Jürgen Rehm, Benjamin Taylor, Satya Mohapatra, Hyacinth Irving, Dolly Baliunas, Jayadeep Patra, Michael Roerecke
Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis.
Drug Alcohol Rev. 2010 Jul;29(4):437-45. doi: 10.1111/j.1465-3362.2009.00153.x.
Abstract/Text
INTRODUCTION AND AIMS: Alcohol is an established risk factor for liver cirrhosis. It remains unclear, however, whether this relationship follows a continuous dose-response pattern or has a threshold. Also, the influences of sex and end-point (i.e. mortality vs. morbidity) on the association are not known. To address these questions and to provide a quantitative assessment of the association between alcohol intake and risk of liver cirrhosis, we conducted a systematic review and meta-analysis of cohort and case-control studies.
DESIGN AND METHODS: Studies were identified by a literature search of Ovid MEDLINE, EMBASE, Web of Science, CINAHL, PsychINFO, ETOH and Google Scholar from January 1980 to January 2008 and by searching the references of retrieved articles. Studies were included if quantifiable information on risk and related confidence intervals with respect to at least three different levels of average alcohol intake were reported. Both categorical and continuous meta-analytic techniques were used to model the dose-response relationship.
RESULTS: Seventeen studies met the inclusion criteria. We found some indications for threshold effects. Alcohol consumption had a significantly larger impact on mortality of liver cirrhosis compared with morbidity. Also, the same amount of average consumption was related to a higher risk of liver cirrhosis in women than in men.
DISCUSSION AND CONCLUSIONS: Overall, end-point was an important source of heterogeneity among study results. This result has important implications not only for studies in which the burden of disease attributable to alcohol consumption is estimated, but also for prevention.
U Becker, A Deis, T I Sørensen, M Grønbaek, K Borch-Johnsen, C F Müller, P Schnohr, G Jensen
Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective population study.
Hepatology. 1996 May;23(5):1025-9. doi: 10.1002/hep.510230513.
Abstract/Text
The association between self-reported alcohol intake and the risk of future liver disease was studied in a large population-based prospective cohort with 12-year follow-up. Alcohol intake was assessed in 13,285 men and women aged 30 to 79 years by a self-administered questionnaire. Diagnoses indicating alcohol-induced liver disease (n = 261) or alcohol-induced cirrhosis (n = 124) were obtained from death certificates and the hospital discharge register, and data were analyzed by multiplicative Poisson regression models. The total cumulated observation time was 130,558 person-years. The overall incidence rates of alcohol-induced cirrhosis were 0.2% per year in men and 0.03% per year in women. The nadir of the estimated relative risk of developing liver disease was observed at an alcohol intake of 1 to 6 beverages per week, and above this level a steep increase in relative risk was observed. The risk function was independent of age and stable over time. The level of alcohol intake above which the relative risk was significantly greater than 1 was observed at 7 to 13 beverages per week for women and 14 to 27 beverages per week for men. Women had a significantly higher relative risk of developing alcohol-related liver disease than men for any given level of alcohol intake. We observed a dose-dependent increase in relative risk of developing alcohol-induced liver disease for both men and women, with the steepest increase among women. In the general population, self-reported current alcohol intake is a good predictor of the future risk of alcohol-induced liver disease.
J B Saunders, M Davis, R Williams
Do women develop alcoholic liver disease more readily than men?
Br Med J (Clin Res Ed). 1981 Apr 4;282(6270):1140-3.
Abstract/Text
The sudden increase in alcoholic liver disease among women in the past 10 years has caused much speculation that they may be more susceptible to the hepatotoxic effects of alcohol than men. Women tend to present with more severe liver disease, particularly alcoholic hepatitis, and do so after a shorter period of excessive drinking and at a lower daily alcohol intake. Differences in body size and composition are partly responsible for the greater susceptibility of women, but differences in immune reactivity between the sexes may also play a part. Greater emphasis must be placed on designing abstinence programmes specifically for female patients, on earlier detection of liver disease, and on educating women about hazardous drinking levels.
G L Bird
Investigation of alcoholic liver disease.
Baillieres Clin Gastroenterol. 1993 Sep;7(3):663-82.
Abstract/Text
In heavy drinkers with clinical evidence of liver disease, routine investigations should exclude the possibility of other chronic liver diseases of non-alcoholic aetiology requiring specific therapy--these include chronic viral hepatitis, autoimmune diseases of the liver, Wilson's disease and genetic haemochromatosis. If abnormalities in liver biochemistry persist despite abstinence, or if the diagnosis of alcoholic liver disease is in doubt, a liver biopsy should be carried out. Studies evaluating the role of liver biopsy in alcoholic liver disease suggest that without histological confirmation the diagnosis will be inaccurate in 10-20% of patients. Serum biochemistry and the currently available imaging modalities have severe limitations in determining the relative contributions of fatty liver, alcoholic hepatitis and cirrhosis to the overall picture in alcoholic liver disease. Histological examination is therefore of additional value in determining the prognosis, which is worst in patients with a combination of alcoholic hepatitis and cirrhosis. There are a number of indices available, based on clinical and laboratory information, for evaluating the short-term prognosis, but these can only be used with accuracy if the histological pattern of damage has initially been evaluated.
D R Harris, R Gonin, H J Alter, E C Wright, Z J Buskell, F B Hollinger, L B Seeff, National Heart, Lung, and Blood Institute Study Group
The relationship of acute transfusion-associated hepatitis to the development of cirrhosis in the presence of alcohol abuse.
Ann Intern Med. 2001 Jan 16;134(2):120-4.
Abstract/Text
BACKGROUND: Although concomitant alcoholism is widely believed to enhance liver disease progression in persons with hepatitis C virus (HCV) infection, this relationship has not been well quantified.
OBJECTIVE: To quantify the relationship of transfusion-associated HCV infection and history of heavy alcohol abuse to development of cirrhosis.
DESIGN: Retrospective cohort study.
SETTING: Liver clinics in university and government hospitals.
PATIENTS: Extended follow-up of 1030 patients in prospective investigations of transfusion-associated viral hepatitis conducted in the United States between 1968 and 1980.
MEASUREMENTS: Development of cirrhosis and history of heavy alcohol abuse were determined from review of interviews with patients or their proxies, medical records, death certificates, and autopsy and biopsy reports. Logistic regression was used to estimate the risk for cirrhosis associated with transfusion-associated HCV infection and history of heavy alcohol abuse.
RESULTS: The absolute risk for cirrhosis was 17% among patients with transfusion-associated HCV; 3.2% among patients with transfusion-associated non-A, non-B, non-C hepatitis; and 2.8% among controls. Patients with transfusion-associated HCV were more likely than controls to develop cirrhosis (odds ratio, 7.8 [95% CI, 4.0 to 15.1]). A history of heavy alcohol abuse was associated with a fourfold increased risk for cirrhosis. Hepatitis C virus infection plus a history of heavy alcohol abuse led to a substantial increase in risk for cirrhosis (odds ratio, 31.1 [CI, 11.4 to 84.5]) compared with controls without such a history.
CONCLUSIONS: Heavy alcohol abuse greatly exacerbates the risk for cirrhosis among patients with HCV infection. This finding emphasizes the need to counsel such patients about their drinking habits.
E H Forrest, C D J Evans, S Stewart, M Phillips, Y H Oo, N C McAvoy, N C Fisher, S Singhal, A Brind, G Haydon, J O'Grady, C P Day, P C Hayes, L S Murray, A J Morris
Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score.
Gut. 2005 Aug;54(8):1174-9. doi: 10.1136/gut.2004.050781.
Abstract/Text
INTRODUCTION: Alcoholic hepatitis is associated with a high short term mortality. We aimed to identify those factors associated with mortality and define a simple score which would predict outcome in our population.
METHODS: We identified 241 patients with alcoholic hepatitis. Clinical and laboratory data were recorded on the day of admission (day 1) and on days 6-9. Stepwise logistic regression was used to identify variables related to outcome at 28 days and 84 days after admission. These variables were included in the Glasgow alcoholic hepatitis score (GAHS) and its ability to predict outcome assessed. The GAHS was validated in a separate dataset of 195 patients.
RESULTS: The GAHS was derived from five variables independently associated with outcome: age (p = 0.001) and, from day 1 results, serum bilirubin (p<0.001), blood urea (p = 0.019) and, from day 6-9 results, serum bilirubin (p<0.001), prothrombin time (p = 0.002), and peripheral blood white blood cell count (p = 0.001). The GAHS on day 1 had an overall accuracy of 81% when predicting 28 day outcome. In contrast, the modified discriminant function had an overall accuracy of 49%. Similar results were found using information at 6-9 days and when predicting 84 day outcome. The accuracy of the GAHS was confirmed by the validation study of 195 patients The GAHS was equally accurate irrespective of the use of the international normalised ratio or prothrombin time ratio, or if the diagnosis of alcoholic hepatitis was biopsy proven or on the basis of clinical assessment.
CONCLUSIONS: Using variables associated with mortality we have derived and validated an accurate scoring system to assess outcome in alcoholic hepatitis. This score was able to identify patients at greatest risk of death throughout their admission.
M R Teli, C P Day, A D Burt, M K Bennett, O F James
Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver.
Lancet. 1995 Oct 14;346(8981):987-90.
Abstract/Text
"Pure" alcoholic fatty liver has been widely assumed to be "benign" with very low risk of progression to cirrhosis. Studies thus far have included either patients with coexisting recognised precursor lesions of cirrhosis or have been restricted to short-term histological follow-up. We have followed 88 patients, first seen between 1978 and 1985, with a histological diagnosis of pure alcoholic fatty liver and no evidence of fibrosis or alcoholic hepatitis, for a median of 10.5 years, to determine any factors predictive of disease progression. Of the 88, at follow-up nine had developed cirrhosis and a further seven fibrosis. Eight of nine patients with cirrhosis had continuing alcohol consumption of more than 40 units per week at follow-up; in the other patients, consumption was unknown. Independent histological predictors of progression on index biopsy were: presence of mixed macro/microvesicular fat, and presence of giant mitochondria. We can no longer regard alcoholic fatty liver as benign. In the presence of continuing high alcohol consumption the above histological features identified those at high risk (47-61%) of disease progression. Therefore, patients with these features should be counselled intensively regarding their alcohol consumption.
S A Borowsky, S Strome, E Lott
Continued heavy drinking and survival in alcoholic cirrhotics.
Gastroenterology. 1981 Jun;80(6):1405-9.
Abstract/Text
Survival of 64 male chronic alcoholic cirrhotics with first-onset ascites discharged from a gastrointestinal convalescent service was examined over a 32-mo period of study. Of 54 patients discharged as improved, 23 (43%) remained abstinent for a mean time of 14.0 mo and 15 (28%) resumed heavy drinking (greater than 2 g/kg/day). Twelve of 15 heavy drinkers died in a mean time of 7.2 mo, while all but one abstainer were alive. Differences in survival were statistically significantly different (p less than 0.001) when examined by the life-table method. Survival of 16 "moderate or binge" drinkers was not significantly different from abstainers. However, the number of rehospitalizations for liver disease was increased in this group. The study indicates that continued heavy drinking is associated with poor survival of alcoholic cirrhotics.
F Pessione, M J Ramond, L Peters, B N Pham, P Batel, B Rueff, D C Valla
Five-year survival predictive factors in patients with excessive alcohol intake and cirrhosis. Effect of alcoholic hepatitis, smoking and abstinence.
Liver Int. 2003 Feb;23(1):45-53.
Abstract/Text
AIM: To evaluate 5-year survival predictive factors in hospitalised patients with excessive alcohol intake and cirrhosis, including in a multivariate analysis the severity of the liver disease, gastrointestinal bleeding, concomitant viral B or C infection, smoking status, presence of alcoholic hepatitis at inclusion and abstinence from alcohol during follow-up.
METHODS: In a non-concurrent cohort study, 122 patients with excessive alcohol intake and cirrhosis were followed up at least five years or till death. Two patients were lost to follow-up.
RESULTS: The 5-year survival rates were 43% in the 122 patients and 66%, 50% and 25% in Child-Pugh class A, B and C patients, respectively. In multivariate analysis, age (P = 0.01), Child-Pugh score (P = 0.0001), gastrointestinal bleeding (P = 0.01), presence of HBs Ag and/or anti-HCV (P = 0.03), smoking (P = 0.01), absence of histologically proven alcoholic hepatitis (P = 0.05) and persistent alcohol intake (P = 0.002) were associated with significantly increased risk ratios of death.
CONCLUSIONS: In hospitalised patients with excessive alcohol intake and cirrhosis: (1) age, liver failure, gastrointestinal bleeding, concomitant viral B or C infection and persistent alcohol intake are independent poor prognostic markers, (2) smoking may contribute to the aggravation of cirrhosis, and (3) alcoholic hepatitis, being a potentially reversible cause of liver failure, has a favourable prognostic significance.
A Chedid, C L Mendenhall, P Gartside, S W French, T Chen, L Rabin
Prognostic factors in alcoholic liver disease. VA Cooperative Study Group.
Am J Gastroenterol. 1991 Feb;86(2):210-6.
Abstract/Text
Two hundred eighty-one alcoholic patients were prospectively evaluated by clinical, biochemical, and histologic parameters during a 4-yr period to assess their prognosis. They were stratified into four categories of injury: 1) fatty liver (26 patients), 2) acute alcoholic hepatitis (106), 3) cirrhosis (39), and 4) cirrhosis with superimposed alcoholic hepatitis (111). The rate of survival and variables correlating with survival varied according to the group. At 48 months, 70% of the patients with fatty liver were alive, 58% in the alcoholic hepatitis group, 49% in cirrhosis, and 35% in alcoholic hepatitis superimposed upon cirrhosis. Within group one, deaths were due to causes unrelated to liver disease. In the alcoholic hepatitis group, factors significantly correlating with survival were ascites, alanine amino-transferase levels, grams of alcohol consumed, continuation of alcohol intake, and clinical severity of disease. Survival in patients of group three correlated significantly with prothrombin time and histologic severity score. Patients with combined cirrhosis and alcoholic hepatitis exhibited the worst prognosis, with the most significant predictors of survival being age, grams of alcohol consumed, the ratio of serum aminotransferases (AST:ALT) and the histologic and clinical severity of the disease. Although a different pattern of correlates was observed for each pathologic level of injury, knowledge of the various correlates aids in prognostic assessment.
J T Galambos
Natural history of alcoholic hepatitis. 3. Histological changes.
Gastroenterology. 1972 Dec;63(6):1026-35.
Abstract/Text
Yoshinori Horie, Yoshiyuki Yamagishi, Hirotoshi Ebinuma, Toshifumi Hibi
Therapeutic strategies for severe alcoholic hepatitis.
Clin Res Hepatol Gastroenterol. 2011 Nov;35(11):738-44. doi: 10.1016/j.clinre.2011.07.005. Epub 2011 Aug 15.
Abstract/Text
BACKGROUND AND AIMS: Severe alcoholic hepatitis (SAH) is an inflammatory response with multiple morbidity factors like leucocytosis, hepatomegaly, renal failure, hepatic encephalopathy, endotoxemia, and has a high mortality rate. Accordingly, identifying therapeutic interventions that can support prognosis is the goal of research.
METHODS: Questionnaires were sent to 1234 medical institutions asking for information on patients with SAH during 2004 to 2008 including patients' demography, disease profile and the therapeutic interventions patients had received during hospitalization.
RESULTS: Twenty-nine hospitals had treated SAH patients, and provided full demographic data on 62 patients. Twenty-seven patients had received no treatment, 10 patients had received granulocytes/monocytes apheresis (GMA) to deplete elevated myeloid linage leucocytes, the rest had received one or more of the following treatments, corticosteroids, plasma exchange (PE) and haemodialysis (HD). Further, 23 patients had died and 39 had survived within 100 days of hospitalization. Serum creatinine (Cr) was higher in patients who had died vs patients who had survived (P=0.026). Likewise, patients with white blood cells (WBC) ≥ 10(4)/μL had higher mortality rate vs patients with WBC<10(4)/μL (P=0.039). GMA in patients with WBC ≥ 10(4)/μL showed 100% prognosis vs patients with WBC ≥ 10(4)/μL who did not receive GMA (P=0.0007). Corticosteroids, PE and HD did not significantly impact prognosis of SAH patients.
CONCLUSIONS: Our perception is that, patients with elevated myeloid leucocytes benefit most from GMA, while PE appears to support patients with coagulation deficiency or high plasma bilirubin and HD has indication in patients with high Cr.
Copyright © 2011 Elsevier Masson SAS. All rights reserved.
A Rambaldi, H H Saconato, E Christensen, K Thorlund, J Wetterslev, C Gluud
Systematic review: glucocorticosteroids for alcoholic hepatitis--a Cochrane Hepato-Biliary Group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials.
Aliment Pharmacol Ther. 2008 Jun;27(12):1167-78. doi: 10.1111/j.1365-2036.2008.03685.x. Epub 2008 Mar 20.
Abstract/Text
BACKGROUND: Glucocorticosteroids versus placebo or no intervention for patients with alcoholic hepatitis have been evaluated for more than 35 years. However, the results of randomized trials and meta-analyses differ substantially.
AIM: To review all randomized clinical trials of glucocorticosteroids vs. placebo or no intervention for patients with alcoholic hepatitis.
METHODS: We searched for randomized trials published before July 2007. The trials were assessed for risk of bias.
RESULTS: We included 15 trials with a total of 721 randomized patients. The overall mortality rate was 39.5%. Twelve of the fifteen trials were at risk of bias. Glucocorticosteroids did not statistically reduce mortality compared with placebo or no intervention (relative risk 0.83, 95% CI 0.63-1.11). Glucocorticosteroids significantly reduced mortality in the subgroup of trials with patients with Maddrey's score of at least 32 or hepatic encephalopathy and with low-bias risk. In all analyses, heterogeneity was significant and substantial. Trial sequential analyses using heterogeneity-adjusted information size demonstrated no significant effect of glucocorticosteroids on mortality. Weighted logistic regression analyses taking prognostic factors at randomization into consideration found no significant effect of glucocorticosteroids on mortality.
CONCLUSIONS: The current evidence base of mainly heterogeneous with high bias risk trials does not support the use of glucocorticosteroids in alcoholic hepatitis. Large, low-bias risk placebo-controlled randomized trials are needed.
F Stickel, B Hoehn, D Schuppan, H K Seitz
Review article: Nutritional therapy in alcoholic liver disease.
Aliment Pharmacol Ther. 2003 Aug 15;18(4):357-73.
Abstract/Text
Chronic alcohol consumption may lead to primary and secondary malnutrition. In particular, protein energy malnutrition not only aggravates alcoholic liver disease but also correlates with impaired liver function and increased mortality. Therefore, in these patients, adequate nutritional support should be implemented in order to improve their prognosis. Clinical trials addressing this issue have shown that nutritional therapy either enterally or parenterally improves various aspects of malnutrition, and there is increasing evidence that it may also improve survival. Therefore, malnourished alcoholics should be administered a diet rich in carbohydrate- and protein-derived calories preferentially via the oral or enteral route. Micronutrient deficiencies typically encountered in alcoholics, such as for thiamine and folate, require specific supplementation. Patients with hepatic encephalopathy may be treated with branched-chain amino acids in order to achieve a positive nitrogen balance. Fatty liver represents the early stage of alcoholic liver disease, which is usually reversible with abstinence. Metadoxine appears to improve fatty liver but confirmatory studies are necessary. S-adenosyl-L-methionine may be helpful for patients with severe alcoholic liver damage, since various mechanisms of alcohol-related hepatotoxicity are counteracted with this essential methyl group donor, while a recent large trial showed that the use of polyenylphosphatidylcholine is of limited efficacy.
E Cabré, P Rodríguez-Iglesias, J Caballería, J C Quer, J L Sánchez-Lombraña, A Parés, M Papo, R Planas, M A Gassull
Short- and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial.
Hepatology. 2000 Jul;32(1):36-42. doi: 10.1053/jhep.2000.8627.
Abstract/Text
Steroids are recommended in severe alcohol-induced hepatitis, but some data suggest that artificial nutrition could also be effective. We conducted a randomized trial comparing the short- and long-term effects of total enteral nutrition or steroids in these patients. A total of 71 patients (80% cirrhotic) were randomized to receive 40 mg/d prednisolone (n = 36) or enteral tube feeding (2,000 kcal/d) for 28 days (n = 35), and were followed for 1 year or until death. Side effects of treatment occurred in 5 patients on steroids and 10 on enteral nutrition (not significant). Eight enterally fed patients were prematurely withdrawn from the trial. Mortality during treatment was similar in both groups (9 of 36 vs. 11 of 35, intention-to-treat) but occurred earlier with enteral feeding (median 7 vs. 23 days; P =.025). Mortality during follow-up was higher with steroids (10 of 27 vs. 2 of 24 intention-to-treat; P =. 04). Seven steroid patients died within the first 1.5 months of follow-up. In contrast to total enteral nutrition (TEN), infections accounted for 9 of 10 follow-up deaths in the steroid group. In conclusion, enteral feeding does not seem to be worse than steroids in the short-term treatment of severe alcohol-induced hepatitis, although death occurs earlier with enteral nutrition. However, steroid therapy is associated with a higher mortality rate in the immediate weeks after treatment, mainly because of infections. A possible synergistic effect of both treatments should be investigated.
M Plauth, E Cabré, O Riggio, M Assis-Camilo, M Pirlich, J Kondrup, DGEM (German Society for Nutritional Medicine), P Ferenci, E Holm, S Vom Dahl, M J Müller, W Nolte, ESPEN (European Society for Parenteral and Enteral Nutrition)
ESPEN Guidelines on Enteral Nutrition: Liver disease.
Clin Nutr. 2006 Apr;25(2):285-94. doi: 10.1016/j.clnu.2006.01.018. Epub 2006 May 16.
Abstract/Text
Enteral nutrition (EN) by means of oral nutritional supplements (ONS) and tube feeding (TF) offers the possibility to increase or to insure nutrient intake in case of insufficient oral food intake. The present guideline is intended to give evidence-based recommendations for the use of ONS and TF in patients with liver disease (LD). It was developed by an interdisciplinary expert group in accordance with officially accepted standards and is based on all relevant publications since 1985. The guideline was discussed and accepted in a consensus conference. EN by means of ONS is recommended for patients with chronic LD in whom undernutrition is very common. ONS improve nutritional status and survival in severely malnourished patients with alcoholic hepatitis. In patients with cirrhosis, TF improves nutritional status and liver function, reduces the rate of complications and prolongs survival. TF commenced early after liver transplantation can reduce complication rate and cost and is preferable to parenteral nutrition. In acute liver failure TF is feasible and used in the majority of patients.
G R Swart, M C Zillikens, J K van Vuure, J W van den Berg
Effect of a late evening meal on nitrogen balance in patients with cirrhosis of the liver.
BMJ. 1989 Nov 11;299(6709):1202-3.
Abstract/Text
OBJECTIVE: To assess whether a late evening meal would improve nitrogen balance in patients with cirrhosis of the liver.
DESIGN: Randomised crossover study of meal schedules comparing three meals a day with four or six meals a day, the four and six meal schedules both including a late evening meal (2300).
SETTING: Metabolic ward.
PATIENTS: Seven men and two women aged 34-66 with cirrhosis of the liver (Child's grade B).
INTERVENTIONS: Patients spent two seven day periods in the ward. For five days of each period they received, in random order, isonitrogenous isocaloric diets supplied in three meals a day and in four or six meals a day.
MAIN OUTCOME MEASURE: Nitrogen balance, calculated as the difference between dietary intake and the total of urinary, faecal, and integumental nitrogen loss.
RESULTS: Faecal nitrogen loss was no different between three meals a day and four or six meals a day. On both four and six meals a day, however, patients had nitrogen balances that were more positive (or less negative) than on three meals a day (1.26 (SD 2.1) g/24 h v 0.26 (2.2) g/24 h, p less than 0.01). Six meals a day did not produce significantly better improvements in nitrogen balance than four meals a day.
CONCLUSIONS: A late evening meal seemed to improve the efficiency of nitrogen metabolism, but longer term studies are needed to assess whether this leads to a better nutritional state.
