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Attributable risk for symptomatic liver cirrhosis in Italy
Journal of Hepatology 1998; 28: 608–614 Printed in Denmark ¡ All rights reserved Munksgaard ¡ Copenhagen
Copyright C European Association for the Study of the Liver 1998
Journal of Hepatology ISSN 0168-8278
Attributable risk for symptomatic liver cirrhosis in Italy Giovanni Corrao1, Antonella Zambon1, Pierfederico Torchio1, Sarino Arico`2, Carlo La Vecchia3, Ferdinando di Orio4 and Collaborative Groups for the Study of Liver Diseases in Italy5 1 Institute of Statistical and Mathematical Sciences, Chair of Medical Statistics and Epidemiology, University of Milan; 2Division of Gastroenterology, Hospital Mauriziano Umberto I, Turin; 3Institute of Biometrics and Medical Statistics, Chair of Epidemiology, University of Milan, Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’, Milan; and 4Department of Internal Medicine and Public Health, University of L’Aquila, Italy
Backgrounds/Aims: Knowledge of the proportion of liver cirrhosis attributable to the main risk factors is largely based on methodologically questionable clinical reports. Methods: The proportion of newly diagnosed cases of symptomatic liver cirrhosis attributable to known risk factors was estimated by a case-control study performed during 1989–1996 in 23 medical divisions of several hospitals distributed throughout Italy. Cases were 462 inpatients with cirrhosis admitted for the first time for liver decompensation. Controls were 651 patients admitted during the same period and to the same hospitals as the cases, for acute diseases unrelated to alcohol and virus infection. The proportion of symptomatic liver cirrhosis cases due to alcohol intake and hepatitis B and C viruses and the combination of these was expressed as the population attributable risk.
Received 9 June; revised 24 September; accepted 29 October 1997
Correspondence: Giovanni Corrao, Dipartimento di Scienze Statistiche, Universita` degli Studi di Milano, Viale Scarza, 202, 20126 Milan, Italy. Tel: 39 2 6487054. Fax: 39 2 6473312. 5
Results: Attributable risks were 67.9% (95% confidence interval (CI): 53.8–79.4) for alcohol, 40.1% (95% CI: 35.3–45.2) for hepatitis C virus and 4.4% (95% CI: 2.5–7.6) for hepatitis B virus. The three factors together explained 98.1% (95% CI: 81.6–99.6) of cases in men and 67.0% (95% CI: 50.4–85.8) in women. Conclusions: Alcohol is the risk factor with the highest impact on symptomatic liver cirrhosis risk in Italy. From a public health viewpoint, with the elimination of the well-known risk factors (particularly alcohol and hepatitis C virus), liver cirrhosis should become a rare disease.
Key words: Alcohol intake; Attributable risk; Hepatitis B virus; Hepatitis C virus; Liver cirrhosis.
countries, symptomatic cirrhosis of the liver is a serious public health problem, representing one of the ten leading causes of death (1), with almost 150 000 deaths every year (2). There is a general consensus on the role of alcohol intake and of chronic hepatitis B and C virus (HBV
I
Collaborative Groups for the Study of Liver Cirrhosis in Italy: Collaborative GESIA (Epidemiologic Group of the Italian Society of Alcohology) Group for the Italian Study on Liver Cirrhosis Determinants (SIDECIR Project): Morelli D, Moscatello MR, Stefanini GF (Bologna); Chiesa R, Donato F, Tomasoni V (Brescia); Guglielmini V, Manghisi OG, Petruzzi J, (Castellana Grotte); Monica M, Sardi GF (Lanzo Torinese); Ajello A, Freni MA, Spadaro A (Messina); Gravina M, Longo G, Mangano C (Messina); Ascione A, De Luca M, Galeota Lanza A (Napoli); Del Vecchio Blanco G, Fedezico A, Loguercio C (Napoli); Burra P, Mioni D, Naccarato R (Padova); Guarnone F, Pallavicini C, Vittadini G (Pavia); Arico` S (Torino). Collaborative Group for the Study of Chronic Liver Disease in the Province of L’Aquila: Del Bove Orlandi G, Marchionni F, Rabitti G (Avezzano); Caracciolo P, Cincis M, Giovannone M (Castel di Sangro), Attili A, Caione F, Ercole C, Festuccia V, Giandomenico G, Giusti A, Grimaldi A, Iannessi A, Lepore AR, Mariani M, Miccoli C, Necozione S, Pantaleo G, Pozone M, Rapone C, Tonietti G, Tullio G (L’Aquila), Biocca A, Colitti L (Pescina), Cercone S, Sgro` G, (Sulmona), Bernardini E, Bruccoleri F, Capobianchi P, Santini S, Zepponi E (Tagliacozzo). Collaborative AISF (Italian Association for the Study of Liver) Group for the Study of Alcohol and Liver Disease: Cerrato C, Cerrato G, Tringali M (Aosta); Bruno A, De Vita A, Iaquinto G (Avellino); Scifo G, Risicato R (Avola); Altomare E, Vendemiale G (Bari); Addolorato G, Gasbarrini G, Stefanini GF (Bologna); Leandro G, Manghisi OG, Petruzzi J, Plantone F (Castellana Grotte); Belmonte A, Manno G, Mollica A, Sabatino A (Cosenza); Ajello A, Ferrau` MA, Freni MA, Spadaro A (Messina); Longo G, Raimondo G, Rodino` G, Russo F (Messina); Coltorti M, Del Vecchio Blanco C, Loguercio C (Napoli); Budillon G, Cuomo R, Nardone G (Napoli); Ascione A, De Luca M, Di Costanzo GG (Napoli); Ambrosone (Napoli); Burra P, Naccarato R, Salvagnini M (Padova); Giudici Cipriani A, Marenco G, Ponassi I (Pietra Ligure); Disalvo D (Potenza); Beltrami M, Fornaciari G, Plancher AC (Reggio Emilia); Arico` S, Galatola G, Tabone M (Torino); Brezza E, D’Alessandro A, Rizzo A (Vicenza)
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Alcohol, viruses and liver cirrhosis
and HCV) infections in liver cirrhosis (3–5). This implies that the risk of onset of the disease for an individual exposed to each of these factors is much greater than for an unexposed individual. However, the high individual risk in exposed subjects is not informative on the proportion of the disease due to the exposure in a given population, since the impact of a factor in causing disease is also a function of the prevalence of exposure in that population (6). There is therefore a need for data on the proportion of liver cirrhosis attributable to the major risk factors in various countries, in order to plan public health intervention programs. Unfortunately, our knowledge is largely based on the clinically-based etiological attribution of each individual patient. Although symptomatic liver cirrhosis represents only one of the potential points of observation of the natural history of the disease, this condition is the main object of medical research. We have therefore used data from three Italian casecontrol studies to estimate the proportion of symptomatic liver cirrhosis attributable to these factors in Italy.
Subjects and Methods Selection of cases and controls We used data from three case-control studies performed with the same design in several Italian areas. Cases were patients admitted for symptomatic liver cirrhosis (SLC) – signs of liver decompensation (ascites, jaundice, oedema) or bleeding from ruptured oesophageal varices – in whom the diagnosis of cirrhosis was made for the first time. Diagnoses were based on clinical criteria. A percutaneous liver biopsy was obtained when clinically requested. Exclusion criteria were invalidating hepatic encephalopathy, coexisting hepatocellular carcinoma, a final diagnosis of primary biliary cirrhosis and acute causes of liver damage. Patients resident outside the areas covered by the collaborative centres were also excluded. The 462 cases included: (i) 115 patients admitted to the medical departments of the six district hospitals of the Province of L’Aquila (Central Italy: first study) during the period November 1989 to May 1990; (ii) 170 patients admitted to the gastroenterology unit of a district hospital of Turin (Northern Italy: second study) during the period February to November 1993; (iii) 177 patients admitted to the medical departments of 16 hospitals distributed throughout the country (ongoing Italian Study on the Determinants of Liver Cirrhosis, SIDECIR project: third study) from May 1994 to June 1996. Controls were patients resident in the study areas and admitted during the same periods as the cases to the same hospitals for acute conditions. Exclusion cri-
teria were: actual admission to orthopaedic, infectious disease, psychiatry, gynaecology and obstetric departments; and gastroenterological, metabolic, neoplastic and cardiovascular diseases. No matching procedure was used in selecting controls, but they were randomly selected from the eligible patients. Thus, we enrolled 651 controls (167, 250 and 234 in the first, second and third study, respectively) admitted for minor surgical operations (47.9%), acute urinary tract diseases (22.1%), and non-traumatic dental/ocular or ear-nosethroat diseases (30.0%). Data collection Cases and controls were interviewed a few days after admission by trained interviewers, who were blinded with respect to the aim of the study. The interview was a part of the patients’ medical history routinely recorded by the hospitals involved in the study. Thus, no specific patient consent was required by the local ethical authority and the participation rate was 100%. A structured questionnaire was used to collect social, demographic and life-style information, including alcohol consumption. Alcohol consumption was assessed retrospectively, dividing the patient’s life into 10-year periods and recorded as the average amount of ethanol consumed daily; the different alcohol concentrations in the five types of beverages were investigated separately (12% for wine, 5% for beer, 18% for aperitifs, 30% for digestive alcoholic drinks and 40% for spirits). The ages when alcohol consumption began and ended were also recorded. The average life-time daily alcohol intake (LDAI) during the period of consumption was calculated as the weighted mean of alcohol intake between periods. LDAI was grouped into four categories (0: lifetime abstainers; drinkers less than 50 g/day; drinkers from 50 to 100g/day drinkers more than 100 g/day) in order to obtain a sufficient number of patients for the analysis. The reproducibility of the questionnaire, estimated by interviewing the relatives of a sample of patients, was satisfactory, without appreciable differences between cases and controls series and between genders (7,8). Sera from all patients were obtained a few days after admission and subsequently analysed to detect hepatitis B virus surface antigen (HBsAg) and anti-HCV antibodies. Serum HBsAg was detected by a commercial immunoenzymatic assay. Anti-HCV antibodies were measured using a second-generation enzymelinked immunosorbent assay (Abbott Laboratories, Chicago, Illinois, USA). Anti-HCV-positive sera were retested using a second-generation recombinant immunoblot assay (RIBA; Chiron Corporation, Emeryville,
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California, USA). Both the ELISA and RIBA assays were considered: results were considered positive when two HCV antigens were detected, indeterminate if antibodies to only one HCV antigen were present. ELISA positive, but RIBA indeterminate, sera were also considered positive taking account of the lower sensitivity of the RIBA assay (9). Exploring representativeness of the case sample To verify whether our case group can be considered representative of Italian SLC patients for the risk factors investigated, the distribution of LDAI categories and the prevalence of serum HBsAg positivity observed in our cases were compared with those reported in a multicentre study carried out between 1990 and 1992, where a sample of 1258 incident SLC cases recruited by 17 medical centres homogeneously distributed throughout Italy was interviewed (10). Expected numbers of HBsAg positive patients and of drinkers in each LDAI category were calculated on the basis of the proportions reported in each gender and age category of the Italian SLC sample (indirectly standardised for gender and age). Data analysis The SLC risk associated with the factors considered was estimated, using several logistic regression models, and expressed as odds ratio (OR) and corresponding 95% confidence interval (CI). Models included as covariates the HBsAg status, the anti-HCV status and the LDAI categories. Since no matching procedure was used in the selection of controls, all estimates were adjusted for age, gender, education and study variable (first, second or third study). For all models we estimated the parameters by maximising the unconditional likelihood function (11).
The SLC risks attributable to alcohol intake, to the presence of serological signs of HBV or HCV chronic infections and to each combination of these three factors were estimated by the model-based method described by Bruzzi et al. (12). In brief, provided that the cases can be assumed to be representative of the diseased population in terms of exposure distribution, and that the ORs are unbiased, the method estimates the population attributable risk (AR) and of the corresponding 95% CI from case-control studies, taking into account exposure factors with multiple levels and allowing for confounders (13). Under the logistic model, the overall AR for two or more factors combined is not the sum of the adjusted ARs for each factor. Moreover, the sum of the adjusted ARs for each factor may exceed 100% (14).
Results Table 1 shows the general characteristics of the three series of cases and controls. The proportion of men was higher in cases than in controls. Mean age ranged from 54 years (controls of the third study) to 61 years (controls of the first study). The proportion of patients with higher education was higher in cases than in controls in all series. The prevalence of lifetime teetotallers was higher in controls than in cases in all three series. The mean lifetime daily alcohol intake and the prevalence of positivity for HBsAg and anti-HCV were significantly higher in cases than in controls in all three series. Controls in the three studies did not significantly differ for mean lifetime daily alcohol intake (one-way analysis of the variance: FΩ2.49, pΩ0.08) and for prevalences of anti-HCV positive (c2Ω3.33, pΩ0.19), HBsAg positive (c2Ω5.40, pΩ0.07) and lifetime teetotallers (c2Ω3.01, pΩ0.22).
TABLE 1 Distribution of 462 cases of symptomatic liver cirrhosis and 651 controls according to selected characteristics. Italy, 1989–1996
Gender: men Age (years) Education (years) Æ5 6–8 Ø9 LDAI4 Lifetime teetotallers Anti-HCV positive HBsAg positive 1 2 3 4
First study1
Second study
2
Third study3
Cases (nΩ115) Controls (nΩ167)
Cases (nΩ170) Controls (nΩ250)
Cases (nΩ177) Controls (nΩ234)
n (%) means∫sd
80 (69.6) 58.0∫15.9
92 (55.1) 60.5∫15.5
119 (70.0) 58.9∫12.8
142 (56.8) 60.1∫15.2
101 (57.1) 55.6∫15.0
121 (51.7) 53.7∫14.2
n (%) n (%) n (%) means∫sd n (%) n (%) n (%)
24 (20.9) 56 (48.7) 35 (30.4) 95.4∫108.7 9 (7.8) 37 (32.2) 14 (12.2)
35 (21.0) 100 (59.9) 32 (19.2) 50.3∫69.3 25 (15.0) 8 (4.8) 1 (0.6)
37 (21.8) 81 (47.6) 52 (30.6) 102.6∫114.2 10 (5.9) 74 (43.5) 22 (12.9)
56 (22.4) 152 (60.8) 42 (16.8) 52.3∫69.4 46 (18.4) 13 (5.2) 1 (0.4)
42 (23.7) 85 48.0) 50 (28.2) 87.4∫99.5 11 (6.2) 97 (54.8) 24 (13.6)
49 (20.9) 135 (57.7) 50 (21.4) 39.1∫53.8 51 (21.8) 5 (2.1) 6 (2.6)
Study conducted in L’Aquila (Central Italy) during the years 1989–1990. Study conducted in Turin (Northern Italy) during the year 1993. Ongoing multicentric study (SIDECIR Project); data were collected during the years 1994–1996. Lifetime daily alcohol intake.
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Alcohol, viruses and liver cirrhosis TABLE 2 Comparison between observed and expected number of drinkers and of HBsAg positive patients in the pooled case series
1
2
LDAI categories(g)
0 ∞50 ∞100 Ø100
HBsAg
positive
Observed1
Expected1
SPR (95% CI)2
30 152 97 183
28.2 145.5 92.4 195.9
1.1 1.0 1.1 0.9
60
65.45
(0.7–1.5) (0.9–1.2) (0.9–1.3) (0.8–1.1)
0.9 (0.7–1.2)
The observed distribution of the 462 cases in the lifetime daily alcohol intake (LDAI) categories, and in the category of HBsAg positivity were compared with those expected on the basis of the proportions of drinkers and of HBsAg positivity, in each gender and age class of the sample of Italian liver cirrhosis patients (17). Standardised Prevalence Ratio (SPR) (observed/expected ratio) and its 95% confidence interval(CI). *p∞0.05.
TABLE 3 Distribution of 462 cases of symptomatic liver cirrhosis and 651 controls according to lifetime daily alcohol intake (LDAI), anti-HCV and HBsAg status and corresponding odds ratio (OR). Italy, 1989–1996 Cases
1
Controls
OR1
95% CI1
n
(%)
n
(%)
LDAI categories (g) 0 ∞50 ∞100 Ø100
30 152 97 183
(6.5) (32.9) (21.0) (39.6)
122 409 70 50
(18.7) (62.8) (10.8) (7.7)
1.0 2.0* 9.0* 31.2*
reference 1.2–3.5 4.6–17.6 15.8–61.6
Anti-HCV status Negative Positive
254 208
(55.0) (45.0)
625 26
(96.0) (4.0)
1.0 20.7*
reference 13.0–33.2
HBsAg status Negative Positive
402 60
(87.0) (13.0)
643 8
(98.8) (1.2)
1.0 8.6*
reference 3.9–18.9
Odds ratio estimated by multiple logistic regression including terms for gender, age, education and study variable (first, second or third study); 95% confidence interval. * p∞0.05.
TABLE 4 Risk of symptomatic liver cirrhosis attributable to alcohol, HCV and HBV and their combination. Italy, 1989–1996 Men AR Alcohol HCV HBV AlcoholπHCV AlcoholπHBV HCVπHBV AlcoholπHCVπHBV 1
1
85.9 40.6 8.2 97.6 87.9 47.8 98.1
Women 95% CI
1
67.7–94.7 34.7–46.8 3.6–10.7 81.6–99.6 67.7–94.7 41.7–54.1 81.6–99.6
AR
1
46.8 39.6 2.5 65.4 48.1 40.5 67.0
Menπwomen 95% CI
1
25.6–69.4 31.4–48.4 0.0–53.0 44.7–81.6 30.3–73.2 32.1–49.6 50.4–85.8
AR1
95% CI1
67.9 40.1 4.4 82.3 70.7 44.3 85.5
53.8–79.4 35.3–45.2 2.5–7.6 70.7–90.0 56.8–81.6 40.3–50.5 74.4–92.3
Population attributable risk (AR) was expressed as fraction of 100 and estimated from a multiple logistic regression model, including terms for gender, age, education and study variable and the main effects of the three factors considered, and assuming a multiplicative effect; 95% confidence interval (CI).
The observed and expected distribution of alcohol consumption and HBsAg positivity are reported in Table 2. The distribution of our pooled cases group in the LDAI categories, as well as the prevalence of serum HBsAg positivity, did not significantly differ from those found in the sample of the Italian SLC patients. Table 3 shows the ORs for alcohol intake, anti-HCV
and HBsAg status and the risk of SLC. A dose-response relationship between LDAI and risk of cirrhosis was observed. The risk of SLC associated with both anti-HCV and HBsAg positivity was significant. The estimated attributable risks for the three factors are shown in Table 4. All ARs were higher for men than for women. For both genders, the single factor
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with the highest AR was alcohol consumption, which accounted for 86% and 47% of SLC cases in men and in women, respectively. Anti-HCV positivity as a single factor explained about 40% of both male and female cases, whereas HBsAg positivity was less important than the other two factors, accounting only for 4% of SLC cases. The three factors together were responsible for 98% of SLC cases in men and 67% in women. For both genders, the combined action of the three factors explained 86% of the SLC cases.
Discussion The present study confirms and quantifies the well-established association between alcohol intake, chronic HCV and HBV infections and the risk of liver cirrhosis. The new findings of our study suggest that: (i) over two-thirds of SLC in Italy is attributable to alcohol consumption, while a lower proportion of cases is explained by HCV infection (40%) and only 4% by HBV infection; and (ii) over 85% of SLC in Italy is explained by the investigated risk factors, and this proportion reaches 98% in men. It has been suggested that HCV infection is the major determinant of liver cirrhosis in western countries. This suggestion is based on the high proportion of anti-HCV in liver cirrhosis series. In a recent paper, a sample of 1829 Italian patients with cirrhosis with and without associated hepatocellular carcinoma, was classified into pre-established ‘‘aetiologic categories’’; the following prevalences were found: 72% for anti-HCV, 14% for HBsAg and only 9% for alcohol abuse (15). Several criticisms should be made of such an approach. Firstly, the aetiologic attribution to alcohol cannot be referred only to alcohol abuse, since no consensus exists on a threshold of alcohol consumption under which the risk of liver cirrhosis is equal to that of abstainers (3). In the present study, we observed a significant effect of low doses of alcohol (∞50 g/day, which are believed to be clinically innocuous, especially in men. We have recently shown that, although genderrelated differences exist in susceptibility to alcohol-induced liver damage, such low doses of alcohol consumption are a significant risk factor also for men (16). Secondly, investigation of alcohol consumption in the period preceding the current hospital admission leads to an underestimation of the dose responsible for the onset of the disease, since many patients stop or reduce their intake when symptoms appear. Thirdly, since alcohol consumption (17) and persistent viral replication influence the survival of patients with cirrhosis, the distribution of risk factors in prevalent cases might be different from that of patients identified at diagnosis. Fourthly, in the absence of a control group, it is incor-
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rect to attribute all the exposed cases to a risk factor, since not all the exposed subjects develop the disease. Serum HBsAg and anti-HCV are not markers of active viral replication and can be found in healthy subjects. Analogously, not all heavy drinkers progress to symptomatic liver cirrhosis. Finally, we believe that aetiologic diagnosis should not be confused with aetiologic attribution. We can assume that the impact of a risk factor on the occurrence of a disease in a given population is a positive function of two quantities: its relative risk and its prevalence in that population. In our study (Table 3), we estimated that drinking 100 or more g/ day had a higher relative risk than anti-HCV positivity (31 and 21, respectively) and also a higher prevalence (8% and 4%, respectively). Furthermore, the increased relative risks observed for low doses of alcohol consumption, though of smaller entities (ORΩ2 for 50 or less g/day and ORΩ9 for 100 g/day or less), greatly increase the alcohol-attributable fraction of the disease due to the high prevalence of the exposure. These observations lead to results which can be in disagreement with clinical experience. However, it must be noted that it is easier for clinicians to determine viral infections in patients with chronic liver diseases than to measure their alcohol intake, and furthermore, that it is difficult to attribute the observed disease to low doses of consumption. We attempted to estimate the attributable risk with an approach that: (i) considered the lifetime exposure to alcohol in a quantitative form, (ii) determined chronic viral infections on the basis of common serological markers; (iii) used a case-control approach to estimate the attributable risks; (iv) enrolled as controls hospitalised patients with acute conditions; (v) considered only new diagnoses of SLC as entry criteria for our cases. Each of these methodological choices might have biased our estimates. A bias in retrospectively measuring life-time alcohol intake could be determined by variability of the intake throughout the years (18). This is not likely to have occurred in our study, since Italians consume constant daily amounts of alcohol throughout their lives, mainly in the form of wine (10). An alcohol-information differential bias should also have scarcely affected our results, considering the satisfactory reproducibility found between alcohol intake measured from the patients and from interviewing a sample of relatives, with no differences between cases and controls (7,8). Viral factors may also be active in the absence of common serological markers. In fact, in 10% of serum HBsAg negative alcoholics, circulating HBV-DNA was found (19). Underestimation of the risk associated with HBV and HCV cannot therefore be excluded.
Alcohol, viruses and liver cirrhosis
A case-control study aiming to estimate the population-attributable risk should be representative of all the new cases of the disease which occurred in the target population, and the odds ratio should be unbiased. Our investigations were not designed to be populationbased studies. However, we investigated all the consecutive diagnoses made in 23 medical divisions of several reference hospitals distributed throughout Italy. In addition, the distribution of alcohol consumption reported by our cases, as well as the prevalence of HBsAg-positive patients, were similar to those found in another large Italian study (10). Surprisingly, no data are available on the prevalence of HCV infection in newly diagnosed liver cirrhosis. The use of hospital controls has been criticised on the assumption that they might be selected from the underlying population. We tried to minimise this possible bias by selecting control patients with acute diseases, excluding those with diseases positively or negatively associated with the investigated factors, and using a wide range of diagnostic categories as sources of our controls. It is conceivable that recruiting other groups of patients, like those admitted to orthopaedic, psychiatric or infectious diseases wards, would lead to higher prevalences of alcohol intake and/or HCV infection. However, the goal in selecting the control group is not to find those who have been exposed, but to obtain data on the distribution of the study factors in the general population. On the other hand, selecting a sample of the general population would lead to other sources of bias, such as: reduced reliability of alcohol intake questionnaires, as shown by our previous experience (7); a higher frequency of non-responding; and difficulties in blood collection for HBsAg and antiHCV testing. Thus, we think that our methodological choice in selecting controls is a good way to obtain a reference group representative of the population which has generated our patients with cirrhosis. In fact, our controls showed prevalence figures similar to those reported from community-based Italian surveys, in terms of both mean daily alcohol intake (20), and HBV (21, 22) and HCV (21, 23) infections. The prevalence of asymptomatic liver cirrhosis was 0.8% in a communitybased Italian survey (21). Assuming the same prevalence in our control group, we expected 5 of our 651 controls to have asymptomatic liver cirrhosis. This, of course, would not affect our results at all. With all these precautions, however, we cannot exclude unpredictable sources of bias in selecting our controls. The choice to include as cases only symptomatic patients and to exclude patients with cirrhosis without liver decompensation, with evidence of associated hepatocellular carcinoma (HCC), with primary biliary
cirrhosis (PBC) and with invalidating encephalopathy could be criticised. We have previously reported that the development of cirrhosis in the symptomatic phase likely depends on a high alcohol intake (8,24). This leads to the selection of cases with a higher consumption than the whole cirrhotic population and, consequently, to an overestimation of the relative and of the attributable risk associated with alcohol intake. It must be noted that not all asymptomatic patients with cirrhosis receive medical attention for cirrhosis during their lifetimes (25), so that relying on hospitalised patients with compensated cirrhosis would introduce various unpredictable selection biases (serological evidence of viral markers during occasional investigations, careful monitoring of health, and other medical problems). In contrast, it is rare for a symptomatic patient to escape medical observation and hospitalisation, whatever the aetiology of the cirrhosis. The exclusion of patients with evidence of hepatocellular carcinoma (HCC) could also have selected our cases for a higher alcohol intake, as suggested by our previous report on the negative association between alcohol and the risk of developing HCC in patients with cirrhosis (26). In Italy, liver cirrhosis is the major risk factor for the development of HCC (26), and the longer the survival of patients with cirrhosis, the higher is the probability of the onset of HCC (26). Therefore, the inclusion of HCC patients in the sample of cases would imply selection of patients for variables influencing survival, like gender, age, and aetiology of the disease (27). However, we cannot exclude that HCC may be present in some of the included cases. The exclusion of patients with primary biliary cirrhosis was justified by its known pathogenesis independent of the investigated risk factors. Finally, patients with invalidating encephalopathy were excluded due to the impossibility of collecting data on their alcohol intake. In the present paper we have estimated that almost 15% of cases of symptomatic liver cirrhosis in Italy could not be attributed to alcohol and to HCV and HBV infections. This unexplained proportion of the SLC cases is higher in women (33%). Apart from a greater measurement error, it is therefore conceivable that some other factors could be involved in the occurrence of the disease, particularly in women. The above-mentioned considerations explain why the data in the literature regarding the aetiologic attribution of liver cirrhosis are scarce and questionable, in spite of its relevance. Our results partially cover the required information, since they provide data only on the fraction of clinically evident disease. Methodolog-
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ical and ethical considerations make it impossible to perform prospective studies on the natural history of liver cirrhosis, since liver biopsy cannot be performed in the absence of clinical indications and advice to stop alcohol intake should be given to subjects at risk of progressive liver damage. Our results were obtained in the Italian epidemiological setting. We need to know the attributable risks for SLC in other countries with different prevalences of viral infections and different patterns of alcohol consumption. At present, in particular, we have only partial information on the worldwide prevalence of HCV (28). In conclusion, this study suggests that alcohol intake is the main cause of symptomatic liver cirrhosis in Italy. From a public health viewpoint, with the elimination of a few well-known risk factors (particularly alcohol and HCV), liver cirrhosis should become a rare disease. We believe that these findings may help to direct clinical attention towards the alcoholic aetiology of liver cirrhosis, in planning public health interventions, and in exploring unknown risk factors of the disease.
References 1. Halliday ML, Coates RA, Rankin JG. Changing trends of cirrhosis mortality in Ontario, Canada, 1911–1986. Int J Epidemiol 1991; 20: 199–208. 2. World Health Organisation, Global Estimates for Health Situation. Assessment and Project – 1990. Division of Epidemiology, Surveillance and Health Situation and Trend Assessment. Geneva, Switzerland: WHO; 1990. 3. Rode´s J, Salaspuro M, Sørensen TIA. Alcohol and liver disease. In: Health Issues Related to Alcohol Consumption. Verschuren PM, editor. Washington CD, USA: International Life Sciences Institute Press; 1992. p. 167–220. 4. Di Bisceglie AM, Goodman ZD, Ishak KG, Hoofnagle JH, Melpolder JJ, Alter HJ. Long-term clinical and histopathological follow-up of chronic post-transfusion hepatitis. Hepatology 1991; 14: 969–74. 5. Delladetsima JK, Rassidakis G, Tassopoulos NC, Papatheodoridis GV, Smymoff T, et al. Histopathology of chronic hepatitis C in relation to epidemiological factors. J Hepatol 1996; 24: 27–32. 6. Elsen GM, Sandler RS, Wurzelmann JI, Ransohoff DF, Talal A. Evaluating risk: a primer for gastroenterologists. Am J Gastroenterol 1995; 90: 704–7. 7. Corrao G, Busellu GP, Valenti M, Valenti M. Torchio P, Galatola G. Reproducibility of measuring lifetime alcohol consumption by a simple interview administered questionnaire. Alcologia 1994; 6: 127–35. 8. Arico` S, Galatola G, Tabone M, Corrao G, Torchio P, Valenti M. The measure of lifetime alcohol consumption in cirrhotic patients: reproducibility and clinical relevance. Liver 1995; 15: 202–8. 9. Van Der Poel, Reesing HW, Schaasberg W. Infectivity of blood seropositive for hepatitis C virus antibodies. Lancet 1990; 335: 558–60. 10. Arico` S, Galatola G, Tabone M, Corrao G. Amount and duration of alcohol intake in patients with chronic liver dis-
614
11. 12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22. 23.
24.
25.
26.
27.
28.
ease. An Italian Multicentric Study. Ital J Gastroenterol 1994; 26: 59–65. McCullagh RJ, Nelder JA. Generalized Linear Models. Cambridge: Chapman and Hall University Press; 1988. Bruzzi P, Green SB, Byar DP, Brinton LA, Schairer C. Estimating the population attributable risk for multiple risk factors using case-control data. Am J Epidemiol 1985; 122: 904–14. Mezzetti M, Ferraroni M, Decarli A, La Vecchia C, Benichou J. Software for attributable risk and confidence interval estimation in case-control studies. Computers and Biomedical Research 1996; 29: 63–75. Coughlin SS, Benichou J, Weed DL. Attributable risk estimation in case-control studies. Epidemiol Rev 1994; 16: 51– 64. De Bac C, Stroffolini T, Gaeta GB, Taliani G, Giusti G. Pathogenic factors in cirrhosis with and without hepatocellular carcinoma: a multicenter Italian study. Hepatology 1994; 20: 1225–30. Corrao G, Arico` S, Zambon A, Torchio P, di Orio F. Female sex and the risk of liver cirrhosis. Scand J Gastroenterol 1997; 32: 1174–80. D’Amico G, Morabito A, Pagliaro L, Marubini E. Survival and prognostic indicators in compensated and decompensated cirrhosis. Dig Dis Sci 1986; 31: 468–75. Orrego H, Blendis LM, Blake JE. Unreliability of assessment of alcohol intake based on personal interviews in a liver clinic. Lancet 1979; ii: 1354–6. Pol S, Thiers V, Nalpas B, Degos F, Gazengel C, Carnot F. Monoclonal anti-HBs antibodies radioimmunoassay and serum HBV-DNA hybridization as diagnostic tools of HBV infection: relative prevalence among HBsAg-negative alcoholics, patients with chronic hepatitis or hepatocellular carcinomas and blood donors. Eur J Clin Invest 1987; 17: 515–21. National Institute of Nutrition. Nutrition in Italy. Aspects, Problems, Proposals. Rome: International Conference on Nutrition, F.A.O./W.H.O., December 1992. 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: 1442–9. Stroffolini T, Pasquini P, Mele A. HBsAg carriers among pregnant women in Italy. Public Health 1988; 102: 329–33. Stroffolini T, Menchinelli M, Taliani G. High prevalence of hepatitis C virus infection in a small central Italian town: lack of evidence of parenteral exposure. Ital J Gastroenterol 1995; 27: 235–8. Corrao G, Arico` S, Carle F, Russo R, Galatola G, Tabone M. A case-control study on alcohol consumption and the risk of chronic liver disease. Rev Epidemiol Sante 1991; 39: 333–43. Tiribelli C, Croce LS, Polo S, Sodde M, Stanta G. Incidence of hepatocellular carcinoma in Italy: what could we learn from autoptic studies? Ital J Gastroenterol 1991; 23: 448–51. Arico` S, Corrao G, Torchio P, Galatola G, Tabone M, Valenti M. A strong negative association between alcohol consumption and the risk of hepatocellular carcinoma in cirrhotic patients: a case-control study. Eur J Epidemiol 1994; 10: 251–7. Stroffolini T, Chiaramonte M, Tiribelli C, Villa E, Simonetti RG, Rapicetta M, et al. Hepatitis C virus infection, HBsAg carrier state and hepatocellular carcinoma: relative risk and population attributable risk from a case-control study in Italy. J Hepatol 1992; 16: 360–3. Richard V. Epidemiologie des he´patites C dans le monde. Med Trop 1996; 56: 393–9.
Copyright C European Association for the Study of the Liver 1998
Journal of Hepatology ISSN 0168-8278
Attributable risk for symptomatic liver cirrhosis in Italy Giovanni Corrao1, Antonella Zambon1, Pierfederico Torchio1, Sarino Arico`2, Carlo La Vecchia3, Ferdinando di Orio4 and Collaborative Groups for the Study of Liver Diseases in Italy5 1 Institute of Statistical and Mathematical Sciences, Chair of Medical Statistics and Epidemiology, University of Milan; 2Division of Gastroenterology, Hospital Mauriziano Umberto I, Turin; 3Institute of Biometrics and Medical Statistics, Chair of Epidemiology, University of Milan, Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’, Milan; and 4Department of Internal Medicine and Public Health, University of L’Aquila, Italy
Backgrounds/Aims: Knowledge of the proportion of liver cirrhosis attributable to the main risk factors is largely based on methodologically questionable clinical reports. Methods: The proportion of newly diagnosed cases of symptomatic liver cirrhosis attributable to known risk factors was estimated by a case-control study performed during 1989–1996 in 23 medical divisions of several hospitals distributed throughout Italy. Cases were 462 inpatients with cirrhosis admitted for the first time for liver decompensation. Controls were 651 patients admitted during the same period and to the same hospitals as the cases, for acute diseases unrelated to alcohol and virus infection. The proportion of symptomatic liver cirrhosis cases due to alcohol intake and hepatitis B and C viruses and the combination of these was expressed as the population attributable risk.
Received 9 June; revised 24 September; accepted 29 October 1997
Correspondence: Giovanni Corrao, Dipartimento di Scienze Statistiche, Universita` degli Studi di Milano, Viale Scarza, 202, 20126 Milan, Italy. Tel: 39 2 6487054. Fax: 39 2 6473312. 5
Results: Attributable risks were 67.9% (95% confidence interval (CI): 53.8–79.4) for alcohol, 40.1% (95% CI: 35.3–45.2) for hepatitis C virus and 4.4% (95% CI: 2.5–7.6) for hepatitis B virus. The three factors together explained 98.1% (95% CI: 81.6–99.6) of cases in men and 67.0% (95% CI: 50.4–85.8) in women. Conclusions: Alcohol is the risk factor with the highest impact on symptomatic liver cirrhosis risk in Italy. From a public health viewpoint, with the elimination of the well-known risk factors (particularly alcohol and hepatitis C virus), liver cirrhosis should become a rare disease.
Key words: Alcohol intake; Attributable risk; Hepatitis B virus; Hepatitis C virus; Liver cirrhosis.
countries, symptomatic cirrhosis of the liver is a serious public health problem, representing one of the ten leading causes of death (1), with almost 150 000 deaths every year (2). There is a general consensus on the role of alcohol intake and of chronic hepatitis B and C virus (HBV
I
Collaborative Groups for the Study of Liver Cirrhosis in Italy: Collaborative GESIA (Epidemiologic Group of the Italian Society of Alcohology) Group for the Italian Study on Liver Cirrhosis Determinants (SIDECIR Project): Morelli D, Moscatello MR, Stefanini GF (Bologna); Chiesa R, Donato F, Tomasoni V (Brescia); Guglielmini V, Manghisi OG, Petruzzi J, (Castellana Grotte); Monica M, Sardi GF (Lanzo Torinese); Ajello A, Freni MA, Spadaro A (Messina); Gravina M, Longo G, Mangano C (Messina); Ascione A, De Luca M, Galeota Lanza A (Napoli); Del Vecchio Blanco G, Fedezico A, Loguercio C (Napoli); Burra P, Mioni D, Naccarato R (Padova); Guarnone F, Pallavicini C, Vittadini G (Pavia); Arico` S (Torino). Collaborative Group for the Study of Chronic Liver Disease in the Province of L’Aquila: Del Bove Orlandi G, Marchionni F, Rabitti G (Avezzano); Caracciolo P, Cincis M, Giovannone M (Castel di Sangro), Attili A, Caione F, Ercole C, Festuccia V, Giandomenico G, Giusti A, Grimaldi A, Iannessi A, Lepore AR, Mariani M, Miccoli C, Necozione S, Pantaleo G, Pozone M, Rapone C, Tonietti G, Tullio G (L’Aquila), Biocca A, Colitti L (Pescina), Cercone S, Sgro` G, (Sulmona), Bernardini E, Bruccoleri F, Capobianchi P, Santini S, Zepponi E (Tagliacozzo). Collaborative AISF (Italian Association for the Study of Liver) Group for the Study of Alcohol and Liver Disease: Cerrato C, Cerrato G, Tringali M (Aosta); Bruno A, De Vita A, Iaquinto G (Avellino); Scifo G, Risicato R (Avola); Altomare E, Vendemiale G (Bari); Addolorato G, Gasbarrini G, Stefanini GF (Bologna); Leandro G, Manghisi OG, Petruzzi J, Plantone F (Castellana Grotte); Belmonte A, Manno G, Mollica A, Sabatino A (Cosenza); Ajello A, Ferrau` MA, Freni MA, Spadaro A (Messina); Longo G, Raimondo G, Rodino` G, Russo F (Messina); Coltorti M, Del Vecchio Blanco C, Loguercio C (Napoli); Budillon G, Cuomo R, Nardone G (Napoli); Ascione A, De Luca M, Di Costanzo GG (Napoli); Ambrosone (Napoli); Burra P, Naccarato R, Salvagnini M (Padova); Giudici Cipriani A, Marenco G, Ponassi I (Pietra Ligure); Disalvo D (Potenza); Beltrami M, Fornaciari G, Plancher AC (Reggio Emilia); Arico` S, Galatola G, Tabone M (Torino); Brezza E, D’Alessandro A, Rizzo A (Vicenza)
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and HCV) infections in liver cirrhosis (3–5). This implies that the risk of onset of the disease for an individual exposed to each of these factors is much greater than for an unexposed individual. However, the high individual risk in exposed subjects is not informative on the proportion of the disease due to the exposure in a given population, since the impact of a factor in causing disease is also a function of the prevalence of exposure in that population (6). There is therefore a need for data on the proportion of liver cirrhosis attributable to the major risk factors in various countries, in order to plan public health intervention programs. Unfortunately, our knowledge is largely based on the clinically-based etiological attribution of each individual patient. Although symptomatic liver cirrhosis represents only one of the potential points of observation of the natural history of the disease, this condition is the main object of medical research. We have therefore used data from three Italian casecontrol studies to estimate the proportion of symptomatic liver cirrhosis attributable to these factors in Italy.
Subjects and Methods Selection of cases and controls We used data from three case-control studies performed with the same design in several Italian areas. Cases were patients admitted for symptomatic liver cirrhosis (SLC) – signs of liver decompensation (ascites, jaundice, oedema) or bleeding from ruptured oesophageal varices – in whom the diagnosis of cirrhosis was made for the first time. Diagnoses were based on clinical criteria. A percutaneous liver biopsy was obtained when clinically requested. Exclusion criteria were invalidating hepatic encephalopathy, coexisting hepatocellular carcinoma, a final diagnosis of primary biliary cirrhosis and acute causes of liver damage. Patients resident outside the areas covered by the collaborative centres were also excluded. The 462 cases included: (i) 115 patients admitted to the medical departments of the six district hospitals of the Province of L’Aquila (Central Italy: first study) during the period November 1989 to May 1990; (ii) 170 patients admitted to the gastroenterology unit of a district hospital of Turin (Northern Italy: second study) during the period February to November 1993; (iii) 177 patients admitted to the medical departments of 16 hospitals distributed throughout the country (ongoing Italian Study on the Determinants of Liver Cirrhosis, SIDECIR project: third study) from May 1994 to June 1996. Controls were patients resident in the study areas and admitted during the same periods as the cases to the same hospitals for acute conditions. Exclusion cri-
teria were: actual admission to orthopaedic, infectious disease, psychiatry, gynaecology and obstetric departments; and gastroenterological, metabolic, neoplastic and cardiovascular diseases. No matching procedure was used in selecting controls, but they were randomly selected from the eligible patients. Thus, we enrolled 651 controls (167, 250 and 234 in the first, second and third study, respectively) admitted for minor surgical operations (47.9%), acute urinary tract diseases (22.1%), and non-traumatic dental/ocular or ear-nosethroat diseases (30.0%). Data collection Cases and controls were interviewed a few days after admission by trained interviewers, who were blinded with respect to the aim of the study. The interview was a part of the patients’ medical history routinely recorded by the hospitals involved in the study. Thus, no specific patient consent was required by the local ethical authority and the participation rate was 100%. A structured questionnaire was used to collect social, demographic and life-style information, including alcohol consumption. Alcohol consumption was assessed retrospectively, dividing the patient’s life into 10-year periods and recorded as the average amount of ethanol consumed daily; the different alcohol concentrations in the five types of beverages were investigated separately (12% for wine, 5% for beer, 18% for aperitifs, 30% for digestive alcoholic drinks and 40% for spirits). The ages when alcohol consumption began and ended were also recorded. The average life-time daily alcohol intake (LDAI) during the period of consumption was calculated as the weighted mean of alcohol intake between periods. LDAI was grouped into four categories (0: lifetime abstainers; drinkers less than 50 g/day; drinkers from 50 to 100g/day drinkers more than 100 g/day) in order to obtain a sufficient number of patients for the analysis. The reproducibility of the questionnaire, estimated by interviewing the relatives of a sample of patients, was satisfactory, without appreciable differences between cases and controls series and between genders (7,8). Sera from all patients were obtained a few days after admission and subsequently analysed to detect hepatitis B virus surface antigen (HBsAg) and anti-HCV antibodies. Serum HBsAg was detected by a commercial immunoenzymatic assay. Anti-HCV antibodies were measured using a second-generation enzymelinked immunosorbent assay (Abbott Laboratories, Chicago, Illinois, USA). Anti-HCV-positive sera were retested using a second-generation recombinant immunoblot assay (RIBA; Chiron Corporation, Emeryville,
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California, USA). Both the ELISA and RIBA assays were considered: results were considered positive when two HCV antigens were detected, indeterminate if antibodies to only one HCV antigen were present. ELISA positive, but RIBA indeterminate, sera were also considered positive taking account of the lower sensitivity of the RIBA assay (9). Exploring representativeness of the case sample To verify whether our case group can be considered representative of Italian SLC patients for the risk factors investigated, the distribution of LDAI categories and the prevalence of serum HBsAg positivity observed in our cases were compared with those reported in a multicentre study carried out between 1990 and 1992, where a sample of 1258 incident SLC cases recruited by 17 medical centres homogeneously distributed throughout Italy was interviewed (10). Expected numbers of HBsAg positive patients and of drinkers in each LDAI category were calculated on the basis of the proportions reported in each gender and age category of the Italian SLC sample (indirectly standardised for gender and age). Data analysis The SLC risk associated with the factors considered was estimated, using several logistic regression models, and expressed as odds ratio (OR) and corresponding 95% confidence interval (CI). Models included as covariates the HBsAg status, the anti-HCV status and the LDAI categories. Since no matching procedure was used in the selection of controls, all estimates were adjusted for age, gender, education and study variable (first, second or third study). For all models we estimated the parameters by maximising the unconditional likelihood function (11).
The SLC risks attributable to alcohol intake, to the presence of serological signs of HBV or HCV chronic infections and to each combination of these three factors were estimated by the model-based method described by Bruzzi et al. (12). In brief, provided that the cases can be assumed to be representative of the diseased population in terms of exposure distribution, and that the ORs are unbiased, the method estimates the population attributable risk (AR) and of the corresponding 95% CI from case-control studies, taking into account exposure factors with multiple levels and allowing for confounders (13). Under the logistic model, the overall AR for two or more factors combined is not the sum of the adjusted ARs for each factor. Moreover, the sum of the adjusted ARs for each factor may exceed 100% (14).
Results Table 1 shows the general characteristics of the three series of cases and controls. The proportion of men was higher in cases than in controls. Mean age ranged from 54 years (controls of the third study) to 61 years (controls of the first study). The proportion of patients with higher education was higher in cases than in controls in all series. The prevalence of lifetime teetotallers was higher in controls than in cases in all three series. The mean lifetime daily alcohol intake and the prevalence of positivity for HBsAg and anti-HCV were significantly higher in cases than in controls in all three series. Controls in the three studies did not significantly differ for mean lifetime daily alcohol intake (one-way analysis of the variance: FΩ2.49, pΩ0.08) and for prevalences of anti-HCV positive (c2Ω3.33, pΩ0.19), HBsAg positive (c2Ω5.40, pΩ0.07) and lifetime teetotallers (c2Ω3.01, pΩ0.22).
TABLE 1 Distribution of 462 cases of symptomatic liver cirrhosis and 651 controls according to selected characteristics. Italy, 1989–1996
Gender: men Age (years) Education (years) Æ5 6–8 Ø9 LDAI4 Lifetime teetotallers Anti-HCV positive HBsAg positive 1 2 3 4
First study1
Second study
2
Third study3
Cases (nΩ115) Controls (nΩ167)
Cases (nΩ170) Controls (nΩ250)
Cases (nΩ177) Controls (nΩ234)
n (%) means∫sd
80 (69.6) 58.0∫15.9
92 (55.1) 60.5∫15.5
119 (70.0) 58.9∫12.8
142 (56.8) 60.1∫15.2
101 (57.1) 55.6∫15.0
121 (51.7) 53.7∫14.2
n (%) n (%) n (%) means∫sd n (%) n (%) n (%)
24 (20.9) 56 (48.7) 35 (30.4) 95.4∫108.7 9 (7.8) 37 (32.2) 14 (12.2)
35 (21.0) 100 (59.9) 32 (19.2) 50.3∫69.3 25 (15.0) 8 (4.8) 1 (0.6)
37 (21.8) 81 (47.6) 52 (30.6) 102.6∫114.2 10 (5.9) 74 (43.5) 22 (12.9)
56 (22.4) 152 (60.8) 42 (16.8) 52.3∫69.4 46 (18.4) 13 (5.2) 1 (0.4)
42 (23.7) 85 48.0) 50 (28.2) 87.4∫99.5 11 (6.2) 97 (54.8) 24 (13.6)
49 (20.9) 135 (57.7) 50 (21.4) 39.1∫53.8 51 (21.8) 5 (2.1) 6 (2.6)
Study conducted in L’Aquila (Central Italy) during the years 1989–1990. Study conducted in Turin (Northern Italy) during the year 1993. Ongoing multicentric study (SIDECIR Project); data were collected during the years 1994–1996. Lifetime daily alcohol intake.
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Alcohol, viruses and liver cirrhosis TABLE 2 Comparison between observed and expected number of drinkers and of HBsAg positive patients in the pooled case series
1
2
LDAI categories(g)
0 ∞50 ∞100 Ø100
HBsAg
positive
Observed1
Expected1
SPR (95% CI)2
30 152 97 183
28.2 145.5 92.4 195.9
1.1 1.0 1.1 0.9
60
65.45
(0.7–1.5) (0.9–1.2) (0.9–1.3) (0.8–1.1)
0.9 (0.7–1.2)
The observed distribution of the 462 cases in the lifetime daily alcohol intake (LDAI) categories, and in the category of HBsAg positivity were compared with those expected on the basis of the proportions of drinkers and of HBsAg positivity, in each gender and age class of the sample of Italian liver cirrhosis patients (17). Standardised Prevalence Ratio (SPR) (observed/expected ratio) and its 95% confidence interval(CI). *p∞0.05.
TABLE 3 Distribution of 462 cases of symptomatic liver cirrhosis and 651 controls according to lifetime daily alcohol intake (LDAI), anti-HCV and HBsAg status and corresponding odds ratio (OR). Italy, 1989–1996 Cases
1
Controls
OR1
95% CI1
n
(%)
n
(%)
LDAI categories (g) 0 ∞50 ∞100 Ø100
30 152 97 183
(6.5) (32.9) (21.0) (39.6)
122 409 70 50
(18.7) (62.8) (10.8) (7.7)
1.0 2.0* 9.0* 31.2*
reference 1.2–3.5 4.6–17.6 15.8–61.6
Anti-HCV status Negative Positive
254 208
(55.0) (45.0)
625 26
(96.0) (4.0)
1.0 20.7*
reference 13.0–33.2
HBsAg status Negative Positive
402 60
(87.0) (13.0)
643 8
(98.8) (1.2)
1.0 8.6*
reference 3.9–18.9
Odds ratio estimated by multiple logistic regression including terms for gender, age, education and study variable (first, second or third study); 95% confidence interval. * p∞0.05.
TABLE 4 Risk of symptomatic liver cirrhosis attributable to alcohol, HCV and HBV and their combination. Italy, 1989–1996 Men AR Alcohol HCV HBV AlcoholπHCV AlcoholπHBV HCVπHBV AlcoholπHCVπHBV 1
1
85.9 40.6 8.2 97.6 87.9 47.8 98.1
Women 95% CI
1
67.7–94.7 34.7–46.8 3.6–10.7 81.6–99.6 67.7–94.7 41.7–54.1 81.6–99.6
AR
1
46.8 39.6 2.5 65.4 48.1 40.5 67.0
Menπwomen 95% CI
1
25.6–69.4 31.4–48.4 0.0–53.0 44.7–81.6 30.3–73.2 32.1–49.6 50.4–85.8
AR1
95% CI1
67.9 40.1 4.4 82.3 70.7 44.3 85.5
53.8–79.4 35.3–45.2 2.5–7.6 70.7–90.0 56.8–81.6 40.3–50.5 74.4–92.3
Population attributable risk (AR) was expressed as fraction of 100 and estimated from a multiple logistic regression model, including terms for gender, age, education and study variable and the main effects of the three factors considered, and assuming a multiplicative effect; 95% confidence interval (CI).
The observed and expected distribution of alcohol consumption and HBsAg positivity are reported in Table 2. The distribution of our pooled cases group in the LDAI categories, as well as the prevalence of serum HBsAg positivity, did not significantly differ from those found in the sample of the Italian SLC patients. Table 3 shows the ORs for alcohol intake, anti-HCV
and HBsAg status and the risk of SLC. A dose-response relationship between LDAI and risk of cirrhosis was observed. The risk of SLC associated with both anti-HCV and HBsAg positivity was significant. The estimated attributable risks for the three factors are shown in Table 4. All ARs were higher for men than for women. For both genders, the single factor
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with the highest AR was alcohol consumption, which accounted for 86% and 47% of SLC cases in men and in women, respectively. Anti-HCV positivity as a single factor explained about 40% of both male and female cases, whereas HBsAg positivity was less important than the other two factors, accounting only for 4% of SLC cases. The three factors together were responsible for 98% of SLC cases in men and 67% in women. For both genders, the combined action of the three factors explained 86% of the SLC cases.
Discussion The present study confirms and quantifies the well-established association between alcohol intake, chronic HCV and HBV infections and the risk of liver cirrhosis. The new findings of our study suggest that: (i) over two-thirds of SLC in Italy is attributable to alcohol consumption, while a lower proportion of cases is explained by HCV infection (40%) and only 4% by HBV infection; and (ii) over 85% of SLC in Italy is explained by the investigated risk factors, and this proportion reaches 98% in men. It has been suggested that HCV infection is the major determinant of liver cirrhosis in western countries. This suggestion is based on the high proportion of anti-HCV in liver cirrhosis series. In a recent paper, a sample of 1829 Italian patients with cirrhosis with and without associated hepatocellular carcinoma, was classified into pre-established ‘‘aetiologic categories’’; the following prevalences were found: 72% for anti-HCV, 14% for HBsAg and only 9% for alcohol abuse (15). Several criticisms should be made of such an approach. Firstly, the aetiologic attribution to alcohol cannot be referred only to alcohol abuse, since no consensus exists on a threshold of alcohol consumption under which the risk of liver cirrhosis is equal to that of abstainers (3). In the present study, we observed a significant effect of low doses of alcohol (∞50 g/day, which are believed to be clinically innocuous, especially in men. We have recently shown that, although genderrelated differences exist in susceptibility to alcohol-induced liver damage, such low doses of alcohol consumption are a significant risk factor also for men (16). Secondly, investigation of alcohol consumption in the period preceding the current hospital admission leads to an underestimation of the dose responsible for the onset of the disease, since many patients stop or reduce their intake when symptoms appear. Thirdly, since alcohol consumption (17) and persistent viral replication influence the survival of patients with cirrhosis, the distribution of risk factors in prevalent cases might be different from that of patients identified at diagnosis. Fourthly, in the absence of a control group, it is incor-
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rect to attribute all the exposed cases to a risk factor, since not all the exposed subjects develop the disease. Serum HBsAg and anti-HCV are not markers of active viral replication and can be found in healthy subjects. Analogously, not all heavy drinkers progress to symptomatic liver cirrhosis. Finally, we believe that aetiologic diagnosis should not be confused with aetiologic attribution. We can assume that the impact of a risk factor on the occurrence of a disease in a given population is a positive function of two quantities: its relative risk and its prevalence in that population. In our study (Table 3), we estimated that drinking 100 or more g/ day had a higher relative risk than anti-HCV positivity (31 and 21, respectively) and also a higher prevalence (8% and 4%, respectively). Furthermore, the increased relative risks observed for low doses of alcohol consumption, though of smaller entities (ORΩ2 for 50 or less g/day and ORΩ9 for 100 g/day or less), greatly increase the alcohol-attributable fraction of the disease due to the high prevalence of the exposure. These observations lead to results which can be in disagreement with clinical experience. However, it must be noted that it is easier for clinicians to determine viral infections in patients with chronic liver diseases than to measure their alcohol intake, and furthermore, that it is difficult to attribute the observed disease to low doses of consumption. We attempted to estimate the attributable risk with an approach that: (i) considered the lifetime exposure to alcohol in a quantitative form, (ii) determined chronic viral infections on the basis of common serological markers; (iii) used a case-control approach to estimate the attributable risks; (iv) enrolled as controls hospitalised patients with acute conditions; (v) considered only new diagnoses of SLC as entry criteria for our cases. Each of these methodological choices might have biased our estimates. A bias in retrospectively measuring life-time alcohol intake could be determined by variability of the intake throughout the years (18). This is not likely to have occurred in our study, since Italians consume constant daily amounts of alcohol throughout their lives, mainly in the form of wine (10). An alcohol-information differential bias should also have scarcely affected our results, considering the satisfactory reproducibility found between alcohol intake measured from the patients and from interviewing a sample of relatives, with no differences between cases and controls (7,8). Viral factors may also be active in the absence of common serological markers. In fact, in 10% of serum HBsAg negative alcoholics, circulating HBV-DNA was found (19). Underestimation of the risk associated with HBV and HCV cannot therefore be excluded.
Alcohol, viruses and liver cirrhosis
A case-control study aiming to estimate the population-attributable risk should be representative of all the new cases of the disease which occurred in the target population, and the odds ratio should be unbiased. Our investigations were not designed to be populationbased studies. However, we investigated all the consecutive diagnoses made in 23 medical divisions of several reference hospitals distributed throughout Italy. In addition, the distribution of alcohol consumption reported by our cases, as well as the prevalence of HBsAg-positive patients, were similar to those found in another large Italian study (10). Surprisingly, no data are available on the prevalence of HCV infection in newly diagnosed liver cirrhosis. The use of hospital controls has been criticised on the assumption that they might be selected from the underlying population. We tried to minimise this possible bias by selecting control patients with acute diseases, excluding those with diseases positively or negatively associated with the investigated factors, and using a wide range of diagnostic categories as sources of our controls. It is conceivable that recruiting other groups of patients, like those admitted to orthopaedic, psychiatric or infectious diseases wards, would lead to higher prevalences of alcohol intake and/or HCV infection. However, the goal in selecting the control group is not to find those who have been exposed, but to obtain data on the distribution of the study factors in the general population. On the other hand, selecting a sample of the general population would lead to other sources of bias, such as: reduced reliability of alcohol intake questionnaires, as shown by our previous experience (7); a higher frequency of non-responding; and difficulties in blood collection for HBsAg and antiHCV testing. Thus, we think that our methodological choice in selecting controls is a good way to obtain a reference group representative of the population which has generated our patients with cirrhosis. In fact, our controls showed prevalence figures similar to those reported from community-based Italian surveys, in terms of both mean daily alcohol intake (20), and HBV (21, 22) and HCV (21, 23) infections. The prevalence of asymptomatic liver cirrhosis was 0.8% in a communitybased Italian survey (21). Assuming the same prevalence in our control group, we expected 5 of our 651 controls to have asymptomatic liver cirrhosis. This, of course, would not affect our results at all. With all these precautions, however, we cannot exclude unpredictable sources of bias in selecting our controls. The choice to include as cases only symptomatic patients and to exclude patients with cirrhosis without liver decompensation, with evidence of associated hepatocellular carcinoma (HCC), with primary biliary
cirrhosis (PBC) and with invalidating encephalopathy could be criticised. We have previously reported that the development of cirrhosis in the symptomatic phase likely depends on a high alcohol intake (8,24). This leads to the selection of cases with a higher consumption than the whole cirrhotic population and, consequently, to an overestimation of the relative and of the attributable risk associated with alcohol intake. It must be noted that not all asymptomatic patients with cirrhosis receive medical attention for cirrhosis during their lifetimes (25), so that relying on hospitalised patients with compensated cirrhosis would introduce various unpredictable selection biases (serological evidence of viral markers during occasional investigations, careful monitoring of health, and other medical problems). In contrast, it is rare for a symptomatic patient to escape medical observation and hospitalisation, whatever the aetiology of the cirrhosis. The exclusion of patients with evidence of hepatocellular carcinoma (HCC) could also have selected our cases for a higher alcohol intake, as suggested by our previous report on the negative association between alcohol and the risk of developing HCC in patients with cirrhosis (26). In Italy, liver cirrhosis is the major risk factor for the development of HCC (26), and the longer the survival of patients with cirrhosis, the higher is the probability of the onset of HCC (26). Therefore, the inclusion of HCC patients in the sample of cases would imply selection of patients for variables influencing survival, like gender, age, and aetiology of the disease (27). However, we cannot exclude that HCC may be present in some of the included cases. The exclusion of patients with primary biliary cirrhosis was justified by its known pathogenesis independent of the investigated risk factors. Finally, patients with invalidating encephalopathy were excluded due to the impossibility of collecting data on their alcohol intake. In the present paper we have estimated that almost 15% of cases of symptomatic liver cirrhosis in Italy could not be attributed to alcohol and to HCV and HBV infections. This unexplained proportion of the SLC cases is higher in women (33%). Apart from a greater measurement error, it is therefore conceivable that some other factors could be involved in the occurrence of the disease, particularly in women. The above-mentioned considerations explain why the data in the literature regarding the aetiologic attribution of liver cirrhosis are scarce and questionable, in spite of its relevance. Our results partially cover the required information, since they provide data only on the fraction of clinically evident disease. Methodolog-
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ical and ethical considerations make it impossible to perform prospective studies on the natural history of liver cirrhosis, since liver biopsy cannot be performed in the absence of clinical indications and advice to stop alcohol intake should be given to subjects at risk of progressive liver damage. Our results were obtained in the Italian epidemiological setting. We need to know the attributable risks for SLC in other countries with different prevalences of viral infections and different patterns of alcohol consumption. At present, in particular, we have only partial information on the worldwide prevalence of HCV (28). In conclusion, this study suggests that alcohol intake is the main cause of symptomatic liver cirrhosis in Italy. From a public health viewpoint, with the elimination of a few well-known risk factors (particularly alcohol and HCV), liver cirrhosis should become a rare disease. We believe that these findings may help to direct clinical attention towards the alcoholic aetiology of liver cirrhosis, in planning public health interventions, and in exploring unknown risk factors of the disease.
References 1. Halliday ML, Coates RA, Rankin JG. Changing trends of cirrhosis mortality in Ontario, Canada, 1911–1986. Int J Epidemiol 1991; 20: 199–208. 2. World Health Organisation, Global Estimates for Health Situation. Assessment and Project – 1990. Division of Epidemiology, Surveillance and Health Situation and Trend Assessment. Geneva, Switzerland: WHO; 1990. 3. Rode´s J, Salaspuro M, Sørensen TIA. Alcohol and liver disease. In: Health Issues Related to Alcohol Consumption. Verschuren PM, editor. Washington CD, USA: International Life Sciences Institute Press; 1992. p. 167–220. 4. Di Bisceglie AM, Goodman ZD, Ishak KG, Hoofnagle JH, Melpolder JJ, Alter HJ. Long-term clinical and histopathological follow-up of chronic post-transfusion hepatitis. Hepatology 1991; 14: 969–74. 5. Delladetsima JK, Rassidakis G, Tassopoulos NC, Papatheodoridis GV, Smymoff T, et al. Histopathology of chronic hepatitis C in relation to epidemiological factors. J Hepatol 1996; 24: 27–32. 6. Elsen GM, Sandler RS, Wurzelmann JI, Ransohoff DF, Talal A. Evaluating risk: a primer for gastroenterologists. Am J Gastroenterol 1995; 90: 704–7. 7. Corrao G, Busellu GP, Valenti M, Valenti M. Torchio P, Galatola G. Reproducibility of measuring lifetime alcohol consumption by a simple interview administered questionnaire. Alcologia 1994; 6: 127–35. 8. Arico` S, Galatola G, Tabone M, Corrao G, Torchio P, Valenti M. The measure of lifetime alcohol consumption in cirrhotic patients: reproducibility and clinical relevance. Liver 1995; 15: 202–8. 9. Van Der Poel, Reesing HW, Schaasberg W. Infectivity of blood seropositive for hepatitis C virus antibodies. Lancet 1990; 335: 558–60. 10. Arico` S, Galatola G, Tabone M, Corrao G. Amount and duration of alcohol intake in patients with chronic liver dis-
614
11. 12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22. 23.
24.
25.
26.
27.
28.
ease. An Italian Multicentric Study. Ital J Gastroenterol 1994; 26: 59–65. McCullagh RJ, Nelder JA. Generalized Linear Models. Cambridge: Chapman and Hall University Press; 1988. Bruzzi P, Green SB, Byar DP, Brinton LA, Schairer C. Estimating the population attributable risk for multiple risk factors using case-control data. Am J Epidemiol 1985; 122: 904–14. Mezzetti M, Ferraroni M, Decarli A, La Vecchia C, Benichou J. Software for attributable risk and confidence interval estimation in case-control studies. Computers and Biomedical Research 1996; 29: 63–75. Coughlin SS, Benichou J, Weed DL. Attributable risk estimation in case-control studies. Epidemiol Rev 1994; 16: 51– 64. De Bac C, Stroffolini T, Gaeta GB, Taliani G, Giusti G. Pathogenic factors in cirrhosis with and without hepatocellular carcinoma: a multicenter Italian study. Hepatology 1994; 20: 1225–30. Corrao G, Arico` S, Zambon A, Torchio P, di Orio F. Female sex and the risk of liver cirrhosis. Scand J Gastroenterol 1997; 32: 1174–80. D’Amico G, Morabito A, Pagliaro L, Marubini E. Survival and prognostic indicators in compensated and decompensated cirrhosis. Dig Dis Sci 1986; 31: 468–75. Orrego H, Blendis LM, Blake JE. Unreliability of assessment of alcohol intake based on personal interviews in a liver clinic. Lancet 1979; ii: 1354–6. Pol S, Thiers V, Nalpas B, Degos F, Gazengel C, Carnot F. Monoclonal anti-HBs antibodies radioimmunoassay and serum HBV-DNA hybridization as diagnostic tools of HBV infection: relative prevalence among HBsAg-negative alcoholics, patients with chronic hepatitis or hepatocellular carcinomas and blood donors. Eur J Clin Invest 1987; 17: 515–21. National Institute of Nutrition. Nutrition in Italy. Aspects, Problems, Proposals. Rome: International Conference on Nutrition, F.A.O./W.H.O., December 1992. 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: 1442–9. Stroffolini T, Pasquini P, Mele A. HBsAg carriers among pregnant women in Italy. Public Health 1988; 102: 329–33. Stroffolini T, Menchinelli M, Taliani G. High prevalence of hepatitis C virus infection in a small central Italian town: lack of evidence of parenteral exposure. Ital J Gastroenterol 1995; 27: 235–8. Corrao G, Arico` S, Carle F, Russo R, Galatola G, Tabone M. A case-control study on alcohol consumption and the risk of chronic liver disease. Rev Epidemiol Sante 1991; 39: 333–43. Tiribelli C, Croce LS, Polo S, Sodde M, Stanta G. Incidence of hepatocellular carcinoma in Italy: what could we learn from autoptic studies? Ital J Gastroenterol 1991; 23: 448–51. Arico` S, Corrao G, Torchio P, Galatola G, Tabone M, Valenti M. A strong negative association between alcohol consumption and the risk of hepatocellular carcinoma in cirrhotic patients: a case-control study. Eur J Epidemiol 1994; 10: 251–7. Stroffolini T, Chiaramonte M, Tiribelli C, Villa E, Simonetti RG, Rapicetta M, et al. Hepatitis C virus infection, HBsAg carrier state and hepatocellular carcinoma: relative risk and population attributable risk from a case-control study in Italy. J Hepatol 1992; 16: 360–3. Richard V. Epidemiologie des he´patites C dans le monde. Med Trop 1996; 56: 393–9.