Journal of Hepatology
Volume 35, Issue 4 , Pages 531-537, October 2001

The spectrum of liver disease in the general population: lesson from the Dionysos study

  • Stefano Bellentani

      Affiliations

    • Fondo Studio Malattie del Fegato, Trieste, Italy
    • ,
  • Claudio Tiribelli

      Affiliations

    • Fondo Studio Malattie del Fegato, Trieste, Italy
    • CSF, Department BBCM, University of Trieste, Via Giorgieri 1, 34127 Trieste, Italy
    • Corresponding Author InformationCorresponding author. Tel.: +39-40-399-4927; fax: +39-40-399-4924

Received 30 April 2001; accepted 14 June 2001.

Article Outline

 

The idea of the Dionysos study (DS) originated in an airport lounge in the summer of 1988 when we realized that, differently for what happened for heart and cardiovascular diseases [1], [2], no data were available on the prevalence of liver disorders in the general population. Rather, most of the data were based on selected series not representing the real picture of the population, but only ‘the peak of the iceberg’. Based on these considerations we started planning a cohort study aimed to obtain data on how frequent liver disease was in the general population. Although aware of the difficulties of this type of study, our motivation laid on the expectation that what collected could be of importance in unraveling the still undefined spectrum of liver diseases in a much representative sample, i.e. the general population. In less than 12 months the no-profit association Fondo per lo Studio delle Malattie del Fegato succeeded in collecting two-thirds of the budget and we were then ready to go. Among the skepticism of other colleagues, the study started on January 1, 1991 and the first part ended in December 1993. Since originally one of the main goals of the study was to understand the role of food (wine included) in determining alterations in liver functions, the study was named Dionysos [3] in honor of the Greek deity protecting food, wine and earth products (Baccus for the Romans).

Back to Article Outline

1. Study design 

Two comparable towns in Northern Italy (Campogalliano, Modena, and Cormons, Gorizia) (Fig. 1) were selected on the basis of number of inhabitants, census and socio-economic background. All the 10,151 inhabitants, ranging in age between 12 and 65 years were considered eligible for the study, of whom 6917 were screened with an overall compliance of 70%, a percentage adequate to validate this type of study [4]. In each patient several parameters were collected: (1) A careful medical history including previous diagnosis of liver disease, gallstone disease, surgical operations, blood transfusions, drug abuse, dental procedures, dog or other domestic animal bites, homosexuality, tattooing; (2) A semi-quantitative, color-illustrated, food questionnaire including detailed questions on the use of alcoholic beverages. Each subject was asked in multiple-choice form whether they drank beer, red wine, white wine, alcoholic aperitifs or hard liquors ‘daily’, ‘weekly’, ‘monthly’, or ‘hardly ever/never’. Total amount of alcohol taken lifetime (in kg) was computed by multiplying the daily alcohol intake (in g) by the duration of alcohol intake (in years). Alcohol consumption collected with the semi-quantitative questionnaire was also validated by cross-checking both the alcohol consumption declared by the enrollee with family members and data relative to the sales of the alcoholic beverage in the two towns during the 2 years the study was performed; (3) A detailed physical examination to detect liver and biliary diseases or physical signs related to chronic liver disease; the body mass index (BMI) was also recorded; (4) Blood sample for alanino-aminotransferase (ALT), aspartate-aminotransferase (AST), gamma-glutamyltransferase (GGT), mean corpuscular volume (MCV) and platelet count, and hepatitis B virus (HBV) and hepatitis C virus (HCV) markers When one or more clinical or biochemical parameters was altered, subjects were also studied with ultrasonography of the liver.

Back to Article Outline

2. Prevalence of HBV and HCV infection 

Since one of the major products of the Dionysos study was to understand the true prevalence of hepatropic viruses infection in the general population, the protocol included the serum assay of the markers for HBV and HCV. Previous studies reported data on this medically and socially relevant issue, but unavoidable biases in the selection of the sample screened (blood donors, medical personnel, confined and selected communities) limited the validity of extrapolating the data to the entire population.

The prevalence of HBV infection, as assessed by the positivity of HBsAg, was found to be 1.2%. The vast majority (two-thirds) of the HBV infected subjects followed up for 9 years (up to the end of 2000) showed persistently normal ALT levels, while only the remaining 25% showed alteration of ALT and had and histologically proven chronic liver disease (4.5% with compensated Child A cirrhosis). Of notice was the observation that during the 9 years follow up, no hepatocellular carcinoma (HCC) were found among the HBsAg positive subjects. These findings suggest a rather slow progress of HBV-related liver disease and fit with other series obtained in different clinical settings [5], [6].

Rather different was what we observed for HCV. The overall prevalence of the positivity of HCV antibody was found to be 3.2% [3], [7] which was somehow six times higher that that reported previously [8], [9]. This rather surprising finding was even more striking when the prevalence was analyzed according to the different classes of age. While the prevalence was rather low (below 1%) up to 40 years, it raised sharply thereafter to reach a value of 10% in subjects older that 60 years, suggesting that the infection probably occurred in late 60’s. Subsequent studies, performed in different geographical regions of Italy demonstrated that the overall prevalence of HCV infection may be even higher since values around 8% was observed in central Italy [10] and around 25% in the southern portion of the country [11]. These numbers differ from those reported in other regions of the world, where prevalence varying from 2% in the US [12] up to 50% in Egypt [13] have been found. More important was the observation that while in some countries (US and Australia) the prevalence of anti HCV positivity is rather stable over the years, in others (Italy and Japan) there is a clear trend of a higher positivity in older subjects, suggesting a cohort effect [14], as recently confirmed in a retrospective analysis of archival samples of liver cirrhosis [15]. While more studies are clearly needed to establish the true prevalence of HCV infection in the population worldwide, the Dionysos study was the first report suggesting that the extent on HCV infection was much higher that that formerly believed.

The study of the distribution of the different HCV genotypes in the Dionysos population revealed that 12% were false positive (HCV RNA negative) while more that 60% of HCV infection was due to the presence of type 1 virus. HCV-RNA positivity increased progressively with age, and was higher in females. Drug use, blood transfusions received before 1990, history of previous hepatitis among the cohabitants and history of animal (mainly dogs) bites were significantly associated with HCV infection, independently from age and sex. Multivariate analysis revealed that, independently from age, sex and alcohol intake, genotype 1 infection (with or without coinfection with other genotypes) was the major risk factor for cirrhosis and /or HCC. During the 9 year follow up, 35% of the HCV RNA positive subjects had persistently a normal ALT value, and HCC developed with an incidence rate of 2.5% per year as also previously shown in other series [16]. Collectively, the DS data indicated that HCV infection is widespread in the general population much more that what formerly believed, but that only less than 50% of the HCV infection, particularly that with genotype 1, are associated with a severe, clinically evident liver disease, as already described in smaller series [17], [18], [19]. These data also support the conclusion that HCV infection is, in general, a mild, slow progressing disease is line with data collected in different clinical series both in children [20] and adults [21].

Due to the availability of ethanol consumption, it was also possible to demonstrate the long believed, but never fully demonstrated clinical assumption that alcohol consumption greater that 30 g/day significantly aggravates the natural course of the disease. The risk of developing cirrhosis for HCV-RNA positive drinkers was three times higher than that in HCV-RNA negative drinkers, and the mean age of HCV-RNA positive cirrhotic patients was significantly lower in drinking than in not drinking subjects [22].

Back to Article Outline

3. Autoimmunity and HCV infection 

The DS also allowed to better understand the possible relationship between HBV and HCV infection and autoimmune liver disease. The prevalence of non-organ specific autoantibodies (NOSA) such as anti-nuclear antibody (ANA), anti-smooth muscle antibody (SMA) and liver/kidney microsomes type 1 antibody (LKM1) were investigated in a cohort of HBV and HCV positive subjects and compared with controls pair-matched for sex and age, after exclusion of confounding factors as excessive alcohol intake [23]. The overall prevalence of NOSA was significantly higher in anti-HCV positive than in both HBV positive patients and controls (25 vs. 6 and 7%, respectively); the presence of NOSA was 5.1 times higher in anti-HCV subjects. Interestingly, the presence of NOSA correlates with the activity of liver disease, suggesting a hypothetical role of autoimmune markers in the progression of liver damage. The HCV genotypes most frequently associated with NOSA were genotype 1 (22%) and 2 (15.4%). At multivariate analysis, the presence of NOSA was significantly associated with genotype 1, either alone or in combination with more than one genotype. These data confirmed in the general population that the prevalence of NOSA is higher in anti-HCV positive subjects than in normal or HBsAg positive controls, and that NOSA are associated with a more active disease in terms of ALT activity.

Back to Article Outline

4. Alcohol consumption and risk for liver disease 

The important question of ‘how much is too much’ for ethanol intake, or ‘how much can I safely drink’ has been often addressed in the past with confusing and undefined answers. This uncertainty is due mainly to the heterogeneity in the sampling population and to the lack of reliable record for ethanol consumption. The Dionysos study allowed to answer this relevant question since for each subject a detailed record on alcohol consumption was available [3]. It was shown that alcoholic liver disease does not develop below a lifetime alcohol ingestion of 100 kg, equivalent to an average daily alcohol intake of 30 g corresponding to two to three glasses of wine for 10 years [3], [24]. As shown in Table 1, the risk for developing liver damage steadily increases when ethanol consumption exceeds 30 g per day. Above the 30 g/day threshold, the incidence of alcoholic liver disease and of cirrhosis increases linearly with increasing alcohol intake. Interestingly, and contrary to what reported in other series [25], [26], [27], no gender difference was observed. At multivariate analysis, the toxic effects of alcohol intake are independent from BMI or, most important, type of alcoholic beverage used (wine, beer, and spirits). It was also shown that, in addition to the total amount of alcohol ingested, the pattern of drinking is a clear determinant of the development of alcoholic liver disease. For equal amounts of alcohol ingested, individuals who consumed alcohol both at mealtime and outside meal experienced an incidence of alcoholic liver disease and cirrhosis which was from three to five times higher than that of the individuals who ingested alcohol only at mealtime [24]. Such increased risk began to be significant in heavy drinkers after the age of 50 years indicating that the damage is additive. From these studies we concluded that the minimum alcohol intake associated with a significant increase in the prevalence of alcohol-related liver disease was 30 g/day for both sexes and that the risk increased in a dose-related relationship, with no sex differences. However, the most striking result was that not only the quantity of alcohol intake, but also the pattern of drinking was an important determinant in the risk of having non cirrhotic liver damage or cirrhosis [28]. Drinking without food, independently of the amount drunk, is associated with a significantly increased prevalence of alcohol-related liver disease [24].

Table 1. Relationship between daily alcohol consumption and alcoholic liver cirrhosis as derived from the cohort Dionysos population. The odds ratio for the developing of liver damage is also indicated
Alcohol Intake (g per day)No damage (%)Cirrhosis (%)Odds ratio for cirrhosis
Teetotaler99.90.040
<3099.30.150
31-6097.21.010.9
61-9093.02.325.0
91-12091.64.952.9
>12086.55.763.2

Back to Article Outline

5. Prevalence of liver diseases and population attributable risk 

Table 2 reports the ‘true prevalence’ of various liver diseases in the population screened. It also reports on the prevalence of ‘bright liver’ at ultrasonography, obesity and inappropriate drinking as defined from the data obtained in the study (body mass index >24 in females and 25 in males and more 30 g ethanol per day or 100 kg ethanol during lifetime, respectively) [3], [24]. It is impressive that an alteration of one or more of the commonly used liver function tests was found in more that one-seventh of the Dionysos cohort, 58% of people had liver steatosis, and more than a quarter of the population was obese, indicating that also in Italy disorders related to an excessive food consumption are frequent. Also intriguing was the observation that the overall prevalence of cirrhosis was 1% but only 40% of this condition was due to excessive drinking, although the two towns screened are located in areas with an historically high wine production and consumption. Collectively, these findings indicate that liver diseases are a true social problem, a finding which is seldom acknowledge by health authorities. They also point to the conclusion that when compared with a frequency of 10% of cirrhosis discovered at autopsy [29], only one patient out of ten show a clinically evident disease. Another rather striking observation is that in spite of a prevalence of inadequate drinkers of 30%, this condition is associated with liver disorder only in less than 10% of them, confirming the crucial role of additional factors in determining this condition (see below).

Table 2. Prevalence of liver disease and related conditions in the general populationa
ConditionPrevalence (%)
LFTs > upper normal level *17.5
HBV infection1.2
HCV infection3.2
Liver Cirrhosis1.0
Inappropriate Drinkers **30
Inappropriate Drinkers with liver disease2.3
Liver steatosis (‘bright liver’ at ultrasonography)58.3
Obesity25

a Liver Function Tests=ALT, AST, GTT. **Subjects drinking more that 30 g ethanol/day or more that 100 kg lifetime.

The DS also defined the relative role of the exposure to different risk factors in the development of liver disease. The Population Attributable Risk Percent (PARP), commonly used in several clinical epidemiological studies [30], [31], [32] but never applied before to hepatology, allowed to determine the percentage of the total risk for the disease of interest (liver cirrhosis in this case) due to different risk factors. Table 3 reports the Population Attributable Risk Percent (PAR%) and the Attributable Risk percent in the Exposed (AR%exposed) for cirrhosis and hepatocellular carcinoma (HCC) due to the four different major risk factors: (1) excessive alcohol consumption (>30 g/day) alone; (2) HCV alone; (3) HBV alone; and (4) the combination of at least two of the previous factors. The highest PAR% and AR%exposed were found when two risk factors (i.e. HCV infection and excessive alcohol consumption) were present (92.3% and 91.6%, respectively), indicating that in the general population 92.3% of the risk for cirrhosis and HCC is due to the concomitant presence of both viral infection and alcohol abuse. It also indicates that among those who have HCV (or HBV infection) and drink more than 30 g of alcohol per day, 91.6% of the total risk is due to the presence of both risk factors.

Table 3. Attributable Risk Percent to different risk factors (AR%exposed) and Population Attributable Risk Percent (PAR%) for cirrhosis and HCC (histologically confirmed) in the Dionysos population (6917 subjects)
Risk factors for cirrhosis and HCCAR%exposedPAR%
excessive alcohol consumption (>30 g/day. i.e. level of risk in Dionysos population)83.965
HCV infection alone88.538
HBV infection alone60.47
Excessive alcohol consumption and viral infection91.692.4

From these data it is also evident that when only one risk factor is present, the major percentage of attributable risk for cirrhosis and HCC in the general population is an alcohol consumption greater than 30 g/day (PAR%=65%), followed by HCV infection (PAR%=38%) and HBV infection (PAR%=7%) (Table 3). The surprisingly lower percentage of attributable risk for cirrhosis and HCC of HBV infection is probably due to the features of our cohort, where 75% of the HBV infected subjects followed for 9 years remained healthy and where confined to the adult population.

Back to Article Outline

6. Fatty liver: Who, Why and When 

Although the role of alcohol abuse and obesity in inducing fatty liver has been reported, the relative role of each of them is still undefined. Though hepatic steatosis is a rather common findings in clinical practice, especially in an outpatient setting, and it is very often associated with slight alteration of either ALT or GGT or both, the real prevalence of fatty liver in the general population has never been correctly established. Previous studied reported a prevalence of steatosis from 3 [33] to 22% [34], such a great variability probably due to the different types of population studied. In spite of this variability in prevalence, there is an overall agreement to consider fatty liver more frequent in men and that obesity, alcohol abuse and hyperinsulinemia may be important in determining this.

The Dionysos study allowed understanding the real prevalence of steatosis and defining the subjects at risk for the hepatic fat accumulation. After exclusion of HBV and HCV positive subjects, and those who consumed any type of drugs during the previous 6 months, subjects were randomly assigned in four groups: controls, teetotallers with normal BMI; obese teetotallers; heavy drinkers (more than 60 g of alcohol per day) with normal BMI; and heavy drinkers and obese. As shown in Fig. 2 the prevalence of steatosis (at ultrasound) increased from control (16%) to heavy drinker (46%), and obese (76%); steatosis was found in virtually all cases (95%) when obesity and heavy drinking were both present. The risk ratio of steatosis significantly increased in heavy drinkers (2.8), obese (4.6) and obese and heavy drinkers (5.8). Obesity increased 2.0 fold the risk of steatosis in heavy drinker while heavy drinking was associated with only a 1.0 fold risk in obese subjects [35]. Collectively this study allowed to conclude that steatosis is frequently encountered in healthy subjects and it is almost always present in obese subjects drinking more that 60 g/alcohol per day. Most important was the demonstration that steatosis is more strongly associated with obesity than heavy drinking, suggesting a greater role of overweight than inappropriate alcohol consumption in inducing fat accumulation in the liver [35].

Assuming that the data obtained in the population of the Dionysos study may be applicable to a much wider sample, as suggested by similar conclusion obtained in Spain [36] and Japan [37], we can conclude that, in the general population, independently from others confounding factors, an elevation of ALT and triglycerides is the most predictive condition for the presence of hepatic steatosis, and that steatosis is associated more with obesity than with alcohol abuse. When obesity and inappropriate ethanol consumption are associated, steatosis is nearly always present.

Back to Article Outline

7. Genes and alcohol-induced liver damage 

As mentioned above, the large discrepancy between the number of inadequate drinkers and alcohol-induced liver damage (AILD) point to the role of additional factors, among which the importance of genetic factors has long been recognized [38]. A meta-analysis of several studies linking human leucocyte antigens (HLA) with AILD concluded that none of the HLA phenotypes so far investigated in Caucasians can be shown to be significantly more common in AILD than in controls [39]. Other genes, like those encoding for alcohol dehydrogenase (ADH2, ADH3) and aldehyde dehydrogenase (AILDH2), as well for the microsomal ethanol oxidation system [cytochrome P4502E1 (CYP2E1)] have been subject of intensive investigations over the last few years with contradictory results. Some studies in Japanese and Chinese populations indicated that the allele ADH2*2 of the ADH2 gene [40], and allele C2 of the CYP2E1 gene [41] were more associated with AILD. However, other investigations failed to confirm these findings [42], [43], [44]. These discrepancies are even more striking when similar investigation was performed in Caucasians. The effects of genetic variation in ADH2 and ADH3 on AILD showed that ADH3 variations seem to significantly decrease the risk of alcohol dependence up to 2–3 fold and to increase 2 fold the risk of AILD among alcoholics [45].

Altogether, these conflicting results clearly reflect the overall problem in investigating a multifaceted disease such as AILD where several factors in addition to alcohol nay be confounding. From the clinical standpoint, the major problem was the rather small number of patients, their derivation from a selected series and not from an open population, and the difficulty of a precise definition of the disease. From the genetic standpoint, several studies had been conducted in genetically heterogeneous populations with an uncontrolled rate of genetic admixture, and often by analyzing the contribution of alleles which were very rare in the overall population (such is the case of the C2 allele in the Caucasian population). The Dionysos study helped in shading same light on this complicated issue. The distributions of nine different polymorphisms in three genes involved in alcohol metabolism (ADH2, ADH3, and CYP2E1) were investigated among the drinkers reporting comparable high amount of ethanol intake (more than 120 g/day for more than 10 years) but differing for the presence or absence of AILD. In the inhabitants of Campogalliano, the C2 allele in the promoter region of the CYP2E1 gene had a frequency significantly higher in heavy drinkers with AILD as compared with healthy heavy drinkers. This association become even higher in heavy drinkers with cirrhosis. In Cormons, whose inhabitants have different genetic derivation, a prominent association between AILD and homozygosity for allele ADH3*2 of ADH3 was observed, with a prevalence of 31 and 7% in heavy drinkers with or without AILD, respectively [46]. The advantage of this study, as compared to those previously reported, is mainly related to its collection in an open population and in comparing subjects with similar alcohol intake with or without liver disease. These results strongly indicate that, depending on allelic frequencies of the population, the presence of either at least one allele C2 of cytochrome P4502E1 (in Campogalliano) or of the homozygosity for the ADH3*2 allele (in Cormons) are predisposing factors for the development of AILD. Heterozygosity for allele C2 of CYP2E1 and homozygosity for allele ADH3*2 of ADH3 seems to be independent risk factors for AILD in alcohol abusers, and the relative contribution of these genes to AILD is dependent on their allelic frequencies in the population screened. Accordingly, in the Dionysos cohort, heavy drinkers not having either of these two genotypes were 3.2 and 4.3 times more protected from developing AILD, respectively. The identification of two genetic polymorphisms predisposing to AILD reinforces the notion that AILD is a multigenic disorder. Whether this genetic background may be extrapolated to a wider Caucasian population is still undefined and need further co-operative studies.

Back to Article Outline

8. Conclusions and perspective 

Nine years after the beginning of the Dionysos study, still many of the data collected remain to be analyzed and properly interpreted, pointing to the large amount of information obtained by this study. In addition, the possibility to keep following prospective subjects with liver disease at the enrollment will allow to shed further light on the natural history of liver disorders of different etiology (viral, metabolic, nutritional, etc.). However among the several aspects in liver disease unraveled by the first Dionysos study, the most important seems to us the demonstration that these disorders are much more frequent that what previously thought, making liver diseases a real social problem. In January 2000 the second ‘edition’ of Dionysos study started where the incidence and the natural history of liver disease will be analyzed. All the population tested in the first round of DS is currently under rescreening, and at present more that 60% of the sample has been collected.

Admittedly, one of the main limitation of Dionysos study is that the population analyzed belong to a rather limited geographical area (Northern East of Italy) thus questioning the extendibility of what observed to the whole country and/or larger European areas. This is probably the case, as indicated by the large variation observed in the HCV infection rate between Northern and Southern regions of Italy. This conclusion points to the need to export the scheme used in this cohort study to larger geographical regions, Europe in particular. Due to the frequency of liver disorders, this project, though expensive and difficult to organize, will provide important information to be used in the future, in order to reduce the impact and the social cost of liver diseases. We are currently working on this project and we hope to report on it in the near future assuming that the large budget necessary could be raised.

Back to Article Outline

 

The Dionysos study would have never been possible without the support of several public and private institutions. In particular, we are indebted with the Health Authorities of Friuli-Venezia Giulia and Emilia-Romagna regions, Local Health Public Agencies of Modena and Gorizia, Municipalities of Cormons and Campogalliano, Fondazione Cassa Risparmio di Gorizia, Banca Popolare dell'Emilia Romagna, Fondazione Cassa di Risparmio di Trieste for their generous financial and logistic support. The study was also made possible by grants by Telethon (E-396), MURST (Confin 98), Coop Estense, Bracco SpA. Glaxo SpA, Sanofi-Midi SpA, Esaote Ansaldo Biomedica SpA. However, we are particularly grateful to all those persons who, at different level, helped us in collecting and analyzing the results. Special thanks are due to G. Brandi, A. Castiglione, G. Cristianini, L.S. Crocè, C. De Martin, M. Giacca, M. Lenzi, F. Masutti, L. Miglioli, M. Milazzo, A. Monzoni, G. Pozzato, G. Saccoccio, M. Sodde, and U.Volta whose efforts made possible what is reported in this article.

Back to Article Outline

References 

  1. Kannel WB, Schwartz MJ, McNamara PM. Blood pressure and risk of coronary heart disease: the Framingham study. Dis Chest. 1969;56:43–52
  2. Kannel WB, Abbott RD, Savage DD, McNamara PM. Coronary heart disease and atrial fibrillation: the Framingham Study. Am Heart J. 1983;106:389–396
  3. Bellentani S, Tiribelli C, Saccoccio G, Sodde M, Fratti N, De Martin C, et al.  Prevalence of chronic liver disease in the general population of northern Italy: the Dionysos study. Hepatology. 1994;20:1442–1449
  4. Block G, Hartman AM, Dresser CM, Carroll MD, Gannon J, Gardner L. A data-based approach to diet questionnaire design and testing. Am J Epidemiol. 1986;124:453–469
  5. de Franchis R, Meucci G, Vecchi M, Tatarella M, Colombo M, Del Ninno E, et al.  The natural history of asymptomatic hepatitis B surface antigen carriers. Ann Intern Med. 1993;118:191–194
  6. Lunel F, Cadranel JF, Rosenheim M, Dorent R, Di Martino V, Payan C, et al.  Hepatitis virus infections in heart transplant recipients: epidemiology, natural history, characteristics, and impact on survival. Gastroenterology. 2000;119:1064–1074
  7. Bellentani S, Miglioli L, Masutti F, Saccoccio G, Tiribelli C. Epidemiology of hepatitis C virus infection in Italy: the slowly unraveling mystery. Microbes Infect. 2000;2:1757–1763
  8. Sirchia G, Almini D, Bellobuono A, Giovanetti AM, Marconi M, Mercuriali F, et al.  Prevalence of hepatitis C virus antibodies in Italian blood donors. The Italian Cooperative Group. Vox Sang. 1990;59:26–29
  9. Stevens CE, Taylor PE, Pindyck J, Choo QL, Bradley DW, Kuo G, et al.  Epidemiology of hepatitis C virus. A preliminary study in volunteer blood donors. J Am Med Assoc. 1990;263:49–53
  10. Stroffolini T, Guadagnino V, Chionne P, Procopio B, Mazzuca EG, Quintieri F, et al.  A population based survey of hepatitis B virus infection in a southern Italian town. Ital J Gastroenterol Hepatol. 1997;29:415–418
  11. Osella AR, Misciagna G, Leone A, Di Leo A, Fiore G. Epidemiology of hepatitis C virus infection in an area of Southern Italy. J Hepatol. 1997;27:30–35
  12. Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, et al.  The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341:556–562
  13. Darwish MA, Faris R, Clemens JD, Rao MR, Edelman R. High seroprevalence of hepatitis A, B, C, and E viruses in residents in an Egyptian village in The Nile Delta: a pilot study. Am J Trop Med Hyg. 1996;54:554–558
  14. Wasley A, Alter MJ. Epidemiology of hepatitis C: geographic differences and temporal trends. Semin Liver Dis. 2000;20:1–16
  15. Stanta G, Croce LS, Bonin S, Tisminetzky SG, Baralle FE, Tiribelli C. Cohort effect of HCV infection in liver cirrhosis assessed by a 25 year study. J Clin Virol. 2000;17:51–56
  16. Colombo M, de Franchis R, Del Ninno E, Sangiovanni A, De Fazio C, Tommasini M, et al.  Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl J Med. 1991;325:675–680
  17. Lopez-Labrador FX, Ampurdanes S, Gimenez-Barcons M, Guilera M, Costa J, Jimenez de Anta MT, et al.  Relationship of the genomic complexity of hepatitis C virus with liver disease severity and response to interferon in patients with chronic HCV genotype 1b infection [correction of interferon]. Hepatology. 1999;29:897–903
  18. Lopez-Labrador FX, Ampurdanes S, Forns X, Castells A, Saiz JC, Costa J, et al.  Hepatitis C virus (HCV) genotypes in Spanish patients with HCV infection: relationship between HCV genotype 1b, cirrhosis and hepatocellular carcinoma. J Hepatol. 1997;27:959–965
  19. Pozzato G, Moretti M, Franzin F, Croce LS, Tiribelli C, Masayu T, et al.  Severity of liver disease with different hepatitis C viral clones. Lancet. 1991;38:509
  20. Vogt M, Lang T, Frosner G, Klingler C, Sendl AF, Zeller A, et al.  Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. N Engl J Med. 1999;341:866–870
  21. Seeff LB, Miller RN, Rabkin CS, Buskell-Bales Z, Straley-Eason KD, Smoak BL, et al.  45-year follow-up of hepatitis C virus infection in healthy young adults. Ann Intern Med. 2000;132:105–111
  22. Bellentani S, Pozzato G, Saccoccio G, Crovatto M, Croce LS, Mazzoran L, et al.  Clinical course and risk factors of hepatitis C virus related liver disease in the general population: report from the Dionysos study. Gut. 1999;44:874–880
  23. Lenzi M, Bellentani S, Saccoccio G, Muratori P, Masutti F, Muratori L, et al.  Prevalence of non-organ-specific autoantibodies and chronic liver disease in the general population: a nested case-control study of the Dionysos cohort. Gut. 1999;45:435–441
  24. Bellentani S, Saccoccio G, Costa G, Tiribelli C, Manenti F, Sodde M, et al.  Drinking habits as cofactors of risk for alcohol induced liver damage. The Dionysos study Group. Gut. 1997;41:845–850
  25. Becker U, Deis A, Sorensen TI, Gronbaek M, Borch-Johnsen K, Muller CF, et al.  Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective population study. Hepatology. 1996;23:1025–1029
  26. Sorensen TI, Orholm M, Bentsen KD, Hoybye G, Eghoje K, Christoffersen P. Prospective evaluation of alcohol abuse and alcoholic liver injury in men as predictors of development of cirrhosis. Lancet. 1984;2:241–244
  27. Bouchier IA, Hislop WS, Prescott RJ. A prospective study of alcoholic liver disease and mortality. J Hepatol. 1992;16:290–297
  28. Day CP. Alcoholic liver disease: dose and threshold–new thoughts on an old topic. Gut. 1997;41:857–858
  29. Tiribelli C, Melato M, Croce LS, Giarelli L, Okuda K, Ohnishi K. Prevalence of hepatocellular carcinoma and relation to cirrhosis: comparison of two different cities of the world–Trieste, Italy, and Chiba, Japan. Hepatology. 1989;10:998–1002
  30. Basu S, Landis JR. Model-based estimation of population attributable risk under cross- sectional sampling. Am J Epidemiol. 1995;142:1338–1343
  31. Narayan KM, Thompson TJ, Boyle JP, Beckles GL, Engelgau MM, Vinicor F, et al.  The use of population attributable risk to estimate the impact of prevention and early detection of type 2 diabetes on population-wide mortality risk in US males. Health Care Manag Sci. 1999;2:223–227
  32. Hill GB. The value of the population attributable risk percentage. Am J Public Health. 1996;86:1483
  33. Tominaga K, Kurata JH, Chen YK, Fujimoto E, Miyagawa S, Abe I, et al.  Prevalence of fatty liver in Japanese children and relationship to obesity. An epidemiological ultrasonographic survey. Dig Dis Sci. 1995;40:2002–2009
  34. Lonardo A, Bellini M, Tartoni P, Tondelli E. The bright liver syndrome. Prevalence and determinants of a ‘bright’ liver echopattern. Ital J Gastroenterol Hepatol. 1997;29:351–356
  35. Bellentani S, Saccoccio G, Masutti F, Croce LS, Brandi G, Sasso F, et al.  Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med. 2000;132:112–117
  36. Pares A, Tresserras R, Nunez I, Cerralbo M, Plana P, Pujol FJ, et al.  Prevalence and factors associated to the presence of fatty liver in apparently healthy adult men. Med Clin (Barc). 2000;114:561–565
  37. Nomura H, Kashiwagi S, Hayashi J, Kajiyama W, Tani S, Goto M. Prevalence of fatty liver in a general population of Okinawa, Japan. Jpn J Med. 1988;27:142–149
  38. Hrubec Z, Omenn GS. Evidence of genetic predisposition to alcoholic cirrhosis and psychosis: twin concordances for alcoholism and its biological end points by zygosity among male veterans. Alcohol Clin Exp Res. 1981;5:207–215
  39. List S, Gluud C. A meta-analysis of HLA-antigen prevalences in alcoholics and alcoholic liver disease. Alcohol Alcohol. 1994;29:757–764
  40. Yamauchi M, Maezawa Y, Toda G, Suzuki H, Sakurai S. Association of a restriction fragment length polymorphism in the alcohol dehydrogenase 2 gene with Japanese alcoholic liver cirrhosis. J Hepatol. 1995;23:519–523
  41. Chao YC, Young TH, Chang WK, Tang HS, Hsu CT. An investigation of whether polymorphisms of cytochrome P4502E1 are genetic markers of susceptibility to alcoholic end-stage organ damage in a Chinese population. Hepatology. 1995;22:1409–1414
  42. Tsutsumi M, Takada A, Wang JS. Genetic polymorphisms of cytochrome P4502E1 related to the development of alcoholic liver disease. Gastroenterology. 1994;107:1430–1435
  43. Day CP, Bashir R, James OF, Bassendine MF, Crabb DW, Thomasson HR, et al.  Investigation of the role of polymorphisms at the alcohol and aldehyde dehydrogenase loci in genetic predisposition to alcohol-related end-organ damage. Hepatology. 1991;14:798–801
  44. Day CP, James OF, Bassendine MF, Crabb DW, Li TK. Alcohol dehydrogenase polymorphisms and predisposition to alcoholic cirrhosis. Hepatology. 1993;18:230–232
  45. Whitfield JB. Meta-analysis of the effects of alcohol dehydrogenase genotype on alcohol dependence and alcoholic liver disease. Alcohol Alcohol. 1997;32:613–619
  46. Monzoni A, Masutti F, Saccoccio G, Bellentani S, Tiribelli C, Giacca M. Genetic determinants of ethanol-induced liver damage. Molec Med. 2001;7:255–262

PII: S0168-8278(01)00151-9

Journal of Hepatology
Volume 35, Issue 4 , Pages 531-537, October 2001

Article Tools

* Image Usage & Resolution