OBJECTIVE: Evaluation of the interaction between alcohol intake and cofactors [hepatitis B virus (HBV), hepatitis C virus (HCV), body mass index] and coffee consumption on the risk of cirrhosis.
DESIGN: Seven hundred and forty-nine consecutive patients with chronic liver disease referring to units for liver or alcohol diseases in Italy during a 6-months period. Teetotalers were excluded. The odds ratios (OR) for cirrhosis were evaluated using chronic hepatitis cases as the control group.
RESULTS: An alcohol intake of more than 3 units/day resulted associated with the likelihood of cirrhosis both in males (OR 4.3; 95% CI=2.5-7.3) and in females (OR 5.7; 95% CI=2.3-14.5). A multiplicative interaction on the risk of cirrhosis between risky alcohol intake and HBsAg or HCV-Ab/HCV-RNA positivity was observed. A reduction of cirrhosis risk was observed in subjects consuming more than 3 alcohol units/day with increasing coffee intake. The OR for the association with cirrhosis decreased from 2.3 (95% CI=1.2-4.4) in subjects drinking 0-2 cups of coffee/day to 1.4 (95% CI=0.6-3.6) in those drinking more than 2 cups/day.
CONCLUSIONS: In subjects with an alcohol intake >3 units/day the coexistence of HBV or HCV multiplies the risk of cirrhosis. Coffee represents a modulator of alcoholic cirrhosis risk

Addolorato, G

ALMASIO, Pier Luigi

Bellentani, S

Bernardi, M

Cotticelli, G

Del Vecchio Blanco, C

Loguercio, C.

Medda, E

Niosi, M

Petrelli, E

Picardi, A

Salerno, MT

Stroffolini, T

Surace, LA

Archivio istituzionale della ricerca - Università di Palermo

CL IN ICAL STUDIESInteraction ofalcohol intake and cofactors on the riskof cirrhosisTommaso Stroffolini1, Gaetano Cotticelli2, Emanuela Medda3, Marco Niosi2, Camillo Del Vecchio-Blanco2,Giovanni Addolorato4, Enzo Petrelli4, Maria T. Salerno4, Antonio Picardi4, Mauro Bernardi4,Piero Almasio4, Stefano Bellentani4, Lorenzo A. Surace4 and Carmela Loguercio21 Department of Infectious and Tropical Diseases, Policlinico Umberto I, Rome, Italy2 Division of Gastroenterology and Hepatology, Department of Clinical and Experimental Internal Medicine ‘F. Magrassi & A. Lanzara- InteruniversityCentre on Foods, Nutrition and Gastrointestinal Tract (CIRANAD) Second University of Naples, Naples, Italy3 National Institute of Health, Rome, Italy4 AISF-SIA National Group:Vonghia L (Rome), Volpe M (Pesaro), Lomazzo D (Bari), D’Avola D (Rome), Caputo F (Bologna), Cottone C (Palermo),Scaglioni F (Modena), Pontoriero L (Lamezia Terme)Keywordsalcohol – cirrhosis – coffeeCorrespondenceC. Loguercio, Department of Clinical andExperimental Medicine ‘F. Magrassi & A.Lanzara’, Interuniversity Centre for Foods,Nutrition and Gastrointestinal Tract (CIRANAD),Second University of Naples, via Pansini 5,Building 3, 80100 Naples, ItalyTel: 1390815666708Fax: 1390815666837e-mail: gaetano.cotticelli@unina2.itReceived 19 January 2010Accepted 29 March 2010DOI:10.1111/j.1478-3231.2010.02261.xAbstractObjective: Evaluation of the interaction between alcohol intake and cofactors[hepatitis B virus (HBV), hepatitis C virus (HCV), body mass index] andcoffee consumption on the risk of cirrhosis. Design: Seven hundred and forty-nine consecutive patients with chronic liver disease referring to units for liveror alcohol diseases in Italy during a 6-months period. Teetotalers wereexcluded. The odds ratios (OR) for cirrhosis were evaluated using chronichepatitis cases as the control group. Results: An alcohol intake of more than3 units/day resulted associated with the likelihood of cirrhosis both in males(OR 4.3; 95% CI = 2.5–7.3) and in females (OR 5.7; 95% CI = 2.3–14.5).A multiplicative interaction on the risk of cirrhosis between risky alcoholintake and HBsAg or HCV-Ab/HCV-RNA positivity was observed. A reduc-tion of cirrhosis risk was observed in subjects consuming more than 3 alcoholunits/day with increasing coffee intake. The OR for the association withcirrhosis decreased from 2.3 (95% CI = 1.2–4.4) in subjects drinking 0–2 cupsof coffee/day to 1.4 (95% CI = 0.6–3.6) in those drinking more than 2 cups/day. Conclusions: In subjects with an alcohol intake 43 units/day the coex-istence of HBV or HCV multiplies the risk of cirrhosis. Coffee represents amodulator of alcoholic cirrhosis risk.It is well known that ethanol is a major risk factor forchronic liver disease. It has been shown repeatedly that inthe general Italian population, the amount of alcoholintake that causes liver damage is 43 units/day (1–3).Moreover, ethanol may be an important cofactor for theprogression of chronic liver damage when it is presenttogether with other causative agents. It has been shownthat hepatitis C virus (HCV) chronic infection interactsmultiplicatively with alcohol intake in determining cir-rhosis (4), while the role of hepatitis B virus (HBV)chronic infection is still being debated (5). In the pastyears, the role of obesity as an important cofactor ofcirrhosis in alcoholics has also been stressed (6) Finally, ithas also been shown that an inverse relation existsbetween coffee intake and the risk of cirrhosis, and thatcoffee has a favourable effect on alcohol-related cirrhosisrisk (7–9). However, all the reported studies have eval-uated the interaction of alcohol with a single cofactor[i.e. HCV or body mass index (BMI) or coffee], whereasstudies assessing the role of various cofactors in the samecohort of alcoholic patients are lacking. Moreover, theinteraction, if any, between HBsAg and alcohol is stillunclear.The aim of this paper was to evaluate in the samesetting of patients the interaction between alcohol intakeand various cofactors such as chronic HCV infection,chronic HVB infection and BMI on the risk of cirrhosis.The effect of coffee consumption on the risk of alcoholiccirrhosis has also been assessed.Patients and methodsDuring a 6-month period (January–June 2007), all con-secutive patients with chronic liver disease referring to a 9units of internal medicine and/or gastroenterology forthe management of their pathology were recruited. Theseunits were distributed homogeneously across Italy. Tee-totalers were excluded. For each patient, demographical,clinical and aetiological data were recorded using aprecoded questionnaire. The amount of alcohol intakewas determined using a standard questionnaire contain-ing information on the daily alcohol intake of variousLiver International (2010)c 2010 John Wiley & Sons A/S 867Liver International ISSN 1478-3223alcoholic beverages, according to previously codifiedmethods by us and other groups (10, 11). One alcoholicunit corresponds to a glass of wine, a can of beer or ameasure of spirits, and contains 12–13 g of ethanol. Foralcohol intake, we also considered the type of beverageused more frequently, the duration of use and themodalities of ingestion (at fasting, during meals, etc.).We also collected the amount of lifetime coffee consump-tion (at least during the last 10 years), using as the unit ofmeasure the number of cups of ‘espresso’ coffee per day.The use of other types of coffee was absent in our cases.Demographical data also included the evaluation ofcomorbidities such as diabetes, hypertension, dyslipidae-mia or others. Patients who consumed drugs for thenervous system (or other well-known hepatotoxic drugs)were excluded from the study owing to their possibleinterference with liver damage.Hepatitis B surface antigen and antibodies to HCV(anti-HCV) were determined using enzyme-linked im-munosorbent assays. HCV-RNA was assessed by poly-merase chain reaction. Chronic hepatitis was diagnosedon the basis of liver histology or in the presence ofpersistently (46 months) abnormal ALT without clinical,biochemical and ultrasound markers of cirrhosis. Cir-rhosis was diagnosed by liver biopsy or in the presence ofclinical, biochemical and ultrasound signs (12).Statistical analysisThe odds ratio (OR) of cirrhosis and their 95% con-fidence intervals were evaluated using chronic hepatitiscases as the control group . Interaction may be additiveor multiplicative. Additive interaction means that theobserved joint effect of two factors on the diseaseincidence (in this case cirrhosis) exceeds the sum of theeffect of exposure to each single factor minus 1. Multi-plicative interaction means that the observed joint effectof two factors on the disease incidence exceeds theproduct of the effect of exposure to each single factor.To evaluate the interaction between alcohol intake andcofactors, subjects unexposed to either factor were takenas the reference category for all calculations.We dichotomized alcohol intake as 1–3 units/day (lowor moderate drinkers) and 43 units/day (heavy drin-kers), according to the threshold of 3 units of alcoholconsidered necessary for the development of alcohol-mediated injury (13).ResultsA total of 749 cases were enrolled during the studyperiod. A preponderance (66.3%) of males was observed.The majority of subjects (63.4%) reported low or mod-erate alcohol intake (1–3 units/day); nearly a quarteradmitted a very heavy alcohol intake (45 units/day).The proportion of subjects who were HBsAg positivewas 8.1%, while 53.0% of the subjects were anti-HCVandHCV-RNA positive. Chronic hepatitis was diagnosed in81.8% of cases (Table 1). An alcohol intake of 43 units/day resulted associated with the likelihood of cirrhosis inboth males (OR = 4.3; 95% CI = 2.5–7.3) and females(OR = 5.7; 95% CI = 2.3–14.5).The amount of 3 units/day resulted unassociated inboth sexes (Table 2).A multiplicative interaction between alcohol intakeand HBV- or HCV-related disease is observed. In fact,excluding subjects who were HCV/HCV-RNA positive,the OR of cirrhosis for joint exposure to 43 alcoholunits/day and HBsAg positivity was 4.8 (95% CI = 1.9–12.4), while the OR for exposure to only 43 alcoholunits/day was 2.4 (95% CI = 1.3–4.2) and the OR forexposure to only HBsAg positivity was 0.2 (95%Table 1. Characteristics of 749 enrolled patientsCharacteristics %SexMales 66.3Females 33.7Age distribution (years)o45 37.046–65 39.5465 23.5BMIo25 42.4425 57.6Number of drinks/day1–3 63.44 7.65 3.66–10 13.4410 12.0HBsAg1 8.1HCVAb1/HCV-RNA1 53.0Chronic hepatitis 81.8Cirrhosis 18.2BMI, body mass index; HCV, hepatitis C virus.Table 2. Progression from chronic hepatitis to cirrhosis according to amount of alcohol intake stratified by sexNumber of drinks/dayMales (n= 510) Females (n= 259)Chronic hepatitis Cirrhosis OR (95% CI) Chronic hepatitis Cirrhosis OR (95% CI)1–2 n= 192 n= 23 1 n= 190 n= 14 13 n= 49 n= 7 1.2 (0.5–2.9) n= 17 n= 1 0.8 (0.1–6.5)43 n= 158 n= 81 4.3 (2.5–7.3) n= 26 n= 11 5.7 (2.3–14.5)Crude odds ratios (O.R.) derived by univariate analysis.Liver International (2010)868 c 2010 John Wiley & Sons A/SInteraction of alcohol intake and cofactors Stroffolini et al.CI = 0.1–1.1). Similarly, excluding HBsAg-positive sub-jects, the OR of cirrhosis for joint exposure to 43 alco-hol units/day and HCV/HCV-RNA positivity was 3.2(95% CI = 1.8–5.7), while the OR for exposure to only43 alcohol units/day was 2.4 (95% CI = 1.3–4.2) and theOR for exposure to only HCV/HCV-RNA positivity was0.2 (95% CI = 0.2–0.8). No interaction was found insubjects exposed to the joint effect of obesity and riskyalcohol intake (OR = 2.0; 95% CI = 0.7–5.6) (Table 3).Other aspects such as the type of alcoholic beverage used,the duration of use and the presence of comorbidities didnot significantly influence the results. A reduction incirrhosis risk was observed in subjects consuming 43alcohol units/day with increasing coffee intake. The ORfor the association with cirrhosis decreased from 2.3(95% CI = 1.2–4.4) in subjects drinking 0–2 cups ofcoffee/day to 1.4 (95% CI = 0.6–3.6) in those drinking42 cups/day. (Table 4).DiscussionFirstly, the present findings confirm previous studies(1–3) showing that the amount of alcohol intake thatcauses liver damage is 43 units/day. In order to evaluatethe interaction between alcohol intake and cofactors onthe risk of cirrhosis, we have used an internal control,which is the best control group. Cases (i.e. cirrhoticpatients) and controls (i.e. chronic hepatitis cases) weresubjects extracted from the same population (i.e. subjectswith chronic liver disease) and thus exposed to the samepotential selective factors. In a case–control study com-parability between cases and controls is the crucial factor,which means avoidance of potential selective factorsregarding the enrollment of cases and controls.The present findings confirm previous report that insubjects with risky alcohol intake, the coexistence ofHCV infection multiplies the risk of cirrhosis (4). Severallines of evidence provide the biological plausibility forthis epidemiological finding.Firstly, both HCV and alcohol may stimulate hepatic-oxidative stress, which leads to the activation of liverfibrogenic cells, and the consequent acceleration offibrogenesis (14–16).Secondly, immune response is affected by alcohol;finally, alcohol may promote apoptosis in hepatocytesinfected by HCV (17–19).The observed joint effect in terms of multiplicativeinteraction between alcohol intake and HBV infection onthe risk of cirrhosis is a new finding. However, a clearbiological plausibility for that has not yet been provided.It may be presumed that the mechanisms enhancing liverdamage are similar to those involved in HCV infection(i.e. enhanced oxidative stress, interaction with immuneresponse and activation of pro-inflammatory cytokinepathways).An interesting finding, even though not new is that ofthe protective effect of coffee on alcohol-related cirrhosisrisk. There is a continuum of clinical and epidemiologi-cal evidence to support a favourable effect of coffee onliver function (8) and liver disease, including cirrhosis(20) and hepatocellular carcinoma (21). There is someconcern that the inverse relation observed between coffeeintake and liver disease may be spurious, as a conse-quence of the fact that subjects with liver disease mayreduce their coffee consumption. Hypothetically, somepersons with liver disease might have reduced coffeeintake or quit drinking coffee, thus spuriously increasingthe risk of the referral group. However, as the coffeeconsumption concerned the last 10 years and the controlgroup was represented by subjects with chronic liverdisease (and thus exposed to similar selective factors thancases), this bias has resulted likely avoided. Variouscomponents of coffee have been related to act a protectiveeffect including caffeine (via adenosine receptor antago-nists or antioxidant action), cafertol (via induction of theTable 3. Interaction between alcohol intake and cofactors in theprogression from chronic hepatitis to cirrhosisCofactorChronichepatitis CirrhosisLikelihood ofcirrhosisOR (95% CI)HBsAg and alcohol (excluding HCV1cases)HBsAg/1–3 drinks n= 143 n= 25 1HBsAg1/1–3 drinks n= 37 n= 1 0.2 (0.1–1.1)HBsAg/4 3 drinks n= 87 n= 36 2.4 (1.3–4.2)HBsAg143 drinks n= 13 n= 11 4.8 (1.8–12.4)HCV and alcohol (excluding HBsAg1)HCV/1–3 drinks n= 143 n= 25 1HCV1/1–3 drinks n= 260 n= 20 0.4 (0.2–0.8)HCV/4 3 drinks n= 87 n= 36 2.4 (1.3–4.2)HCV1/43 drinks n= 75 n= 42 3.2 (1.8–5.7)BMI and alcohol (excluding HBsAg1and HCV1)BMIo30/1–3 drinks n= 110 n= 22 1BMIZ30/1–3 drinks n= 32 n= 3 0.5 (0.1–1.7)BMIo30/43 drinks n= 69 n= 27 1.3 (1.0–3.7)BMIZ30/4 3 drinks n= 17 n= 7 2.0 (0.7–5.6)Table 4. The effect of coffee intake on the progression from chronic hepatitis to liver cirrhosis according to the amount of alcohol intake(HBsAg1 and HCV1 subjects were excluded from the analysis)Cups of coffee/day0–2 42Chronic hepatitis Cirrhosis OR (95% CI) Chronic hepatitis Cirrhosis OR (95% CI)Number of alcohol drinks/day1–3 n= 101 n= 21 1 n= 40 n= 3 0.4 (0.1–1.3)43 n= 59 n= 28 2.3 (1.2–4.4) n= 27 n= 8 1.4 (0.6–3.6)Liver International (2010)c 2010 John Wiley & Sons A/S 869Stroffolini et al. Interaction of alcohol intake and cofactorssynthesis of glutathione, a cellular protective factor) andanti-oxidant substances from coffee beans, such as flavo-noids and anthocyanes (22–24). However, no definiteevidence is available for any of these components.In conclusion, even though some findings are not new,this is one of the few papers assessing in the setting ofpatients the role of various cofactors on the progressionof liver disease in alcoholics, and the use of an internalcontrol group may have avoided spurious associations.Results indicate that alcohol intake interacts with hepa-titis viruses in the progression of liver disease and, firstly,the role of HBsAg positivity has been defined. Coffeerepresents a modulator of alcoholic cirrhosis risk. In anycase, even if coffee may be considered to be protective,the primary approach to the reduction of alcoholiccirrhosis includes the avoidance or cessation of heavyalcohol drinking.References1. Pendino GM, Mariano A, Surace P, et al. Prevalence andetiology of altered liver tests: a population-based survey ina Mediterranean town. Hepatology 2005; 41: 1151–9.2. Bellentani S, Saccoccio G, Costa G, et al. 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Interaction of alcohol intake and cofactors on the risk of cirrhosis.

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Interaction of alcohol intake and cofactors on the risk of cirrhosis.

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