver disease and risk of liver cancer.
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INTRODUCTION |
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TOPFOOTNOTESABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Hepatitis C virus (HCV) infection is a quiescent disease with patients rarely having clinical symptoms until cirrhosis develops. Following the discovery of an assay for HCV (Kuo et al., 1989
), it was demonstrated that chronic hepatitis C has a prevalence of at least 1% worldwide (Alter, 1995). Mortality associated with chronic hepatitis C results mainly from the development of liver fibrosis and the subsequent occurrence of cirrhosis, with complications such as hepatocellular carcinoma (HCC) (Tong et al., 1995). Ten to thirty per cent of patients with HCV will develop cirrhosis over a 20–30 year period, and 1–4% will develop HCC (Di Bisceglie et al., 1991; Seeff et al., 1992; Takahashi et al., 1993). Host and viral factors that are important in enhancing the progression to cirrhosis are not entirely clear (Tassopoulos, 1996). Proposed contributory factors include viral genotype, circulating viral load, duration of infection, mode of infection, iron overload, and alcohol consumption (Di Bisceglie et al., 1991; Seeff et al., 1992; Takahashi et al., 1993; Tong et al., 1995; Tassopoulos, 1996). It was shown that hepatitis C antibodies were present in one third to one half of alcoholics with alcoholic liver disease in Spain and Italy (Brillanti et al., 1989; Bruix et al., 1989; Esteban et al., 1989; Pares et al., 1990) and similar figures were obtained from studies in the USA, Europe and Japan (Ishii et al., 1990; Mendelhall et al., 1991). In contrast, relatively low frequencies of HCV antibodies in alcoholic liver disease were also reported (Locarnini and Dudley, 1991; Herion et al., 1993). Chronic hepatitis due to HCV in non-alcoholics tends to be somewhat less aggressive than other forms of chronic liver disease, but between 20% and 60% of cases nevertheless progress to cirrhosis (Di Bisceglie et al., 1991; Bach et al., 1992; Scheuer et al., 1992), and it is reasonable to presume that high alcohol intake will exacerbate this process.
Cooksley (1996) reported that although HCV and alcohol produce different histological appearances in the pre-cirrhosis stage, they both progress to cirrhosis slowly and only a minority of people develop cirrhosis despite the combination of HCV and heavy alcoholism. However, the majority of evidence suggests that these insults are probably additive for the progression of fibrosis caused by an interaction of alcohol and HCV in the pathogenesis of chronic liver disease (McFarlane, 1993; Poynard et al., 1997). Alcohol intake has also been implicated as an independent risk factor in the progression of HCV infection, although its overall effect on both the histological and clinical progression of liver disease in patients chronically infected with HCV is still uncertain, and the published reports on this topic are very limited, except one from the United States (Wiley et al., 1998).
In the present retrospective study, we examined the effect of moderate and heavy alcohol intake on the histological and clinical status of patients who were infected with HCV and their associated risk of liver cancer in a group of Japanese patients. Unlike previous studies, we also included patients with alcoholic liver disease without HCV infection as a positive control. Our study also indicates that patients who are infected with HCV and drink alcohol have a higher frequency of cirrhosis and liver cancer, and progress more frequently to clinically apparent liver disease irrespective of the viral load and severity of necroinflammation.
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PATIENTS AND METHODS |
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TOPFOOTNOTESABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients
One hundred and twenty patients with HCV chronic liver diseases were recruited for our current study. The medical records and liver biopsies of patients who were seen at the liver unit of Nagasaki Chuo National Hospital over the last 4 years were reviewed retrospectively. All patients were interviewed by use of a standardized questionnaire to obtain information about the type of alcoholic drink, the amount of alcohol consumed per day, duration of alcohol consumption, mode of HCV infection, and dates of transfusions during a subsequent visit to our hospital. Only cases in which there had been an established drinking pattern for more than 5 years were considered under past exposure. Although the exact duration of alcohol intake was not always recorded in the patient ' medical records, it was noted that this period exceeded 10 years in about two-thirds of the subjects. Therefore, we confirmed the consistency of the recorded alcohol history by subsequent assessment. Informed consent was obtained from all patients detailing the consequence of the study and our approved protocol was granted by the Nagasaki Chuo National Hospital Ethical Committee. Alcohol consumption was estimated by one attending physician (K.N.K.) and quantified in g/day. For this study, excessive alcohol intake consisted of moderate alcohol consumption of <80 g/ day and heavy alcohol consumption of >80 g/day for >5 years during the time the patient was infected with HCV. The duration of exposure to HCV was estimated as being from the first blood transfusion before 1990 to the time of liver biopsy. No patient with a source of infection by intravenous drug use was found.
We divided our patients into four groups depending on the amount of alcohol intake. Group A (14 patients), alcoholic liver disease with an alcohol intake of >80 g/day without any HCV infection; Group B (40 patients), HCV infection only and no regular alcohol intake with the possibility of only chance or social drinking; Group C (42 patients), HCV plus alcohol intake of <80 g/day; Group D (24 patients), HCV plus alcohol intake of >80 g/day. Groups A, C and D consisted of only male patients and Group B initially consisted of 50 patients with 10 female patients. We excluded the 10 female patients from Group B and finally recruited 120 male patients. The clinical profiles and biochemical data of all these patients are shown in Table 1. Patients were considered to have alcoholic liver disease when they fulfilled the following criteria: (1) all viral and immunological markers are negative, (2) aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio greater than 1, (3) histological evidence of Mallory's hyaline, polymorphonucleocytes surrounding hepatocytes, and/or significant central vein fibrosis. Patients were considered to have clinically manifested liver disease if they had a gastro-oesophageal varix with or without episodes of variceal bleeding, ascites, encephalopathy, or developed a hepatocellular carcinoma. The severity of varices was based on the endoscopic formation (F) of varix according to the recommendation of the Japanese Endoscopic Society. F1 varix denotes straight and narrow varix; F2 indicates tortuous varix; F3 denotes large and engorged varix.
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Diagnosis of HCV infection
HCV liver disease was confirmed in each patient by the detection of anti-HCV antibody in serum tested by second generation radioimmunoblot assay or serum HCV RNA by the the polymerase chain reaction. All patients with hepatitis B surface antigen positivity and immunological disorders of chronic liver disease were excluded from our study. Patients who had not received interferon therapy before liver biopsy were included in this study. HCV RNA was measured in serum by the signal amplification technique employing branched deoxyribonucleic acid (bDNA) in a sandwich hybridization assay (Quantiplex version 1.0, Chiron Corp., USA) (Lau et al., 1993
). Serum HCV RNA titres were expressed as mega equivalent copies of viral genome per millilitre of serum (Meq/ml).
Histology
All patients had a liver biopsy perfomed within the last 4 years as part of their standard medical evaluation. Liver biopsy specimens were collected by either blind biopsy or during peritoneoscopy and were fixed in 10% neutral formalin. Sections were cut at 3–4 µm thickness and stained with haematoxylin–eosin and Masson trichrome or silver stain for reticulin fibres (Yano et al., 1996). Tissue specimens were studied independently by a senior pathologist of our Institution (H.Y.). For each biopsy specimen, grading of necroinflammation and staging of fibrosis were based on recommendations by Desmet et al. (1994) and Scheuer (1991). The disease activity was assessed by a final grading of necroinflammation as described before (Yano et al., 1996).
Detection of HCC
HCCs were detected in our recruited patients during follow-up screening by abdominal sonography and finally confirmed by computed tomographic scan, histology and/or angiography. The risks of HCC among the four groups of patients and their occurrence in different stages of fibrosis were analysed. Size and doubling time of all detected tumours were calculated from computer-preserved data files of the patients and based on the formula reported earlier (Collins, 1956; Schwartz, 1961).
Statistical analysis
All results are expressed as means ± SD. Student's t-test and Kruskal–Wallis analysis were obtained for assessing significance of values between non-paired groups and overall transition of fibrosis among four groups. The correlation efficacy in non-paired groups was assessed by Spearman regression analysis.
2-test was also undertaken to analyse the risk of liver cirrhosis, HCC, and appearance of clinical signs of liver disease. P14;< 14;0.05 was considered as statistically significant.
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RESULTS |
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Demographic and biochemical data
There was no difference in the age of all male patients in the alcohol and alcohol-free groups (Table 1
). The median alcohol intake for Groups A and D was similar and was considered indicative of heavy alcohol consumption. The median alcohol intake for Group C was 65 g/day and this was considered as a group of moderate alcohol consumption. The AST/ALT ratio was >1 for Group A, but was <1 for the other groups. We did not find any significant difference in the serum levels of other biochemical parameters in these four groups except gamma-glutamyl transpeptidase (
-GTP) and leucine aminopeptidase (LAP), which showed a higher value in Group A compared to the other groups (Table 1).
Serum levels of HCV RNA titre
We measured serum levels of HCV RNA titre in different patients, to demonstrate the relation of alcohol consumption with HCV RNA replication. HCV RNA titres in serum expressed as Meq/ml in different groups of patients are as follows: Group A, 0; Group B, 2.7 14;± 14;2.9; Group C, 2.314;± 14;2.6; Group D, 2.3 14;± 14;1.7. We did not find any significant difference in serum HCV RNA levels between Groups B, C and D (Fig 1.).
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Interrelation of serum levels of ALT, HCV RNA titre and histological grading of necroinflammation
Since HCV RNA serum levels were not different in the alcohol and alcohol-free groups, we tried to establish whether histological activity of necroinflammation has any correlation with either serum levels of ALT or HCV RNA titre. We did not find any significant correlation between disease activity graded from 1 to 7 and serum levels of ALT (Fig 2
), or between disease activity and serum HCV RNA titre (Fig 3). Again, analysis of the interrelation between serum levels of HCV RNA titre and ALT in different patient groups did not demonstrate any significant correlation between them (Fig 4). This indicates that alcohol intake in HCV-infected patients did not exacerbate the underlying disease activity caused by HCV RNA replication.
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Relation of alcohol consumption with histological severity of necroinflammation, degree of fibrosis and risk of cirrhosis
Although the histological activity of necroinflammation was more severe in Groups B, C, and D compared to Group A patients with alcoholic liver disease only (P 14;< 14;0.001), there was no significant difference in severity of necroinflammation among Groups B, C or D (Table 2
). When we analysed the degree of fibrosis from stage 1 to stage 4 in all our enrolled patients, we found that the degree of fibrosis was significantly higher in HCV plus alcohol-intake group compared to patients with HCV infection alone or alcoholic liver disease only (P 14;< 14;0.01). There was no difference in the degree of fibrosis between Groups A and B, or between Groups C and D. It is interesting to note that, even though the severity of necroinflammation in Group A was significantly lower than the other groups, the degree of fibrosis was significantly higher and similar to Group B. When Kruskal–Wallis regression analysis was performed for analysing the overall stage-dependent transition to fibrosis in all four groups of patients, we found a significant and increasing progression of fibrosis in Groups C and D in contrast to patients with HCV infection only or alcoholic liver disease only (P14;< 14;0.05). A total of 59 patients developed liver cirrhosis among all four groups of patients. The risk of cirrhosis was significantly higher in Groups B, C and D, compared to Group A (P 14;< 14;0.001). Again, the risk of liver cirrhosis in HCV plus alcohol-intake groups was 1.5–2.5-fold greater than patients with HCV infection alone (P 14;< 14;0.01).
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Relation of duration and mode of HCV infection with the development of cirrhosis
We obtained a history of blood transfusion in 41 patients of Groups B, C and D (14 in Group B, 17 in Group C and 10 in Group D). We found (Table 3
) that there was no significant difference in the number of patients with blood transfusion, duration of HCV exposure, and frequency of liver cirrhosis in these three groups of patients. However, the patients of Group D developed cirrhosis a little faster than those of Group B (25.8 14;± 14;3.7 vs 29.7 14;± 14;3.3 years), although not significantly (P 14;= 14;0.08).
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Risk of HCC and other clinical manifestations of liver disease complicated by HCV infection and alcohol consumption
Among 120 recruited patients, HCCs were detected in 55 patients by analysis of follow-up images: five in Group A, 10 in Group B, 26 in Group C, and 14 in Group D (Table 4
). The occurrence of HCC was found to be significantly higher in the HCV plus alcohol intake groups compared to HCV infection only (P 14;< 14;0.01). HCV-infected patients who consumed alcohol moderately to heavily had a 1.5–2.5-fold greater risk of HCC in contrast to alcohol-free HCV-infected patients. The higher prevalence of HCC in Group C than in Group D may be due to the non-homogeneous distribution of patients in these two groups. Similar non-homogeneous distribution of patients in Group B and Group A resulted in a higher occurrence rate of HCC in Group B, compared to Group A (P 14;< 14;0.01).
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When the clinical manifestations of gastro-oesophageal varices, ascites and encephalopathy were analysed and compared in the alcohol and alcohol-free groups, we found a significantly higher occurrence of these clinical manifestations in Groups C and D, compared to Groups B and A (P 14;< 14;0.01). HCV-infected patients showed a higher risk of these clinically apparent liver diseases, in contrast to patients with alcoholic liver disease (P 14;< 14;0.01). The gastro-oesophageal variceal bleeding episodes were higher in Groups A, C and D compared to Group B (Groups C and D vs Group B, P 14;< 14;0.001; Group A vs Group B, P 14;< 14;0.01). When endoscopic formation of varices graded from F1 to F3 was compared among all groups of patients, we found that the frequency of severe varices was much higher in the alcohol-intake groups than alcohol-free HCV-infected patients.
Relation of occurrence of HCC with different staging of fibrosis, size and growth of tumours
We could not detect HCC in 65 patients and the remaining 55 patients developed HCC in the different stages of fibrosis. Forty-two patients displayed HCC at stage 4, 11 patients at stage 3 and two patients at stage 2 liver disease (Table 5). The occurrence of HCC in cirrhotic patients was significantly higher than that in non-cirrhotic patients. The risk of HCC in Groups C and D was 1.5–3-fold greater, compared to Group B, in stage 4 liver disease (cirrhosis). In the remaining stages of liver disease, there was no apparent difference in the occurrence of HCC, except Group C, which displayed a higher risk of HCC in stage 3 liver disease. These results indicate that alcohol consumption increases the risk of HCC once the degree of fibrosis has progressed to liver cirrhosis.
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We also analysed the effect of alcohol intake on the size and growth of HCC (Table 6
). We measured the size of each tumour and calculated the doubling time of each tumour from the computer filing system and using the formula already described (Collins, 1956; Schwartz, 1961). We did not find any difference in the size of tumours between Groups C and D and Group B. However, a significant difference in the size of the tumours was found between patients with alcoholic liver disease only (Group A) and the other groups of patients (P 14;< 14;0.01). The doubling time of all HCCs as detected in four groups of patients was almost similar and had no relation with the rapidity of tumour growth. This indicates that alcohol consumption did not induce any additive proliferation of tumour cells.
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DISCUSSION |
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TOPFOOTNOTESABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although the drinking habits of Japanese people differ from those in Western countries, the association between alcohol dependence and HCV infection is not uncommon. Usually, most Japanese people are social or occasional drinkers and a minority drinks alcohol at more than 100 g per day for prolonged period. The different genetic factors in alcoholism, as documented by the increased incidence of both the alcohol dehydrogenase (ADH) 2*1/*1 and aldehyde dehydrogenase (ALDH) 2*1/*1 alleles, have been claimed to be responsible for alcohol dependence and the development of alcoholic liver disease among the Japanese (Tanaka et al., 1996
). Bosron and Li (1986) reported ADH 2*1 allele in more than 90% of white patients in a preceding study and 85% of Japanese patients are known to possess ADH 2*2 allele. In addition, the ADH 2*3 allele, which may contribute to the metabolism of ethanol at higher concentration, was found to be negligible in the Japanese population (Bosron and Li, 1986). This variation of genetic factors and absence of some potent enzymes required for the catabolism of ethanol at higher concentration may possibly prompt the Japanese people to consume less alcohol. Therefore we could not expect to identify large numbers of patients with HCV infection who exhibit moderate or heavy alcohol intake for prolonged periods, or patients with alcoholic liver disease, in our retrospective study confined to a single centre.
In the present study, we examined the impact of alcohol ingestion on the histological and clinical progression of liver disease and their asssociated risk of liver cancer in patients infected with HCV. Our study demonstrated that excessive alcohol intake accelerated the degree of hepatic fibrosis, increased the risk of liver cirrhosis, and worsened the clinical outcome of liver disease including higher risk of hepatocellular carcinoma. Although it has been reported that HCV RNA serum levels are higher in patients who drink alcohol — a finding attributed, in part, to impairment of cell-mediated immunity (Takase et al., 1993; Oshita et al., 1994; Pessione et al., 1998) — we did not observe any significant differences in HCV RNA levels in patients with or without alcohol intake. Our findings are in agreement with the recently published report by Wiley et al. (1998). A recent report suggests that alcohol intake does not acutely increase HCV RNA serum levels and even does not affect serum HCV RNA titres after complete abstinence from alcohol for more than 6 months (Anand and Valez, 1997). The liver histology in the alcohol and alcohol-free patients of our study shows a similar pattern of necroinflammatory activity, which is relevant to the serum HCV RNA titre in these patients. These results are in contrast to the findings already described (Rosman et al., 1993; Fong et al., 1994). Cromie et al. (1996) reported an association between increased HCV RNA titre and elevation of serum ALT levels among hepatitis C patients who consumed alcohol to excess. However, when we tried to analyse the correlations between serum ALT and HCV RNA levels or between serum ALT levels and histological grading of necroinflammation, we did not find a parallel association between them. Nakano et al. (1993) reported that HCV-Ab-positive alcoholics are associated with more fibrosis, less piecemeal necrosis and lymphocyte infiltration, than HCV-Ab-positive non-alcoholics. In a later study, Uchimura et al. (1995) demonstrated similar virus-related histological changes in the majority of chronic HCV infected patients with or without alcohol. Although not shown, we were also unable to establish a functional relationship between severity of disease activity and degree of fibrosis.
The decreased natural killer cell activity during prolonged consumption of alcohol may partly explain the decreased disease activity (Laso et al., 1997). Our findings support those of Soldevila-Pico et al. (1996), who demonstrated that excessive alcohol intake was not associated with higher serum HCV RNA level or increased disease activity of HCV infection. The age of the patients may be another contributing factor related to unchanged activity of necroinflammation. A recently published report (Khan et al., 1998) demonstrated that portal activity attained a maximum at 45 years of age and thereafter decreased, and a maximum lobular activity before 35 years is followed by a minimum level by 45 years. However, fibrosis score increased proportionately with increasing age and alcohol consumption. An inverse correlation between alcohol consumption and histological activity index with a very low variation of activity has been recently published (Pessione et al., 1998) and is inconsistent with our results. Since there was no difference in the median age (60 years) of our four groups of patients, we do not know the reason why even toxic levels of alcohol ingestion (>80 g/day) could not induce an increased disease activity. A possible alternative explanation, that the increase in circulating endotoxins leading to activation of Kupffer cells causes ethanol-induced liver damage (Thurman et al., 1998), needs to be evaluated.
The enhanced degree of fibrosis, the 1.5–2.5-fold increased risk of liver cirrhosis and the clinical presentation of liver disease complicated by HCV and alcohol intake, as observed in our current study, concur with the results published recently (Wiley et al., 1998). In a large population-based study from Italy, concomitant HCV infection increased the incidence of cirrhosis 10-fold in chronic alcoholics, compared with alcoholics who were not infected with HCV (Bellentani et al., 1994). A 2-fold greater frequency of cirrhosis was also noted in a French study in HCV-infected patients who drank (Roudot-Thoraval et al., 1997). Also, the prognosis of alcoholic liver disease was worse in patients who were HCV Ab-positive (Mendelhall et al., 1991). In fact, stage 4 fibrosis was significantly higher in the HCV plus alcohol-intake patients, compared to patients with HCV infection only or alcoholic liver disease only.
It is important to note that the histological activity of necroinflammation was significantly lower in patients with alcoholic liver disease without HCV infection, even when they ingested a toxic concentration of ethanol, when compared with the other groups of patients. However, their degree of fibrosis was significantly higher and similar to patients infected only with HCV. In contrast, the patients with concomitant HCV infection and alcohol ingestion displayed a significantly higher degree of fibrosis and consequently increased risk of cirrhosis. Since the median age of our patient population was similar, our findings further confirm the role of alcohol in inducing fibrosis. A relation between fibrosis and age, and fibrosis and past alcohol consumption has already been described (Deny et al., 1994; Mochida et al., 1996; Poynard et al., 1997; Roudot-Thoraval et al., 1997; Khan et al., 1998; Ostapowicz et al., 1998). Although we could not detect other parenteral risk factors, except blood transfusion, in a small group of patients with HCV infection, our study supports other observations indicating that progression of liver disease is not dependent on the mode of infection (Strasser et al., 1991; Kao et al., 1994). Again, the progression to cirrhosis was found to be independent of the length of exposure to HCV infection. However, high-alcohol-consuming patients with HCV infection developed cirrhosis a little faster, although not significantly so. The non-homogeneous distribution of our patients might affect the results as reported recently (Wiley et al., 1998).
In addition to the increased risk of liver cirrhosis, we also reported that about one-half of our recruited patients developed HCC in the clinical course of liver disease. Among these, more than 70% of HCC belonged to the HCV-infected patients who drank either moderate or heavy amounts of alcohol. This means a 1.5–2.5-fold increased risk of HCC was noticed in HCV-infected patients who consumed alcohol. The other clinical complications related to decompensated liver disease, such as gastro-oesophageal varices and their bleeding episodes, endoscopic formation of varices, ascites and encephalopathy, were also markedly higher in HCV-infected patients who consumed alcohol excessively. The increased risk of HCC as a complication of alcohol ingestion was mostly observed in patients with stage 4 liver cirrhosis and was similar to the report by Donato et al. (1997). However, a recent study suggested that the degree of fibrosis was not a significant risk factor for the development of HCC in patients infected with HCV (Kasahara et al., 1998). In the natural course of HCV-infected liver disease, repeated regeneration due to persistent liver injury by HCV may cause hepatocyte DNA to become susceptible to mutagenesis, resulting in gene instability (Shiratori, 1996). Therefore, ethanol-induced enzymatic activation for the conversion of procarcinogens into carcinogens and consequent induction of hepatic neoplasm (Farinati et al., 1985; Lieber et al., 1986; Garro and Lieber, 1990) might be an additional factor for the increased risk of HCC in our study. We did not find any difference of tumour sizes between HCV-infected patients who drank and those who did not. When the doubling times of all these tumours were analysed in all tumour-bearing patients to assess the effect of alcohol on tumour cell proliferation, we did not find any group difference, in contradiction to the results of Matsuhashi et al. (1996). It has been reported that p53 gene mutations are associated with tumour progression as a late event in hepatocarcinogenesis, and that heavy drinking correlates with p53 gene mutations in squamous cell carcinoma of the head and neck (Field et al., 1994; Hayashi et al., 1995). As for HCC, it may be speculated that specific p53 mutations are not associated with HCC patients who are alcohol misusers. More epidemiological and molecular studies are necessary to confirm the effect of alcohol on tumour growth of HCC.
In conclusion, our results further strengthen the evidence that alcohol consumption can be an additional insult for the progression of fibrosis and risk of cirrhosis in HCV liver disease. It is independent of HCV replication and severity of disease activity. Chronic HCV carriers should avoid excessive alcohol consumption if they are to reduce the progression of fibrosis, incidence of liver cirrhosis, clinical manifestations complicating decompensated liver disease and also to reduce the risk of HCC.
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FOOTNOTES |
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* Author to whom correspondence should be addressed.
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TOPFOOTNOTESABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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