The LIVER CARE trial - screening for liver disease in individuals attending treatment for alcohol use disorder: a randomized controlled feasibility trial.

BACKGROUND: Alcohol-related liver disease is a preventable disease with high mortality. If individuals with alcohol-related liver disease were to be diagnosed earlier by screening and they reduced their alcohol consumption, lives lost to alcohol-related liver disease might be saved. A liver stiffness measurement (FibroScan©) is a key tool to screen for alcohol-related liver disease in asymptomatic individuals. No randomized controlled trials have been conducted to test if screening for liver disease reduces alcohol consumption in individuals with alcohol use disorders, in addition to what can be obtained by motivational interventions. We aimed to assess the feasibility of a randomized controlled trial of a screening for liver disease on the prevalence of alcohol abstinence or light consumption after 6 months in individuals attending outpatient treatment for alcohol use disorder. METHODS: We used an interdisciplinary approach to develop the format of the randomized controlled trial. Individuals were recruited from one outpatient treatment facility for alcohol use disorders. Study participants were randomized 1:1 to receive a) a liver stiffness measurement in addition to usual care (intervention) or b) usual care (control). Follow-up on alcohol consumption was assessed by telephone interview after 6 months and corroborated by data from records from public hospitals and the alcohol treatment facility. Feasibility was assessed by probabilities of recruitment, retention, and completion and estimated by the exact binominal test, with success defined as > 50% participation for each endpoint. The study design was evaluated at interdisciplinary meetings with staff and researchers from the outpatient alcohol treatment facility and the hospital clinic. RESULTS: Forty of 57 invited individuals agreed to participate in the study (recruitment = 70% (95% CI: 57-82)); 19 of 20 participants randomized to the intervention showed up for the screening (retention = 95% (95% CI: 75-100)). Follow-up telephone interviews succeeded for 33 of 39 reachable participants (completion = 85% (95% CI: 69-94)). Treatment records indicated that the 6 participants who were lost to follow-up for the telephone interview had not achieved alcohol abstinence or light consumption. There was no evidence that the intervention increased abstinence or light alcohol consumption at follow-up: 45% (95% CI: 23-68) in the intervention group and 65% (95% CI: 41-85) in the control group had a alcohol consumption below 10 standard drinks/week at 6 months. The main obstacle regarding study feasibility was to avoid disappointment in individuals randomized as controls. CONCLUSIONS: This feasibility study developed a study design to test the influence of screening for liver disease on abstinence or light alcohol consumption in individuals attending treatment for alcohol use disorder. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05244720; registered on February 17, 2022.

Population-Based Study of Alcohol-Related Liver Disease in England in 2001-2018: Influence of Socioeconomic Position.

INTRODUCTION: England has seen an increase in deaths due to alcohol-related liver disease (ALD) since 2001. We studied the influence of socioeconomic position on the incidence of ALD and the mortality after ALD diagnosis in England in 2001-2018. METHODS: This was an observational cohort study based on health records contained within the UK Clinical Practice Research Datalink covering primary care, secondary care, cause of death registration, and deprivation of neighborhood areas in 18.8 million residents. We estimated incidence rate and incidence rate ratios of ALD and hazard ratios of mortality. RESULTS: ALD was diagnosed in 57,784 individuals with a median age of 54 years and of whom 43% had cirrhosis. The ALD incidence rate increased by 65% between 2001 and 2018 in England to reach 56.1 per 100,000 person-years in 2018. The ALD incidence was 3-fold higher in those from the most deprived quintile vs those from the least deprived quintile (incidence rate ratio 3.30, 95% confidence interval 3.21-3.38), with reducing inequality at older than at younger ages. For 55- to 74-year-olds, there was a notable increase in the incidence rate between 2001 and 2018, from 96.1 to 158 per 100,000 person-years in the most deprived quintile and from 32.5 to 70.0 in the least deprived quintile. After ALD diagnosis, the mortality risk was higher for patients from the most deprived quintile vs those from the least deprived quintile (hazard ratio 1.22, 95% confidence interval 1.18-1.27), and this ratio did not change during 2001-2018. DISCUSSION: The increasing ALD incidence in England is a greater burden on individuals of low economic position compared with that on those of high socioeconomic position. This finding highlights ALD as a contributor to inequality in health.

Risk of alcohol-associated liver disease in the offspring of parents with alcohol-associated liver disease: A nationwide cohort study.

BACKGROUND AND AIMS: Offspring of patients with alcohol-associated liver disease (ALD) may have a higher risk of ALD. We examined their risk of ALD and survival with ALD. APPROACH AND RESULTS: We used Danish nationwide registries to identify the offspring of patients diagnosed with ALD in 1996-2018 and 20:1 matched comparators from the general population. They were followed for ALD diagnosis through 2018. We used landmark competing risk analysis to estimate the age-specific absolute and relative 10-year risks of ALD. ALD was diagnosed in 385 of 60,707 offspring and 2842 of 1,213,357 comparators during 0.7 and 14.0 million person-years of follow-up, respectively, yielding an incidence rate ratio of 2.73 (95% CI: 2.44-3.03). The risk of being diagnosed with ALD within the next 10 years peaked at age 55 years for offspring and age 57 years for comparators with 10-year risks of 1.66% (95% CI: 1.16-2.30) in offspring and 0.81% (95% CI: 0.68-0.97) in comparators at these ages. Offspring were younger at ALD diagnosis than comparators (median age of 47.4 vs. 48.9 years), yet slightly more of them had developed cirrhosis (60.3% vs. 58.7%). Survival after ALD diagnosis was similar in offspring and comparators, adjusted hazard ratio=1.03 (95% CI: 0.88-1.21), so on average offspring died younger due to their younger age at diagnosis. CONCLUSIONS: Offspring of patients with ALD had a low but increased risk of ALD. Screening offspring for chronic liver disease may be unnecessary, but other interventions to mitigate alcohol-associated harm should be considered.

Cause-specific mortality in patients with alcohol-related liver disease in Denmark: a population-based study.

BACKGROUND: Increased knowledge of the causes of death will be essential to prevent premature death in alcohol-related liver disease. We examined cause-specific mortality, including death due to specific cancers, in the 15 years after diagnosis of alcohol-related liver disease. METHODS: We used nationwide health registries to identify patients (aged ≥18 years) with a first diagnosis of alcohol-related liver disease between Jan 1, 2002, and Dec 31, 2017, in Denmark and followed up patients for their underlying cause of death up to Dec 31, 2019. We estimated the cause-specific mortality and investigated whether the cause-specific mortality differed by sex, age (<50, 50-59, and ≥60 years), alcohol-related liver disease severity at diagnosis (decompensated cirrhosis, compensated cirrhosis, alcoholic hepatitis, and steatosis or unspecified liver disease), and presence of diabetes. FINDINGS: The study included 23 385 patients with incident alcohol-related liver disease. Patients had a median age of 58 years (IQR 51-65), 15 819 (68%) were men and 7566 (32%) were women, and 15 358 (66%) had cirrhosis. During 111 532 person-years of follow-up, 15 692 (67%) patients died. Liver disease was the leading cause of death. In the first 5 years after alcohol-related liver disease diagnosis, liver disease caused almost half of all deaths, and the 5-year risk of death due to liver disease was 25·8% (95% CI 25·3-26·4). Beyond 5 years, causes other than liver disease combined became more common; of these extrahepatic causes, cancer, cardiovascular disease, and alcohol use disorder were the most common. Hepatocellular carcinoma was the dominant cause of cancer death (10-year risk of 2·5%, 95% CI 2·3-2·7), followed by lung cancer (1·9%, 1·7-2·1). The 10-year risk of death due to liver disease (around 30%) was similar for patients in all age groups and independent of sex and diabetes but was three times higher for those with decompensated cirrhosis (46·7%, 44·8-48·4) than steatosis or unspecified liver disease (16·2%, 15·3-17·2). INTERPRETATION: Patients diagnosed with alcohol-related liver disease were at high risk of dying from liver disease many years after diagnosis, irrespective of age and sex. Death due to specific cancers, including hepatocellular carcinoma, each contributed minimally to the total mortality in patients with alcohol-related liver disease. FUNDING: TrygFonden and the Novo Nordisk Foundation.

Influence of vaccination on adverse health outcomes after SARS-CoV-2 infection among individuals with alcohol use disorder: a population-based study.

BACKGROUND AND AIMS: Alcohol use disorders (AUD) have not been included in the priority groups for early vaccine against SARS-CoV-2. We aimed to determine adverse outcomes after SARS-CoV-2 infection among individuals with AUD and how this is modified by vaccination. DESIGN, SETTING AND PARTICIPANTS: This was a registry-based cohort study carried out in Denmark, 27 February 2020 to 15 October 2021, comprising 2157 individuals with AUD and 237 541 without AUD who had had a polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection during the study period. MEASUREMENTS: The association of AUD with the absolute and relative risk of hospitalization, intensive care and 60-day mortality after SARS-CoV-2 infection and of all-cause mortality throughout the follow-up period were measured. Potential interactions with SARS-CoV-2 vaccination, education and sex were explored in stratified analyses and tested by including interaction terms and using likelihood ratio tests. FINDINGS: Individuals with AUD had an increased absolute and relative risk of adverse outcomes, including hospitalization [incidence rate ratio (IRR) = 1.72, 95% confidence interval (CI) = 1.51-1.95], intensive care (IRR = 1.47, 95% CI = 1.07-2.02) and 60-day mortality [mortality rate ratio (MRR) = 2.35, 95% CI = 1.94-2.85] compared with SARS-CoV-2-positive individuals without AUD. Irrespective of AUD, highest risks of these adverse health outcomes were observed for individuals not vaccinated against SARS-CoV-2 infection, for individuals of low educational level and in males. However, for all-cause mortality throughout the follow-up period, SARS-CoV-2 infection showed a lower relative mortality risk increase, whereas being unvaccinated showed a higher relative mortality risk increase, in individuals with AUD than in the reference population without AUD (P of interaction tests < 0.0001). CONCLUSIONS: Both alcohol use disorder and being unvaccinated for SARS-CoV-2 appear to be independent risk factors for adverse health outcomes following SARS-CoV-2 infection.

Social support and risk of mortality in cirrhosis: A cohort study.

Background & Aims: The function and structure of social relationships influence mortality in individuals within the general population. We compared aspects of social relationships in individuals with cirrhosis and a matched comparison cohort and studied their association with health-related quality of life (HRQoL) and mortality in cirrhosis. Methods: Individuals with cirrhosis and comparators were identified among participants of the Danish National Health Surveys 2010-2017. The surveys included questions on functional (social support and loneliness) and structural (living alone/cohabitating and frequency of contacts with relatives and friends) aspects of social relationships and HRQoL (Short Form-12). We estimated associations of aspects of social relationships with HRQoL and all-cause mortality in individuals with cirrhosis through 2020. Results: Of 541 individuals with cirrhosis and 2,157 comparators, low social support (22% in cirrhosis vs. 13% in comparators), loneliness (35% vs. 20%), and living alone (48% vs. 22%) were more frequent in individuals with cirrhosis than comparators, whereas the frequency of contacts with relatives and friends was similar. Except for living alone, weak functional and structural social relationships were associated with lower mental HRQoL in those with cirrhosis. Physical HRQoL was only marginally associated with social relationships. During 2,795 person-years of follow-up, 269 individuals with cirrhosis died. Functional and not structural aspects of social relationships were associated with risk of mortality in cirrhosis. Specifically, the adjusted hazard ratio was 1.4 (95% CI 1.1-1.9), p = 0.011, for low vs. moderate-to-high social support (functional aspect), and 1.0 (95% CI 0.8-1.3), p = 0.85 for living alone vs. cohabitating (structural aspect). Conclusions: Individuals with cirrhosis have weaker functional and structural social relationships than matched comparators. Weak functional relationships are associated with lower mental HRQoL and increased risk of mortality in individuals with cirrhosis. Impact and implications: This study investigated the prevalence of weak social relationships in individuals with cirrhosis and their influence on health-related quality of life and risk of mortality. Individuals with cirrhosis were nearly twice as likely to report low social support, loneliness, and to live alone than a matched comparison cohort. Low social support and loneliness (functional measures of social relationships) were associated with lower mental health-related quality of life and increased risk of mortality risk in cirrhosis, when adjusting for known confounders. We hope that these results will make healthcare providers aware of the functional aspects of the social relationships of individuals with cirrhosis, in addition to the traditional clinical management, and motivate further research of interventions to strengthen the social support of individuals with cirrhosis.

Motivation to Reduce Drinking and Engagement in Alcohol Misuse Treatment in Alcohol-Related Liver Disease: A National Health Survey.

INTRODUCTION: The study aim was to identify predictors of motivation to reduce alcohol consumption and whether motivation predicts engagement in alcohol misuse treatment in alcohol-related liver disease (ALD). METHODS: Data from health surveys and health-care registries were combined. RESULTS: Of 674 patients with ALD, 65% consumed alcohol. Recent hospital admission and severe alcohol problems were associated with motivation to reduce alcohol consumption. Two-year probability for engagement in misuse treatment was 29% for patients with motivation to reduce alcohol consumption versus 6.5% for patients without motivation. DISCUSSION: ALD patients with recent hospital admission were more motivated to cut down alcohol consumption, and motivation predicted engagement in alcohol misuse treatment. This insight can help us target brief interventions.

Treatment of alcohol use disorder in patients with liver disease.

Alcohol contributes to more than 5% of global mortality, and causes more than half of all liver-related deaths. The Alcohol Use Disorders Identification Test (AUDIT) can be used to detect those patients with hazardous drinking and alcohol dependence who will benefit from psychosocial and pharmacological alcohol treatment. Psychosocial treatments range from brief interventions and cognitive behavioral therapy, to experimental neuropsychological treatments. Psychosocial intervention can be combined with acamprosate or naltrexone as first line pharmacological treatments. For patients with liver disease, abstinence increases survival and is therefore an important treatment goal. Acamprosate is a good choice, as it prevents relapse to drinking with a number needed to treat of 12. There are no reports indicating high risks of liver toxicity for acamprosate or naltrexone, but evidence is scarce. We recommend vigorous screening for alcohol use disorder in liver disease patients, followed by psychosocial intervention and complemented by pharmaceutical therapy.

Socioeconomic inequalities in the incidence of alcohol-related liver disease: A nationwide Danish study.

BACKGROUND: There is socio-economic inequality in total alcohol-related harm, but knowledge of inequality in the incidence of specific alcohol-related diseases would be beneficial for prevention. Registry-based studies with nationwide coverage may reveal the full burden of socioeconomic inequality compared to what can be captured in questionnaire-based studies. We examined the incidence of alcohol-related liver disease (ALD) according to socioeconomic status and age. METHODS: We used national registries to identify patients with an incident diagnosis of ALD and their socioeconomic status in 2009-2018 in Denmark. We computed ALD incidence rates by socioeconomic status (education and employment status) and age-group (30-39, 40-49, 50-59, 60-69 years) and quantified the inequalities as the absolute and relative difference in incidence rates between low and high socioeconomic status. FINDINGS: Of 17,473 patients with newly diagnosed ALD, 78% of whom had cirrhosis, 86% had a low or medium-low educational level and only 20% were employed. ALD patients were less likely to be employed in the 10 years prior to diagnosis than controls. The incidence rate of ALD correlated inversely with educational level, from 181 (95% CI, 167-197) to 910 (95% CI, 764-1086) per million person-years from the highest to the lowest educational level. By employment status, the incidence rate per million person-years was 211 (95% CI, 189-236) for employed and 3449 (95% CI, 2785-4271) for unemployed. Incidence rates increased gradually with age leading to larger inequalities in absolute numbers for older age-groups. Although ALD was rare in the younger age-groups, the relative differences in incidence rates between high and low socioeconomic status were large for these ages. The pattern of socioeconomic inequality in ALD incidence was similar for men and women. INTERPRETATION: This study showed substantial socioeconomic inequalities in ALD incidence for people aged 30-69 years. FUNDING: The study was supported by grants from the Novo Nordisk Foundation (NNF18OC0054612) and the Research Fund of Bispebjerg Hospital.

Risk and Outcome of Venous and Arterial Thrombosis in Patients With Cirrhosis: A Danish Nation-wide Cohort Study.

BACKGROUND AND AIMS: Cirrhosis affects hemostasis, but its effects across the spectrum of thromboses remain poorly understood. We examined risks and outcomes of venous and arterial thrombosis. APPROACH AND RESULTS: We used nation-wide Danish health care registries to identify outpatients with cirrhosis and a sex- and age-matched comparison cohort without cirrhosis from the general population. Patients with cirrhosis and comparators were followed until they had a venous thromboembolism (VTE), acute myocardial infarction (AMI), or ischemic stroke (IS) or died. We computed absolute risks and HRs of thrombosis and compared outcomes after thrombosis. We included 5,854 patients with cirrhosis (median Model for End-Stage Liver Disease score, 9; interquartile range, 7-13), and their risk of any of the thrombotic events was 0.8% after 1 year and 6.3% after 10 years. They were more likely than the 23,870 matched comparators to have a VTE (adjusted hazard ratio [aHR], 2.0; 95% CI, 1.5-2.6) or IS (aHR, 1.7; 95% CI, 1.3-2.3), but not AMI (aHR, 0.7; 95% CI, 0.5-0.9). Among patients with cirrhosis, decompensation increased the risk of AMI, but not the other thromboses. Following thrombosis, patients with cirrhosis had higher 90-day mortality than comparators (after VTE: 17% vs. 7%; after AMI: 27% vs. 5%; after IS: 10% vs. 7%) and were less likely to receive antithrombotic treatment. CONCLUSIONS: Patients with cirrhosis had an increased risk of VTE and IS, but not AMI. Among patients with cirrhosis, decompensation increased the risk of AMI, exclusively. Mortality after thrombosis was higher in patients with cirrhosis than in other patients. These findings are relevant for decisions about antithrombotic prophylaxis in patients with cirrhosis.

[Harmful consequences of heavy episodic drinking in young people in Denmark].

Danish young people have a high alcohol intake as summarised in this review. Heavy drinking is associated with risk of adverse events such as accidents, violence, taking drugs or sex that is later regretted. Also, school performance may be affected negatively by heavy drinking, and alcohol may interfere with brain development. The risk of developing alcohol use disorder is increased in individuals who start drinking at an early age. Population-based interventions such as increasing the legal age of buying alcohol from 16 to 18 years, as in many other countries, can be introduced in order to minimise heavy drinking in young people.

[Epidemiology for alcohol-related liver disease].

Alcohol is the dominant cause of liver disease in Denmark. Around 1,000 persons, usually of 40 to 70 years of age, are diagnosed with alcohol-related liver disease (ALD) each year in Denmark. ALD is usually preceded by several years of heavy drinking, during which alcohol cessation could have prevented manifest ALD as argued in this review. There is a substantial inequality in ALD incidence by geography and socioeconomic status in Denmark. ALD is associated with a high mortality: The five-year mortality risk is 54%, although the prognosis for patients with ALD has improved in recent years.

Decreasing Incidence of Alcohol-Related Liver Disease in Denmark: A 25-Year Nationwide Study.

PURPOSE: Alcohol consumption has decreased in Denmark in recent years. We aimed to illustrate and investigate the developments in the incidence, hospital care, and mortality of alcohol-related liver disease (ALD) in Denmark during the last 25 years. PATIENTS AND METHODS: Through nationwide healthcare registries, we identified all Danish patients with incident ALD in 1994-2018. We computed standardized incidence rates by sex, age, and geography, age-specific incidence rates by birth cohort, and standardized prevalence. We enumerated inpatient admissions, days of admission, outpatient visits, and emergency room visits. Lastly, we estimated relative risks of mortality, standardized mortality rates, and the proportion of deaths caused by ALD. RESULTS: The standardized incidence rate decreased from its peak at 357 per 1,000,000 in 2009 to 240 per 1,000,000 in 2018, and the decrease was evident for both sexes and all age groups below 70 years. The standardized prevalence was stable around 0.22% from 2011 onwards. There was an almost fivefold geographic variation in standardized incidence by municipalities, and age-specific incidence rates decreased sequentially with each 5-year birth cohort after 1960. The number of inpatient admissions, days of admission, and emergency room visits decreased during the study period, while the number of outpatient visits was stable. For patients diagnosed in 2014-2018 compared to 1994-1998, the relative risk of 1-year mortality was 0.83 (95% confidence interval: 0.78-0.87), and the standardized mortality along with the proportion of deaths caused by ALD decreased during the study period. CONCLUSION: The incidence of ALD decreased from 357 to 240 per 1,000,000 over the last 10 years in Denmark. During the same period, the prevalence remained stable around 0.22% and mortality decreased. Additionally, the burden of ALD on hospital care decreased significantly between 1994 and 2018. We anticipate a further decrease in the incidence of ALD in the future.

Alcohol and risk of non-traumatic bleeding events requiring hospital care in the general population: A prospective cohort study.

Alcohol has a direct effect on blood coagulation and fibrinolysis. We studied how alcohol is related to common bleeding events (e.g., nose bleeding), as well as life-threatening bleeding events (e.g., hemorrhagic stroke) that required hospital care in the general population. We used data from The Copenhagen City Heart Study, 1991 to 1994 and 2001 to 2003. Baseline information on alcohol consumption and potential confounders was obtained by questionnaires, and participants were followed for incident bleeding events with nationwide registers until 2013. Among the 10,259 included participants, we observed 366 nose or other respiratory organ bleeding events, 149 hemorrhagic stroke events, 470 gastrointestinal bleeding events, 266 unspecified bleeding events, and 1088 any-bleeding events (composite endpoint) during follow-up. Compared to drinkers of 1-6 drinks per week, those drinking ≥35 drinks per week had a higher risk of hemorrhagic stroke [hazard ratio, 2.27 (1.14-4.55)] and non-variceal gastrointestinal bleeding [hazard ratio 2.04 (1.37-3.05)], whereas non-drinkers and drinkers of 7-13, 14-20, 21-27, and 28-34 drinks per week had not. Alcohol consumption was not associated with risk of nose or other respiratory organ bleeding or unspecified bleeding. For non-drinkers and drinkers of 7-13, 14-20, 21-27, 28-34, and 35 or more drinks per week, hazard ratios for the composite endpoint of any bleeding were 1.17 (95% CI: 0.99-1.37), 0.97 (95% CI: 0.81-1.15), 1.00 (95% CI: 0.80-1.26), 0.93 (95% CI: 0.69-1.25), 1.39 (95% CI: 1.00-1.94), and 1.83 (95% CI: 1.39-2.41) compared to drinkers of 1-6 drinks per week. In conclusion, drinking 35 or more drinks per week may be associated with a higher risk of hemorrhagic stroke and non-variceal gastrointestinal bleeding in the general population.

Hospital admissions and mortality in the 15 years after a first-time hospital contact with an alcohol problem: a prospective cohort study using the entire Danish population.

BACKGROUND: Potential benefits of preventing continued alcohol intake in individuals presenting at the hospital with an alcohol problem can be highlighted by studying their excess risk of subsequent morbidity and mortality. METHODS: All Danish residents with a first-time hospital contact with alcohol problems (intoxication, harmful use or dependence) in 1998-2002 were followed through 2012 using healthcare registries. We compared their cause-specific rates of hospital admission and mortality to the expected rates derived from the general population by calculating standardized incidence rate ratios. RESULTS: The 26 716 men and 12 169 women who were hospitalized with alcohol problems (median age 44 years) had more than 10 times the rate of subsequent admission to psychiatric departments and three times the rate of subsequent admission to somatic departments compared with the general population. In particular, the hospital admission rates for gastroenterological disease and injuries were high. The cumulative all-cause 10-year mortality risk was 29% [95% confidence interval (CI), 28-30] in men and 26% (95% CI, 24-27) in women with alcohol problems. The ratios of observed to expected death rate for all-cause mortality were 4.0 (95% CI, 3.8-4.1) in men and 4.3 (95% CI, 4.0-4.7) in women and, for causes of death fully attributable to alcohol, 16 (95% CI, 15-17) in men and 33 (95% CI, 29-38) in women. CONCLUSIONS: Individuals hospitalized with alcohol problems have much higher rates of subsequent alcohol-related hospital admission and mortality than the general population. Increased focus on preventing continued alcohol consumption in these individuals may reduce their subsequent morbidity and mortality.

Number of hospital contacts with alcohol problems predicts later risk of alcoholic liver cirrhosis.

AIMS: Alcoholic liver cirrhosis is usually preceded by years of heavy drinking. We investigated whether the risk of alcoholic liver cirrhosis increases as the number of hospital contacts with alcohol problems goes up. METHODS: This was a supplementary analysis on a nationwide register-based cohort study. All patients in Denmark with an initial hospital contact with alcohol problems (alcohol intoxication, harmful alcohol use or alcohol dependence) 1998-2002, free of liver disease, were followed for diagnosis of alcoholic liver cirrhosis. The number of subsequent hospital contacts with alcohol problems was estimated as a time-dependent variable for each patient. RESULTS: In all, 36,044 hospital patients with an initial hospital contact with alcohol problems were included. These patients had 301,525 subsequent hospital contacts with alcohol problems. Risk of alcoholic liver cirrhosis increased ( p < 0.0001) with number of alcohol hospital contacts in both men and women for up to nine contacts. CONCLUSIONS: The number of prior hospital contacts with alcohol problems might provide clinicians with a helpful metric in deciding whether to offer preventive interventions for alcoholic liver cirrhosis.

Opportunities to Prevent Alcoholic Liver Cirrhosis in High-Risk Populations: A Systematic Review With Meta-Analysis.

BACKGROUND: Alcoholic liver cirrhosis is preventable and caused by heavy drinking. Few in the general population may be at risk and interventions targeting individuals at high risk may be a more feasible opportunity for prevention than interventions targeting the whole population. METHODS: We conducted a systematic review to identify opportunities to prevent alcoholic liver cirrhosis in high-risk populations. Following MOOSE guidelines, we included observational studies published between 1980 and 2017. Prospective studies of alcohol-problem cohorts were included to investigate whether alcohol-problem cohorts qualify as high-risk populations for alcoholic liver cirrhosis. Studies on the alcohol amount consumed by alcoholic liver cirrhosis patients were included to compare with the amount consumed by the general population. Moreover, studies on alcohol-related healthcare contacts prior to alcoholic liver cirrhosis diagnosis were included to identify opportunities to offer prevention interventions. Of 7198 screened references, 38 studies (N = 120,928) were included. RESULTS: Alcohol-problem cohorts qualified as high-risk populations with an incidence of alcoholic liver cirrhosis ranging from 7 to 16% after 8-12 years. The alcohol amount consumed by alcoholic liver cirrhosis patients was high compared to the general population. For example, 45% (95%CI 34, 56) of alcoholic liver cirrhosis patients were drinking >110 g alcohol/day. Finally, there were opportunities to reach alcoholic liver cirrhosis patients prior to diagnosis; 40-61% of alcoholic liver cirrhosis patients had a previous alcohol-related healthcare contact. CONCLUSIONS: We conclude that alcohol-problem cohorts are high-risk populations for alcoholic liver cirrhosis and there seems to be opportunities to reach later alcoholic liver cirrhosis cases with preventive interventions in healthcare settings.

Pharmacological interventions for alcoholic liver disease (alcohol-related liver disease): an attempted network meta-analysis.

BACKGROUND: Alcohol-related liver disease is due to excessive alcohol consumption. It includes a spectrum of liver diseases such as alcohol-related fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. Mortality associated with alcoholic hepatitis is high. The optimal pharmacological treatment of alcoholic hepatitis and other alcohol-related liver disease remains controversial. OBJECTIVES: To assess the comparative benefits and harms of different pharmacological interventions in the management of alcohol-related liver disease through a network meta-analysis and to generate rankings of the available pharmacological interventions according to their safety and efficacy in order to identify potential treatments. However, even in the subgroup of participants when the potential effect modifiers appeared reasonably similar across comparisons, there was evidence of inconsistency by one or more methods of assessment of inconsistency. Therefore, we did not report the results of the network meta-analysis and reported the comparative benefits and harms of different interventions using standard Cochrane methodology. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform and randomised controlled trials registers until February 2017 to identify randomised clinical trials on pharmacological treatments for alcohol-related liver diseases. SELECTION CRITERIA: Randomised clinical trials (irrespective of language, blinding, or publication status) including participants with alcohol-related liver disease. We excluded trials that included participants who had previously undergone liver transplantation and those with co-existing chronic viral diseases. We considered any of the various pharmacological interventions compared with each other or with placebo or no intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently identified trials and independently extracted data. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CIs) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. MAIN RESULTS: We identified a total of 81 randomised clinical trials. All the trials were at high risk of bias, and the overall quality of the evidence was low or very low for all outcomes. Alcoholic hepatitisFifty randomised clinical trials included 4484 participants with alcoholic hepatitis. The period of follow-up ranged from one to 12 months. Because of concerns about transitivity assumption, we did not perform the network meta-analysis. None of the active interventions showed any improvement in any of the clinical outcomes reported in the trials, which includes mortality (at various time points), cirrhosis, decompensated cirrhosis, liver transplantation. None of the trials reported health-related quality of life or incidence of hepatocellular carcinoma. Severe alcoholic hepatitisOf the trials on alcoholic hepatitis, 19 trials (2545 participants) included exclusively participants with severe alcoholic hepatitis (Maddrey Discriminat Function > 32). The period of follow-up ranged from one to 12 months. There was no alteration in the conclusions when only people with severe alcoholic hepatitis were included in the analysis. SOURCE OF FUNDING: Eleven trials were funded by parties with vested interest in the results. Sixteen trials were funded by parties without vested interest in the results. The source of funding was not reported in 23 trials. Other alcohol-related liver diseasesThirty-one randomised clinical trials included 3695 participants with other alcohol-related liver diseases (with a wide spectrum of alcohol-related liver diseases). The period of follow-up ranged from one to 48 months. The mortality at maximal follow-up was lower in the propylthiouracil group versus the no intervention group (OR 0.45, 95% CI 0.26 to 0.78; 423 participants; 2 trials; low-quality evidence). However, this result is based on two small trials at high risk of bias and further confirmation in larger trials of low risk of bias is necessary to recommend propylthiouracil routinely in people with other alcohol-related liver diseases. The mortality at maximal follow-up was higher in the ursodeoxycholic acid group versus the no intervention group (OR 2.09, 95% CI 1.12 to 3.90; 226 participants; 1 trial; low-quality evidence). SOURCE OF FUNDING: Twelve trials were funded by parties with vested interest in the results. Three trials were funded by parties without vested interest in the results. The source of funding was not reported in 16 trials. AUTHORS' CONCLUSIONS: Because of very low-quality evidence, there is uncertainty in the effectiveness of any pharmacological intervention versus no intervention in people with alcoholic hepatitis or severe alcoholic hepatitis. Based on low-quality evidence, propylthiouracil may decrease mortality in people with other alcohol-related liver diseases. However, these results must be confirmed by adequately powered trials with low risk of bias before propylthiouracil can be considered effective.Future randomised clinical trials should be conducted with approximately 200 participants in each group and follow-up of one to two years in order to compare the benefits and harms of different treatments in people with alcoholic hepatitis. Randomised clinical trials should include health-related quality of life and report serious adverse events separately from adverse events. Future randomised clinical trials should have a low risk of bias and low risk of random errors.

[Benzodiazepines should still be first-line treatment for alcohol withdrawal].

In this review, we summarize the evidence for benzodiazepines and barbiturates as alcohol withdrawal treatment and outline a treatment guideline. A number of randomized controlled trials (RCTs) indicate that benzodiazepine treatment decreases alcohol withdrawal seizures and is safe. For barbiturates, only a few RCTs have been undertaken, and barbiturates were not found to be superior to benzodiazepines. Consequently, we suggest that benzodiazepines should still be first-line treatment for alcohol withdrawal.

Risk for alcoholic liver cirrhosis after an initial hospital contact with alcohol problems: A nationwide prospective cohort study.

Alcoholic liver cirrhosis is usually preceded by many years of heavy drinking, in which cessation in drinking could prevent the disease. Alcohol problems are not consistently managed in hospital patients. We followed all Danish patients with an initial hospital contact with alcohol problems (intoxication, harmful use, or dependence) during 1998-2002 for alcoholic liver cirrhosis development (n = 36,044). In this registry-based cohort, we identified predictors of the absolute risk for alcoholic liver cirrhosis. Incidence rate ratios (IRRs) were estimated as the incidence rate of alcoholic liver cirrhosis in these patients relative to the general population. Age and alcohol diagnosis were significant predictors of alcoholic liver cirrhosis risk in men and women, whereas civil status, education, and type of hospital care were not. In men, the 15-year absolute risk was 0.7% (95% confidence interval [CI], 0.4, 0.8) for 20-29 years, 5.5% (95% CI, 4.9, 6.2) for 30-39 years, 9.8% (95% CI, 9.0, 11) for 40-49 years, 8.9% (95% CI, 8.1, 9.8) for 50-59 years, 6.2% (95% CI, 5.1, 7.2) for 60-69 years, and 2.5% (95% CI, 1.7, 3.3) for 70-84 years. According to alcohol diagnosis in men, the 15-year absolute risk was 2.6% (95% CI, 2.3, 2.9) for intoxication, 7.7% (95% CI, 6.4, 7.9) for harmful use, and 8.8% (95% CI, 8.2, 9.4) for dependence. The IRR for alcoholic liver cirrhosis in the cohort relative to the general population was 11 (95% CI, 10, 12) in men and 18 (95% CI, 15, 21) in women. CONCLUSION: Hospital patients with alcohol problems had a much greater risk for alcoholic liver cirrhosis compared to the general population. The risk was particularly increased for patients 40-59 years and for patients diagnosed with harmful use or dependence. (Hepatology 2017;65:929-937).