National Survey of Hepatocellular Carcinoma in Heavy Drinkers in Japan

Background: The major cause of hepatocellular carcinoma (HCC) in the general Japanese population is an infection related to hepatotropic viruses, especially hepatitis virus C (HCV). Even in heavy drinkers, the major cause of HCC is HCV infection. However, HCC without viral infection has been reported in heavy drinkers. Alcohol has been also reported to be associated with an increased risk of cancer. In this study, we investigated aspects of HCC pathogenesis in heavy drinkers in Japan. Methods: Questionnaires were sent to 1350 hospitals authorized by the Japanese Society of Gastroenterology. The questionnaires asked about the number of inpatients with the different types of alcoholic liver diseases, admitted to each hospital between 1998 and 2001. Results: The percentage of heavy drinkers among all admitted patients with liver diseases or liver cirrhosis was approximately 15%. Of the patients with alcoholic liver cirrhosis, the cirrhosis was derived from alcohol alone in 61% and from alcohol plus a virus in 39% of patients. Furthermore, the percentage of patients with alcoholic liver cirrhosis caused by alcohol alone and who did not have HCC was 80%. However, the percentage of HCC patients who tested negative for viral hepatitis serum markers was 27% of the total number of heavy drinkers admitted for HCC. A study mainly on liver cirrhosis performed in the early 1990s demonstrated that the alcohol‐alone group accounted for 44% of admitted patients with alcoholic liver cirrhosis and 18% of heavy drinkers admitted for HCC. Conclusions: Because the consumption of alcohol is increasing in Japan, the frequency and number of cases of alcoholic liver cirrhosis are increasing. Viral hepatitis infection, however, still plays an important role in hepatocarcinogenesis in heavy drinkers. Radiographical examination is recommended even in patients with alcoholic liver cirrhosis who test negative for serum markers of viral hepatitis.     

Comparison of Hepatocellular Carcinoma Patients With Alcoholic Liver Disease and Nonalcoholic Steatohepatitis

Background: Alcoholic hepatitis and nonalcoholic steatohepatitis (NASH) show different clinical features with similar liver histology, but both disorders may progress to cirrhosis and hepatocellular carcinoma (HCC). HCC arising in alcoholic liver disease (ALD) or NASH, without hepatitis B or C virus infection, has been a rare observation, and there are no studies comparing the characteristics of ALD and NASH patients with HCC. Therefore, we compared the characteristics of ALD and NASH patients with HCC.
Methods: A total of 1202 patients received a diagnosis of HCC at Tokyo Women's Medical University from 1989 to 2003, and their clinical data were collected prospectively. A clinical diagnosis was made to diagnose ALD, and clinical and histological changes were required to diagnose NASH. Of these patients, 88 received a diagnosis of HCC arising from ALD. Among them, a biopsy specimen was obtained in 50 patients (ALD-HCC group). We compared the clinical and histological characteristics of 50 ALD and 8 NASH patients (NASH-HCC group) associated with HCC. They all were negative for hepatitis virus infection by serological methods.
Results: The most significant difference between these groups was sex. Women were significantly more common in the NASH-HCC group (6% vs. 63%; p < 0.0001). The median age was 65 years in the ALD-HCC group and 68 years in the NASH-HCC group. The risk factors for NASH all were high in the NASH-HCC group. However, liver function tests were similar in these groups. In the ALD-HCC group, 46 (92%) patients showed severe fibrosis; 2 had septal fibrosis and 44 had cirrhosis. All patients in the NASH-HCC group showed severe fibrosis, and seven had cirrhosis.
Conclusions: Severe fibrosis might be an important risk factor for HCC. Patients who have ALD or NASH with cirrhosis may develop HCC. This seems to occur in a sufficient number of cases to warrant regular screening for this complication.     

Liver disease in heavy drinkers with and without alcohol withdrawal syndrome

BACKGROUND: Withdrawal syndrome is a hallmark of alcohol dependence. The characteristics of alcohol consumption, closely related to dependence, could influence the development of alcoholic liver disease. The study aimed to investigate if patients with severe alcohol withdrawal syndrome have a peculiar profile of liver disease. METHODS: The study included 256 heavy drinkers (aged 19-75 years, 70.3% males) admitted to an Internal Medicine Department. Patients admitted for complications of liver disease were not included. Severe alcohol withdrawal syndrome (seizures, disordered perceptions, or delirium) developed in 150 patients (58.6%). Alcohol consumption (daily quantity, duration, and pattern [regular or irregular]) was assessed by questionnaire. Liver biopsy was performed in all cases. RESULTS: Patients with alcohol withdrawal syndrome showed a lower prevalence of liver cirrhosis and a higher prevalence of alcoholic hepatitis than patients without it. The negative association of alcohol withdrawal syndrome with liver cirrhosis persisted after we adjusted for sex, daily intake, duration, and pattern of alcohol consumption. Alcoholic hepatitis was independently associated with the irregular pattern of alcohol consumption, which was closely associated with severe alcohol withdrawal syndrome. CONCLUSIONS: The profile of liver injury is different in heavy drinkers who develop and who do not develop a severe alcohol withdrawal syndrome when admitted to the hospital.     

Alcohol Consumption and Alcoholic Liver Disease: Evidence of a Threshold Level of Effects of Ethanol

The effects of long-term moderate or "social" alcohol consumption (10-80 g daily intake) on the incidence of features of alcoholic liver disease (ALD) were delineated in a consecutive autopsy series of 210 males. The subjects' daily intake, as well as duration of alcohol consumption, was determined by an interview with the spouse or a close acquaintance and compared with semiquantitative histological scores for stage of ALD.
No significant increase in the incidence of features of ALD could be related to all-year daily intake of ethanol below 40 g (40 g equals 1.1 liter of beer, 0.44 liter of wine, and 0.11 liter of spirits). However, daily intake between 40–80 g increased relative liver weight on average 3.1 g/kg of body weight (p < 0.02), the frequency of fatty liver from 11.7 to 47.2% [relative risk (RR) = 4.4], and the frequency of mainly slight alcoholic hepatitis up to 16.7% (RR = 7.5). The incidence of both bridging fibrosis and liver cirrhosis increased significantly (RR = 8.8) only when daily intake exceeded 80 g. Amounts of ethanol exceeding 80 g did not relate to further increases in incidence of bridging fibrosis or liver cirrhosis.
These findings suggest that, in males, daily ingestion of ethanol below 40 g for a period of 25 years does not increase the risk of alcohol-related liver disease. In contrast, similar duration of daily intake between 40 and 80 g (mean 61.6 g) increased the risk of all but fibrotic liver lesions of ALD significantly and may thus represent a potential threshold level that significantly increases the risk of alcohol-related liver damage. Moreover, our results may suggest that, on an individual level, the risk function for liver fibrosis may not be directly dose-related, but rather, when a permissive threshold level is attained, further consumption is of no or little importance to the progression of ALD.     

Hepatocellular Carcinoma Associated with AlcoholicLiver Disease: A Clinicopathological Study and Genetic Polymorphism of Aldehyde Dehydrogenase 2

In this paper, we describe a clinicopathological study of primary hepatocellular carcinoma (HCC) associated with alcoholic liver disease without hepatitis virus infection. In 180 HCC patients who were admitted to Asahikawa Medical College Hospital from 1987 to 1995, 10 patients (6%) had HCC associated with pure alcoholic liver disease (AI-HCC), whereas the HCC in 165 patients was associated with chronic viral liver diseases, in 2 with primary biliary cirrhosis, in 1 each with coexistence of the hepatitis C virus infection and hemochromatosis, and in 2 with cirrhosis of unknown origin. In the AI-HCC group, all patients were male. The diagnosis of HCC was obtained at the age of 54 to 67 years old, and the duration of ethanol intake was 33 to 40 years. Four cases had a history of temperance. As an underlying liver disease, liver fibrosis was found in three cases and liver cirrhosis in seven cases. HCC was diagnosed histologically in all cases. Serum α-fetoprotein and PIVKA-II were positive in patients with advanced HCC. In cases with small HCC, the tumor was resected surgically in three cases and percutaneous ethanol injection was performed in two cases. In four cases with small HCC, the patients were alive without tumor recurrence during the observation period. In advanced HCC, transcatheter arterial chemolipiodolization was performed. In the analysis of genetic polymorphism of ALDH 2, all AI-HCC had ALDH 2¹/2¹.     

Hepatic Veno-Occlusive Lesions in Severe Alcoholic Hepatitis and Alcoholic Liver Cirrhosis: A Comparative Histopathological Study in Autopsy Cases

Clinicopathological features of veno-occlusive lesions in hepatic veins were studied in autopsy cases of severe alcoholic hepatitis (15 cases) and alcoholic liver cirrhosis (15 cases). All the cases were heavy drinkers and died of liver failure or variceal rupture. The frequency and degree of veno-occlusive lesions, and the diameter and number of hepatic veins were studied from stained sections of liver blocks from each case. The hepatic veins observed ranged from 60 to 3000 μm in diameter. The veno-occlusive lesions were found in hepatic veins mainly 60 to 1200 μm in diameter. These findings were recognized in the majority of severe alcoholic hepatitis cases and alcoholic liver cirrhosis cases. Furthermore, more severe veno-occlusive lesions were noted in severe alcoholic hepatitis, compared with alcoholic liver cirrhosis. In the cases with obstruction in hepatic veins of <400 μm, a decrease in the number of hepatic veins and zonal necrosis were noted. In addition, some of the veno-occlusive lesions were recognized focally in the same cases. Clinical findings also indicated that ascites increased with the progression of the veno-occlusive lesions. We conclude that investigation of veno-occlusive lesions in severe alcoholic liver disease has clinicopathological significance.     

Hepatocellular Carcinoma in Non-alcoholic Fatty Liver Disease: Epidemiology,Pathogenesis, and Prevention

Hepatocellular cancer (HCC) is the fifth most prevalent cancer worldwide and the third leading cause of cancer-related deaths. Non-alcoholic fatty liver disease (NAFLD), a spectrum of hepatic disorders associated with obesity and the metabolic syndrome, is a recognized risk factor for HCC. NAFLD that is advanced to cirrhosis carries the highest risk for HCC, but there is increasing concern that NAFLD-associated HCC may also occur in non-cirrhotic liver. As NAFLD is rapidly becoming the most common liver condition, it has been implicated in the worrisome trend of rising HCC incidence in a number of countries, which may offset successful measures in reducing the effect of virus-related liver cancer. Independently or in synergy with cirrhosis, NAFLD may provide a special oncogenic microenvironment through its pathogenic association with chronic nutrient excess and adipose tissue remodeling, characterized by pro-inflammatory adipokine profiles, lipotoxicity, altered hepatocellular bioenergetics, and insulin resistance. Better understanding of this complex process, and development of reliable biomarkers for HCC will be critical for early recognition and risk prediction. Moreover, correcting deranged lipid metabolism and restoring insulin sensitivity by lifestyle measures and targeted pharmacotherapy holds major promise for effective prevention of NAFLD-associated HCC.     

Hypervascular Liver Nodules in Heavy Drinkers of Alcohol

Background: Three cases of hypervascular nodules in the liver, without hepatitis B or C virus infection and with a history of alcohol abuse (120 ml/day for 15 to 30 years), are presented.
Results: Ultrasound examination revealed hypoechoic nodules in segment 6 (2 cm in diameter, case 1), in the right and left lobes (1–2 cm multiple type, case 2), and in segment 4 (4 cm, case 3). Hepatic angiography and computed tomography during arteriography revealed hypervascular nodules in the three cases. First, hepatocellular carcinoma, focal nodular hyperplasia, hemangioma, hemangioendothelioma, inflammatory pseudotumor, and pseudolymphoma were diagnostically differentiated. Histologically, there was no evidence of hepatocellular carcinoma or of any of the pathologies considered in the differential diagnosis by imaging studies. In case 1, the lesion was composed of an irregular, thin, trabecular-patterned hepatic acinus with slighter hypercellularity than in the nonnodular area. In cases 2 and 3, the lesions were composed mainly of fibrosis without hyperplasia, showing stellate scar–like fibrosis septa dividing the nodule. Marked pericellular fibrosis, neutrophilic infiltration, and Mallory bodies in the cytoplasm were also observed. In cases 1 and 2, small unpaired arteries explaining the hypervascularity of the nodules were observed.
Conclusion: These hypervascular nodules were classified as regenerative, not neoplastic, nodules according to the classification of the International Working Party.     

Use of a high-risk alcohol relapse scale in evaluating liver transplant candidates

BACKGROUND: Methods to improve assessment, selection, and monitoring of patients with alcoholic cirrhosis who pursue liver transplantation are sought continuously. We chose to investigate the use of the High-Risk Alcohol Relapse (HRAR) scale in our transplant population in the hope that it would improve our ability to identify and follow patients at highest risk for alcohol relapse. METHODS: Detailed alcohol histories of 207 patients evaluated for liver transplantation were collected and graded for severity by using the HRAR. The HRAR provides information on the duration of alcohol use (a measure of chronicity), daily quantity of alcohol use, and rehabilitation experiences (treatment responsiveness). Posttransplant alcohol use was monitored through clinical follow-up in the transplant clinic. RESULTS: Although men and women had similar years of heavy drinking pretransplant, women's daily alcohol consumption was significantly less than men's. HRAR scores did not distinguish those listed for transplant from those not listed or those who drank posttransplant from those who did not. Transplant patients were predominantly in the low-risk group (83% had an HRAR score <4). CONCLUSIONS: The HRAR did not have predictive ability in our transplant population. Few of our patients were rated as high risk, and few drank posttransplant. Nevertheless, identifying patients at high risk may improve clinical care and decrease the rate of posttransplant alcohol consumption.     

Polymorphism of N-acetyltransferase 2 gene and the susceptibility to alcoholic liver cirrhosis: interaction with smoking

Background: Polymorphism of N‐acetyltransferase 2 gene was reported to be associated with the susceptibility of various cancers and liver diseases. However, its relationship to alcoholic liver disease is controversial and open to debate. The aim of this study was to evaluate the relationship of NAT2 genetic polymorphisms and the susceptibility to alcoholic liver cirrhosis (ALC) in Chinese, with special emphasis on the interaction of smoking. Methods: Peripheral white blood cell DNA from 148 patients with ALC, 104 patients with long‐term alcoholic drinking but without cirrhosis (ANC) and 209 healthy controls were genotyped for NAT2 using a polymerase chain reaction–restriction fragment length polymorphism method. The possible confounding factors were included for analysis. Results: There was no statistical difference in the frequency of NAT2 genotype or NAT2 acetylator status among the 3 groups. However, among the chronic alcoholic drinkers, the rapid acetylators with smoking habits had higher percentage of ALC than those without smoking habit (18.9% vs. 9.5%, p = 0.002). The adjusted odds ratio for rapid acetylator smoker to have ALC was 3.45 (95% CI = 1.53 to 7.76, p = 0.003). Conclusions: The genetic factor, NAT2 polymorphism, may interact with environmental factor, smoking, to confer different susceptibilities to ALC. NAT2 rapid acetylators with smoking habit may increase the risk of ALC in Chinese.     

A Clinicopathological Study of Acute Hepatitis in Heavy Drinkers, Unrelated to Hepatitis A, B, or C Viruses

Background: There are six histological classifications of alcoholic liver disease (ALD) in Japan. However, it is unclear whether all cases of the disease conform to these criteria. This study investigated the clinicopathological features of eight histologically unusual cases of ALD.
Methods: The characteristic features of alcohol drinking behavior, subjective and objective symptoms, laboratory data on admission, and progress after admission were analyzed for eight patients with acute-onset hepatitis.
Result: The eight patients showed histologically acute hepatitis, with much spotty necrosis that contained granular ceroid pigment by Kupffer cells, which indicated acute parenchymal damage of the liver, but with no Mallory bodies and unremarkable intrasinusoidal neutrophilic infiltration. The only etiological factor for all the cases was habitual alcohol consumption, with increased consumption just before the onset of symptoms. In five cases that were tested, the patients were negative for hepatic viral markers, which included hepatitis G virus RNA and TT virus DNA.
Conclusion: Some cases of ALD may not conform to the current histological classifications in either Japan or Western countries. It seems natural to consider that these cases are developed by other, unknown causes that overlap with ALD rather than as a result of damage from alcoholic overload.     

Roles of Alcohol, Hepatitis Virus Infection, and Gender in the Development of Hepatocellular Carcinoma in Patients with Liver Cirrhosis

To assess the interaction of alcohol, hepatitis C virus (HCV), and hepatitis B virus (HBV) infection in hepatocarcinogenesis, we prospectively observed 449 patients with liver cirrhosis (LC) who presented to our outpatient clinics in 1 month; 164 patients with habitual drinking [alcoholic liver-liver cirrhosis (AL-LC)] who had taken ≥72 g alcohol/day (HCV-positive 81 cases: HCV + AL; HCV-negative 83 cases: AL); 176 patients with HCV infection, but without alcohol intake; 34 patients with HBV infection; 6 patients with HCV and HBV coinfection; and 82 patients with liver diseases from other etiologies, such as primary biliary cirrhosis. In the HCV group, the cumulative occurrence rate of hepatocellular carcinoma (HCC) was 9%, 18%, and 23% in the first, second, and third years, respectively. In the HCV + AL group, that was 13%, 17%, and 28%, respectively. There was no difference in the HCC occurrence rate between the two groups. In the AL group, the cumulative HCC occurrence rate was only 1% during the observation period of 3 years. The occurrence rate was significantly lower in the AL group, compared with the HCV and the HCV + AL groups. In the HBV group, the cumulative occurrence rate of HCC during the observation period of 3 years was 17%, which was similar to that of the HBV + AL group, 14%. We also examined some other variables that might be related to the development of HCC. The cumulative occurrence rate of HCC in male patients was 31%, whereas that was 18% in female patients. In the HCV group, there was a significant increase of HCC occurrence rate in male patients. In contrast, no difference was observed in the HCC occurrence rate between male and female patients in the HBV group. The present study suggests that alcohol alone may not be an independent risk factor for HCC, nor does it accelerate HCC development in LC patients with HCV and HBV infection during the prospective observation of 3 years.     

The Role of Cirrhosis in Memory Functioning of Alcoholics

The effects of alcoholism and liver disease on memory functioning in alcoholics were studied by comparing four groups: normal healthy controls, alcoholics without liver disease, alcoholics with biopsy-confirmed cirrhosis, and nonalcoholics with postnecrotic cirrhosis. Memory capacity was evaluated employing the Benton Visual Retention Test (BVRT), the Rey-Osterreith Complex Figure Test, Digit Span, and the Brown Peterson four-word short-term memory test. A 2 x 2 ANOVA revealed significant main effects for both alcohol and cirrhosis on Digits Forward and the total score on the Brown Peterson test. Additionally, there were significant main effects for cirrhosis on the BVRT. The Brown Peterson test was analyzed using a repeated measures 2 x 2 ANOVA. Significant effects for cirrhosis were observed at all three interpolation periods. The effects for alcohol approached significance at the 30-sec (most difficult) interpolation period. Analysis of error patterns on the Brown Peterson test indicated that overall omission errors were most commonly made among all groups. Significant effects were found for alcohol on omissions and intrusion, while the cirrhosis factor yielded significant effects for phonemic, perseverative, and omission errors. This study demonstrates the importance of liver disease underlying the etiology of memory impairments in alcoholics. The results confirm our earlier findings that neuropsychologic deficits seen in alcoholics may be the result of the combination of alcohol abuse and liver disease.     

Molecular Determinants of Prognosis in Hepatocellular Carcinoma

Hepatocellular carcinoma is one of the leading causes of death by cancer worldwide. Prognosis of hepatocellular carcinoma is determined by characteristics of the tumor and the surrounding cirrhotic liver. Several molecular signatures reflecting tumor biology and derived from tumor analyses predict early tumor recurrence and survival. In contrast, molecular signatures from cirrhotic non-tumor samples are enriched in immunity/inflammation related genes and could predict late tumor recurrence. Moreover, combination of clinical, pathological, and molecular features may refine prognosis prediction in these patients. Finally, molecular signatures from both tumor and non-tumor tissues will be helpful in the future to guide treatments in different clinical settings.     

Hepatocellular Carcinoma in an Adult with Repaired Tetralogy of Fallot

Liver fibrosis is a growing concern among adults with congenital heart disease, particularly for those who have undergone a Fontan operation. Liver fibrosis leads to cirrhosis, a precursor of hepatocellular carcinoma. A few cases of hepatocellular carcinoma in patients with prior palliative surgery for congenital heart disease have been identified in the literature. The current case reports the first known case of hepatocellular carcinoma in a 45‐year‐old male with repaired tetralogy of Fallot.