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Opportunities to Prevent Alcoholic Liver Cirrhosis in High-Risk Populations

A Systematic Review With Meta-Analysis

Askgaard, Gro PhD, MD1,2; Kjær, Mette S. PhD, MD3,4; Tolstrup, Janne S. PhD, Dm Sci2

American Journal of Gastroenterology: February 2019 - Volume 114 - Issue 2 - p 221–232
doi: 10.1038/s41395-018-0282-6
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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.

1Gastro Unit, Copenhagen University Hospital, Bispebjerg Hospital, DK-2400, Copenhagen, Denmark;

2National Institute of Public Health, University of Southern Denmark, DK-1455, Copenhagen, Denmark;

3Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark;

4Department of Hepatology, Copenhagen University Hospital, Rigshospitalet, DK-2100, Copenhagen, Denmark.

Correspondence: Gro Askgaard, PhD, MD. E-mail: gask@dadlnet.dk.

SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/A33, http://links.lww.com/AJG/A34, http://links.lww.com/AJG/A35, http://links.lww.com/AJG/A36, and http://links.lww.com/AJG/A37

Received March 02, 2018

Accepted August 21, 2018

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INTRODUCTION

Alcoholic liver cirrhosis is a preventable life-threatening disease caused by heavy drinking. It is responsible for around 500,000 deaths worldwide per year (1). Opportunities for prevention of alcoholic liver cirrhosis may be considerable, due to its natural history. It is usually preceded by one or two decades of heavy drinking (2–4), during which cessation of drinking will usually stop disease progression (5–7).

Rose (8), a pioneer of preventive medicine, formulated the prevention paradox for cardiovascular disease: “A large number of people exposed to a low risk is likely to produce more cases than a small number of people exposed to a high risk”. The important implication of this paradox is that interventions that would most effectively prevent cardiovascular disease are not those traditionally performed by physicians, caring for the few individuals of high risk by treating their hypertension, for example (8). Rather, the most effective interventions are those that target the risk factor in the whole population—a nationwide exercise-promotion program to help lower blood pressure, for example (9). The prevention paradox expresses the small benefit gained for each participating individual in general population interventions in terms of risk reduction but at the same time the great potential of such to prevent the majority of cases (10). Following this line for the prevention of alcoholic liver cirrhosis, it would be more effective to lower the consumption of alcohol in the general population than in a subset of heavy drinkers at high risk (9,11). General population interventions could include policies that set a minimum price per unit of alcohol sold, or limit the availability of alcohol (12).

However, important distinctions exist between cardiovascular disease and alcoholic liver cirrhosis, which could indicate that prevention of alcoholic liver cirrhosis is more feasible in targeted high-risk populations. The incidence of alcoholic liver cirrhosis is about 30 times lower than that of cardiovascular disease (0.06% versus 2% per person-year in Danish men > 45 years) (13,14). Furthermore, alcoholic liver cirrhosis is mainly attributed to a single cause—heavy alcohol consumption—whereas cardiovascular disease is attributed to several causes that each contribute a little (smoking, blood pressure, and diabetes, among others) (15). The amount of alcohol consumed by alcoholic liver cirrhosis patients may apply to only a minority of the general population (16,17). On the contrary, cardiovascular disease risk factors occur in a substantial fraction of the general population (the prevalence of hypertension is 29% in the US population, for example) (18).

High-risk populations for developing alcoholic liver cirrhosis may include individuals hospitalized with, or seeking treatment for, alcohol problems (Fig. 1) (19,20). Preventive interventions targeting such high-risk individuals include the delivery of brief interventions or cognitive-behavioural therapies (21,22) shown to be associated with decreased mortality (23,24).

Fig. 1

Fig. 1

Should interventions be effective in the prevention of alcoholic liver cirrhosis in high-risk populations, there should be opportunities to reach the majority of patients prior to their diagnosis. Alcohol-related healthcare contacts before alcoholic liver cirrhosis diagnosis represent such an opportunity. These contacts may even be expected, since heavy drinking is associated with high morbidity and hospitalization (19,25).

We conducted a systematic review with meta-analysis to identify opportunities to prevent alcoholic liver cirrhosis in high-risk populations. Specifically, we tested the following hypotheses:

  1. Alcohol-problem cohorts are high-risk populations for alcoholic liver cirrhosis; their incidence of alcoholic liver cirrhosis is much greater than the general population;
  2. The amount of alcohol consumed by alcoholic liver cirrhosis patients is seen in only a minority of the general population; and
  3. A high fraction of alcoholic liver cirrhosis patients had alcohol-related healthcare contacts prior to diagnosis.
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METHODS

This systematic review followed the MOOSE guidelines (26). To provide the context for this review, the following three topics were summarized in a background section (found in the Supplementary material, see http://links.lww.com/AJG/A33, http://links.lww.com/AJG/A34, http://links.lww.com/AJG/A35, http://links.lww.com/AJG/A36, and http://links.lww.com/AJG/A37): The natural history of alcoholic liver disease; alcohol amount and drinking patterns as risk factors; and the main preventive interventions for alcohol-related harm. Reviews on these topics have been conducted recently (12,22,27–30).

Then, a systematic review with meta-analysis was undertaken to answer the following questions:

Question 1: What is the incidence of alcoholic liver cirrhosis in alcohol-problem cohorts?

Question 2: How much alcohol do alcoholic liver cirrhosis patients consume? and

Question 3: To what extent did patients had alcohol-related healthcare contacts prior to diagnosis?

Obesity, chronic viral hepatitis, smoking, iron-overload, and ethnicity are all associated with increased risk of liver cirrhosis in heavy drinkers (7). This review concerns only alcohol (27).

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Literature search

A librarian undertook a literature search in June 2018, using PubMed, Embase, and PsycInfo and combining the terms alcoholism/alcohol/alcohol abuse/alcohol dependence/alcohol use disorders/risky drinking/hazardous drinking/problematic drinking with the terms alcoholic liver cirrhosis/liver cirrhosis/cirrhosis. We included full-text articles published in English from January 1980 onwards, excluding abstracts and unpublished studies. References were screened based on title and abstract by one author, and those remaining were included or excluded independently based on the full text by two authors. Reference lists of included studies and systematic reviews (27,31) were then hand–searched, to complete and verify the literature search.

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Eligibility criteria

  1. For the review of incidence of alcoholic liver cirrhosis in alcohol-problem cohorts, prospective studies of alcohol-problem cohorts were eligible for inclusion. Studies on alcohol-problem cohorts not differentiating between causes of liver cirrhosis endpoint (alcohol, autoimmune, viral) were also included, because of the low expected etiological fraction of liver cirrhosis due to causes other than alcohol (32).
  2. For the review of alcohol consumption of alcoholic liver cirrhosis patients, we included studies reporting alcohol amount in categories (not as the average amount in their cohort). We excluded studies not differentiating between causes of liver cirrhosis endpoint, to estimate alcohol amount in pure alcoholic liver cirrhosis.
  3. Finally, studies on alcohol-related healthcare contacts prior to alcoholic liver cirrhosis diagnosis were eligible for inclusion.

Because patients with alcoholic liver cirrhosis in the liver transplant setting represent a highly selected group, transplant studies were not included (33). We are aware, however, that alcohol problems are frequent in these patients (34). Randomized controlled trials were also excluded to increase the generalizability of our findings.

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Data extraction and bias assessment

We extracted: number of participants, sex, follow-up duration, setting, and data sources.

  1. For studies on alcoholic liver cirrhosis incidence, we extracted information on exclusion of liver cirrhosis at baseline, liver cirrhosis endpoint definition, and number with endpoint.
  2. For studies on amount of alcohol consumed by alcoholic liver cirrhosis patients, data on assessment of alcohol history was extracted.
  3. Regarding studies on alcohol-related healthcare contacts prior to diagnosis, we obtained information on the average number of contacts per patient, and the proportion of patients with such a contact.

Bias assessment was performed with the Newcastle–Ottawa Scale (35) for question 1 and with the instrument proposed by Hoy et al. for questions 2 and 3 (36).

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Statistics

Alcohol consumption measured in standard units was converted to grams of pure ethanol based on the typical alcohol content of one standard unit (UK, 8 g; Australia, 10 g; Denmark, 12 g; USA and Canada, 14 g) (6,37). We quantified between-study heterogeneity using the I2 statistic, which can be interpreted as the proportion of the total variation in the estimated effects for each study that is due to heterogeneity between studies (38). Using inverse-variance weighted random-effect models to allow for between-study heterogeneity, we performed a meta-regression on the (cumulative) incidence of alcoholic liver cirrhosis in alcohol-problem cohorts, measured as the proportion with liver cirrhosis after a specific follow-up. Proportions of alcoholic liver cirrhosis patients consuming different amounts of alcohol were estimated by the same method. Sensitivity analyses for the influence of single studies on the pooled proportions were conducted, omitting studies one by one and re-estimating the pooled proportions. All statistical analysis was carried out in Stata 14 using the Metan command.

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RESULTS

Literature search

The literature search identified 7198 references (Fig. 2). After screening, 308 studies were left for full-text review, and 42 papers describing 38 studies (N = 120,928) were suitable for inclusion. Studies were conducted in Japan, USA, and Sweden (five studies each), Denmark, Italy, and UK (four studies each), Australia, Spain, and India (two studies each), and China, Korea, New Zealand, and Switzerland (one study each). Therefore, most studies were conducted in countries with a low prevalence of viral hepatitis (1,39). Ten studies reported endpoints separately for women and men, but men accounted for the great majority of study cohorts. The number of women in each category of the systematic review was too low to conduct meta-analyses differentiated by sex. Mean age was comparable between studies: about 40–50 years of age in alcohol-problem cohorts and 50–60 years of age in alcoholic liver cirrhosis patients.

Fig. 2

Fig. 2

Question 1: What is the incidence of alcoholic liver cirrhosis in alcohol-problem cohorts?

We identified 23 prospective studies on the incidence of alcoholic liver cirrhosis in alcohol-problem cohorts with mean follow-up times varying from two to 33 years (Table 1). The alcohol-problem cohort was hospital patients with an alcohol problem diagnosis (two studies; N = 82,725), heavy drinkers referred to an internal medicine department (four studies; N = 429), and patients seeking treatment for alcohol problems in specialized treatment centres or psychiatric departments (17 studies; N = 24,518).

Table 1-a

Table 1-a

Table 1-b

Table 1-b

For studies on hospital patients with an alcohol problem diagnosis and patients seeking treatment for alcohol problems. liver cirrhosis endpoint was obtained from health registries. For heavy drinkers referred to internal medicine departments, endpoint was obtained from liver biopsies, clinical examinations, autopsies, and/or health registries.

In general, we assessed the risk of bias to be low, however the risk of bias was high or unclear due to underdetection of liver cirrhosis incidence in studies on patients seeking treatment for alcohol problems (Supplementary table 1, seehttp://links.lww.com/AJG/A37).

Between-study heterogeneity was generally high in meta-analyses of incidence, except for studies of heavy drinkers referred to internal medicine departments (Fig. 3).

Fig. 3

Fig. 3

The incidence of alcoholic liver cirrhosis in hospital patients with an alcohol problem diagnosis was 6.9% (95%CI 4.1, 10) after 8 years. In heavy drinkers referred to an internal medicine department, the incidence was 16% (95%CI 10, 21) after 8–12 years of follow-up. In patients seeking treatment for alcohol problems, the incidence within 5 years, between 5 and 10 years, and after more than 10 years of follow-up was 1.7% (95%CI 0.9, 2.5) (four studies, N = 3558), 6.2% (95%CI 4.0, 8.0) (seven studies, N = 10,148), and 4.6% (95%CI: 2.7, 6.9) (six studies, N = 10,812).

No studies had a major influence on the pooled estimates, when excluded one-by-one from the meta-analysis.

Question 2: How much alcohol do alcoholic liver cirrhosis patients consume?

We identified 12 studies of the amount of alcohol consumed by alcoholic liver cirrhosis patients (N = 2919) (Table 2). Horie et al. accounted for 69% of the included patients (39). This Japanese study obtained information from various hospitals, not clearly stating how the information was provided (39). This was also true of three other studies (40–42). Otherwise, information came from the next of kin of deceased alcoholic liver cirrhosis patients (43), from questionnaires (44), from interviews (2, 45–47), and from medical chart records (48).

Table 2

Table 2

Alcohol amount was defined as the current consumption (17,39,45,48), as the average lifetime amount (2,43,47), and as the highest level of consumption in the patient’s lifetime (46). Categories of alcohol amount were not completely comparable between studies. A high risk of bias due to low external validity was assessed in around half of the studies whereas the risk of bias was low regarding the internal validity of included studies (Supplementary table 2, see http://links.lww.com/AJG/A37). The between-study heterogeneity was high (Supplementary figure 1, see http://links.lww.com/AJG/A33). Our meta-analysis found 31% (95%CI 12, 50) of alcoholic liver cirrhosis patients drank less than 80 g alcohol per day (six studies; N = 477), 44% (95%CI 34, 54) drank 80–160 g alcohol per day (six studies; N = 2556), and 45% (95%CI 34, 56) drank more than 110 g per day (seven studies; N = 2573). No individual study had a major impact on pooled estimates.

Question 3: To what extent did patients have alcohol-related healthcare contacts prior to alcoholic liver cirrhosis diagnosis?

Four studies assessed alcohol-related hospital or primary care contacts prior to diagnosis of alcoholic liver cirrhosis (three study populations, N = 10,337) (Table 3). Two studies were based on health registries (49–51), and one used clinical chart records of prior somatic hospital contacts (52). Too few studies were available to perform a meta-analysis. In general, the risk of bias was assessed to be low (Supplementary table 3, see http://links.lww.com/AJG/A37).

Table 3

Table 3

Two studies assessed healthcare contacts with obvious alcohol problems prior to diagnosis (49,51). Otete et al. estimated that 61% of 2479 patients in the United Kingdom had had a primary care contact where harmful drinking had been recorded prior to diagnosis of alcoholic liver cirrhosis (50). In a nationwide Danish study taking all types of hospital contacts in all types of departments into account, we found that 40% of 7719 patients had had at least one hospital contact prior to diagnosis (51).

Three studies, all performed in the United Kingdom, assessed healthcare contacts that may be alcohol-related – drug overdose, epilepsy, accidents, oral malignancy, etc. – and found that 33–58% had had a contact with such a condition (49,50,52).

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DISCUSSION

In this systematic review on preventing alcoholic liver cirrhosis in high-risk populations based on 36 observational studies, the incidence of alcoholic liver cirrhosis in alcohol-problem cohorts ranged from 7–16% after 8–12 years. Forty-five percent (95%CI 34,56) of alcoholic liver cirrhosis patients consumed more than 110 g alcohol per day, and around half had previous alcoholrelated healthcare contacts.

This review was limited to studies reported in English, leaving the possibility of unidentified studies, though we were able to include studies from a range of countries. Our search strategy might also have left some studies out if liver cirrhosis was not indicated in the title or abstract (53). Another limitation was the inability to estimate outcomes separately for men and women. Men accounted for the majority of study cohorts, and we restrict our conclusions to account for men. Another limitation includes the inability to assess the influence of other potential risk factors for alcoholic liver cirrhosis such as ethnicity, type of alcohol consumption, history of binge drinking, and genetic factors.

In line with current guidelines, potential publication bias was not assessed due to the low number of studies in each category (54). There was a large between-study heterogeneity detected in all meta-analyses. However, between-study heterogeneity is less important when estimates are large as in our analyses (55).

In the following, we describe why our estimations are more likely to be underestimations rather than overestimations. Few of the included studies of patients seeking treatment for alcohol problems excluded liver cirrhosis at baseline, which could potentially lead to an overestimation of the true incidence of alcoholic liver cirrhosis in the meta-analysis. Actually, the greatest incidence of alcoholic liver cirrhosis was found in studies that did exclude liver cirrhosis at baseline. Importantly, most studies were based on causes of death registers, without further validation by autopsy reports or medical charts, likely underestimating the incidence of alcoholic liver cirrhosis (56–59). For example, the proportion of deaths where the cause was alcoholic liver cirrhosis increased from 3% to 12% when information from medical records and autopsy reports were added to registry data in a validation study of 403 deaths (60). The higher incidence found in studies of heavy drinkers referred to internal medicine departments compared to studies on other alcohol-problem cohorts might be explained by the performance of more detailed investigations of liver cirrhosis in this type of patient (5,61–63).

When estimating alcohol consumption, most studies used the current alcohol amount. This may also lead to an underestimation, because data suggest that the current amount in alcoholic liver cirrhosis is lower than that consumed some time prior to diagnosis (64,65). Studies based on interview cannot include severely ill patients. Because heavy drinking is associated with a worsening of liver disease, exclusion of severely ill patients may lead to an underestimation of the average alcohol consumption of alcoholic liver cirrhosis patients (66).

Alcohol-related healthcare contacts prior to diagnosis was studied in only four papers. However, the number of included cases was high (>10,000). Three studies were based on registries (49–51), where alcohol problems may be underreported (67), and alcohol-related healthcare contacts may be underestimated for this reason (67). One study used data on prior somatic hospital contacts, not taking prior psychiatric hospital contacts into account which could also lead to an underestimation (51,52).

Our results support our first hypothesis that the incidence of alcoholic liver cirrhosis in alcohol-problem cohorts is much higher than in the general population – 10–20 times greater, in fact, when compared to the Danish general population of men > 45 years (13). These alcohol-problem cohorts therefore qualify as high-risk populations for alcoholic liver cirrhosis.

Alcoholic liver cirrhosis patients consume much more alcohol than the general population. In the Danish population, fewer than 6% of men drink more than 50 g alcohol daily (68), but we found that roughly half of alcoholic liver cirrhosis patients drank more than 110 g alcohol daily. This is in favour of our second hypothesis that the amount of alcohol consumed by alcoholic liver cirrhosis patients is seen in only a minority of the general population. Earlier cohort studies also observed the greatest number of alcoholic liver cirrhosis cases in men drinking more than 50 g alcohol daily at baseline (6,20,69).

Approximately half of alcoholic liver cirrhosis patients had previous alcohol-related healthcare contacts in primary care or in the hospital. This finding fits well with the many extra-hepatic comorbidities found in these patients (49,51), and supports our third hypothesis that a high fraction of alcoholic liver cirrhosis patients had alcohol-related healthcare contacts prior to their diagnosis.

Together with plenty of evidence pointing to the huge mortality and morbidity associated with alcohol problems (25,31,70), the present systematic review underscores the need for increasing the treatment of patients with alcohol problems in healthcare settings. Treatments could include the implementation of brief interventions for heavy drinkers, and cognitive-behavioural therapies and pharmacological treatments for alcohol dependence. These treatments could help to avoid further morbidity and mortality in these patients (12,23,24). Patients with alcohol-related liver disease seem to present later than patients with liver disease due to other etiologies (71). Assessment of early liver disease by non-invasive methods in alcohol-problem cohorts may enable early diagnosis of alcohol-related liver disease (72).

Still, because of the efficacy of the available interventions for alcohol problems today, their implementation may not prevent most cases of alcoholic liver cirrhosis (Supplementary table 4, see http://links.lww.com/AJG/A37) (73). For example, to decrease alcohol consumption using brief interventions and pharmacological treatments, the number needed to treat is nine, and this effect may not be sustainable over time (74–76).

Observational studies suggest that general population interventions of minimum unit pricing for alcohol and alcohol taxation can decrease alcohol-related mortality (77,78). The potential of such general population interventions for prevention of alcoholic liver cirrhosis may be considerable and should be investigated further.

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CONFLICTS OF INTEREST

Guarantor of the article: Gro Askgaard.

Specific author contributions: Conception and design: All authors; screening of literature: GA and MSK; data analysis: GA; writing the manuscript: GA; critically revising the manuscript: All authors.

Financial support: None.

Potential competing interests: None.

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Study Highlights

WHAT IS KNOWN

  • ✓ Alcoholic liver cirrhosis is preventable and mainly caused by years of heavy drinking.
  • ✓ Alcohol-related healthcare contacts before alcoholic liver cirrhosis diagnosis are expected due to alcohol-related morbidity.

WHAT IS NEW

  • ✓ Different alcohol-problem cohorts have a high risk of alcoholic liver cirrhosis of 7 to 16% after 8–12 years.
  • ✓ The high alcohol amount consumed by alcoholic liver cirrhosis patients apply to few in the general population.
  • ✓ About half of alcoholic liver cirrhosis patients have prior alcohol-related healthcare contacts that may constitute opportunities to offer preventive interventions.
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ACKNOWLEDGEMENTS

Stephen Fritzdorf is acknowledged for his medical writing assistance. Morten Lihn Jørgensen is acknowledged for the preparation of Figure 1.

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REFERENCES

1. Rehm J, Samokhvalov AV, Shield KD. Global burden of alcoholic liver diseases. J Hepatol. 2013;59:160–8.
2. Nakamura Y, Kobayashi Y, Ishikawa A, et al Severe chronic pancreatitis and severe liver cirrhosis have different frequencies and are independent risk factors in male Japanese alcoholics. J Gastroenterol. 2004;39:879–87.
3. Naveau S, Giraud V, Borotto E, et al Excess weight risk factor for alcoholic liver disease. Hepatology. 1997;25:108–11.
4. Barrio E, Tomé S, Rodríguez I, et al Liver disease in heavy drinkers with and without alcohol withdrawal syndrome. Alcohol Clin Exp Res. 2004;28:131–6. http://www.ncbi.nlm.nih.gov/pubmed/14745311.
5. Marbet UA, Bianchi L, Meury U, et al Long-term histological evaluation of the natural history and prognostic factors of alcoholic liver disease. J Hepatol. 1987;4:364–72.
6. Askgaard G, Grønbæk M, Kjær MS, et al Alcohol drinking pattern and risk of alcoholic liver cirrhosis: A prospective cohort study. J Hepatol. 2015;62:1061 http://www.sciencedirect.com/science/article/pii/ S0168827814009234.
7. European Association for the Study of Alcoholic Liver Disease. EASL Clinical Practical Guidelines: management of alcoholic liver disease. J Hepatol. 2012;57:399–420.
8. Rose G. Strategy of prevention: lessons from cardiovascular disease. Br Med J. 1981;282:1847–51.
9. Rose G, Day S. The population mean predicts the number of deviant individuals. BMJ. 1990;301:1031–4.
10. Rose G. Sick individuals and sick populations. Int J Epidemiol. 1985;14:32–38.
11. Sheron N. Alcohol and liver disease in Europe - simple measures have the potential to prevent tens of thousands of premature deaths. J Hepatol. 2015; 64(4):957–67.
12. National Institute for Health and Care Excellence. Alcohol-Use Disorders: Diagnosis, Assessment and Management of Harmful Drinking and Alcohol Dependence. NICE Clinical Guidelines. 2010. https://www.nice.org.uk/guidance/cg115
13. Deleuran T, Vilstrup H, Becker U, et al Epidemiology of alcoholic liver disease in Denmark 2006-2011: a population-based study. Alcohol Alcohol. 2015;50:352. http://www.alcalc.oxfordjournals.org/cgi/doi/10.1093/alcalc/agv003
14. Koch MB, Davidsen M, Juel K. Hjertekar-sygdomme i 2011. Incidens, prævalens og dødelighed samt udviklingen siden 2002. 2014. Access on September 5 2017. http://www.si-folkesundhed.dk/
15. Ezzati M, Obermeyer Z, Tzoulaki I, et al The contributions of risk factor trends and medical care to cardiovascular mortality trends HHS Public Access. Nat Rev Cardiol. 2015;12:508–30.
16. Skog O-J. The prevention paradox revisited. Addiction. 1999;94:751 http://www.ncbi.nlm.nih.gov/pubmed/10912254.
17. Bellentani S, Saccoccio G, Costa G, et al Drinking habits as cofactors of risk for alcohol induced liver damage. Gut. 1997;41:845–50.
18. Fryar CD, Ostchega Y, Hales CM, et al Hypertension prevalence and control among adults: United States, 2015-6. NCHS Data Brief. 2017;1–8. https://www.cdc.gov/nchs/data/databriefs/db289.pdf
19. Piette JD, Barnett PG, Moos RH. First-time admissions with alcohol-related medical problems: a 10-year follow-up of a national sample of alcoholic patients. J Stud Alcohol. 1998;59:89–96.
20. Kamper-Jørgensen M, Grønbaek M, Tolstrup J, et al Alcohol and cirrhosis: dose–response or threshold effect? J Hepatol. 2004;41:25–30.
21. Williams R, Aspinall R, Bellis M, et al Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis. Lancet. 2014;384:1953–97. http://linkinghub.elsevier.com/retrieve/pii/S0140673614618389.
22. Anderson P, Chisholm D, Fuhr DC. Effectiveness and cost-effectiveness of policies and programmes to reduce the harm caused by alcohol. Lancet. 2009;373:2234–46.
23. Mcqueen J, Te H, Allan L, et al Brief interventions for heavy alcohol users admitted to general hospital wards (Review). Cochrane Database Syst Rev. 2011; 10:CD005191.
24. Roerecke M, Gual A, Rehm J. Reduction of alcohol consumption and subsequent mortality in alcohol use disorders: systematic review and meta-analyses. J Clin Psychiatry. 2013;74:e1181–9. http://www.ncbi.nlm.nih.gov/pubmed/24434106.
25. Rehm J. The risks associated with alcohol use and alcoholism. Alcohol Res Heal . 2011;34:135–43.
26. Stroup DF, Berlin JA, Morton SC, et al Meta-analysis of observational studies in epidemiology - a proposal for reporting. JAMA. 2000;283: 2008–12. http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.283.15.2008
27. Rehm J, Taylor B, Mohapatra S, et al Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis. Drug Alcohol Rev. 2010;29:437. http://onlinelibrary.wiley.com/doi/10.1111/j.1465-3362.2009.00153.x/pdf
28. Mathurin P, Bataller R. Trends in the management and burden of alcoholic liver disease. J Hepatol. 2015;62:S38–S46. http://linkinghub.elsevier.com/retrieve/pii/S016882781500166X
29. OECD. Tackling harmful alcohol use: economic and public health policy. Paris: OECD Publishing; 2015. http://www.oecd-ilibrary.org/social-issues-migration-health/tackling-harmful-alcoholuse_9789264181069-en
30. Masarone M, Rosato V, Dallio M, et al Epidemiology and natural history of alcoholic liver disease. Rev Recent Clin Trials. 2016;44:167.
31. Roerecke M, Rehm J. Cause-specific mortality risk in alcohol use disorder treatment patients: a systematic review and meta-analysis. Int J Epidemiol. 2014;43:906–19.
32. Fialla AD, de Muckadell OB, Touborg Lassen A. Incidence, etiology and mortality of cirrhosis: a populationbased cohort study. Scand J Gastroenterol. 2012;47:702–9.
33. Singal AK, Chaha KS, Rasheed K, et al Liver transplantation in alcoholic liver disease current status and controversies. World J Gastroenterol. 2013;19:5953–63.
34. Askgaard G, Tolstrup JS, Gerds TA, et al Predictors of heavy drinking after liver transplantation for alcoholic liver disease in Denmark (1990–2013): a nationwide study with competing risks analyses. Scand J Gastroenterol. 2016;51:225. http://www.tandfonline.com/doi/full/10.3109/00365521.2015.1067903
35. Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P: The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/
36. Hoy D, Brooks P, Woolf A, et al Assessing risk of bias in prevalence studies: Modification of an existing tool and evidence of interrater agreement. J Clin Epidemiol. 2012;65:934. https://doi.org/10.1016/j. jclinepi.2011.11.014
37. Miller WR, Heather N, Hall W. Calculating standard drink units: international comparisons. Br J Addict. 1991;86:43–47. http://www.ncbi.nlm.nih.gov/pubmed/2009396
38. Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.
39. Horie Y, Yamagishi Y, Ebinuma H, et al Obesity, type 2 diabetes, age, and female gender: significant risk factors in the development of alcoholic liver cirrhosis. Hepatol Int. 2012;7:280–5.
40. Ray S. Clinico-biochemical correlation to histological findings in alcoholic liver disease: a single centre study from eastern India. J Clin Diagnostic Res. 2014;8:MC01–5.
41. Alvarez MA, Cirera I, Solà R, et al Long-term clinical course of decompensated alcoholic cirrhosis: a prospective study of 165 patients. J Clin Gastroenterol. 2011;45:906.
42. Aparisi L, Sabater L, Del-Olmo J, et al Does an association exist between chronic pancreatitis and liver cirrhosis in alcoholic subjects? World J Gastroenterol. 2008;14:6171 http://www.wjgnet.com/1007-9327/14/6171.pdf
43. Parrish KM, Dufour MC. Drinking patterns and liver cirrhosis mortality. Alcohol Alcohol Suppl. 1991;1:331–4.
44. Bellentani S, Tiribelli C. The spectrum of liver disease in the general population: lesson from the dionysos study. J Hepatol. 2001;35:531–7.
45. Sarin SK, Sachdev G, Jiloha RC, et al Pattern of psychiatric morbidity and alcohol dependence in patients with alcoholic liver disease. Dig Dis Sci. 1988;33:443–8.
46. Norton R, Batey R, Dwyer T, et al Alcohol consumption and the risk of alcohol related cirrhosis in women. Br Med J. 1987;295: 80–82. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1246961&tool=pmcentrez&rendertype=abstract
47. Batey R, Burns T, Benson RJ, et al Alcohol consumption and the risk of cirrhosis. Med J Aust. 1992;156:413–6.
48. Xie YDi, Feng B, Gao Y, et al Characteristics of alcoholic liver disease and predictive factors for mortality of patients with alcoholic cirrhosis. Hepatobiliary Pancreat Dis Int. 2013;12:594–601. https://doi.org/10.1016/S1499-3872(13)60094-6
49. Otete HE, Orton E, Fleming KM, et al Alcohol-attributable health care attendances up to 10 years prior to diagnosis of alcoholic cirrhosis: a population based case control study. Liver Int. 2015;36:538–46. https://doi.org/10.1111/liv.13002
50. Otete HE, Orton E, West J, et al Sex and age differences in the early identification and treatment of alcohol use: a population-based study of patients with alcoholic cirrhosis. Addiction. 2015;110:1932–40. https://doi.org/10.1111/add.13081
51. Askgaard G, Neermark S, Leon DA, et al Hospital contacts with alcohol problems prior to liver cirrhosis or pancreatitis diagnosis. World J Hepatol. 2017;9:1332–9.
52. Verrill C, Smith S, Sheron N. Are the opportunities to prevent alcohol related liver deaths in the UK in primary or secondary care? A retrospective clinical review and prospective interview study. Subst Abus Treat Prev Policy. 2006;5:1–5.
53. Polich J, Armor D, Braiker H. The course of alcoholism: four years after treatment. New York: John Wiley & Sons; 1981.
54. Sterne JAC, Sutton AJ, Ioannidis JPA, et al Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343:d4002 http://www.ncbi.nlm.nih.gov/pubmed/21784880.
55. Cochrane Collaboration. Cochrane handbook. http://handbook-5-1.cochrane.org/chapter_9/9_5_2_i
56. Romelsjo A, Karlsson G, Henningsohn L, et al The prevalence of alcohol-related mortality in both sexes: variation between indicators, Stockholm, 1987. Am J Public Health. 1993;83:838–44.
57. Prytz H, Anderson H. Underreporting of alcohol-related mortality from cirrhosis is declining in Sweden and Denmark. Scand J Gastroenterol. 1988;23:1035–43.
58. Berglund M. Mortality in alcoholics related to clinical state at first admission. A study of 537 deaths. Acta Psychiatr Scand. 1984;70:407–16.
59. Blake JE, Compton KV, Schmidt W, Orrego H. Accuracy of death certificates in the diagnosis of alcoholic liver cirrhosis. Alcohol Clin Exp Res.1988;12:168–72.
60. Ågren G, Jakobsson SW. Validation of diagonses on death certificates for male alcoholics in Stockholm. Forensic Sci Int. 1987;33:231–41.
61. Sørensen TI, Orholm M, Bentsen KD, et al Prospective evaluation of alcohol abuse and alcoholic liver injury in men as predictors of development of cirrhosis. Lancet. 1984;4:241–4.
62. Motoo Y, Wakatsuki T, Nakanuma Y. Long-term histologic follow-up study of alcoholic liver disease. Intern Med. 1992;31:33–38.
63. Teli MR, Day CP, James OFW, et al Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver. Lancet. 1995;346: 987–90.
64. Verrill C, Markham H, Templeton A, et al Alcohol-related cirrhosis–early abstinence is a key factor in prognosis, even in the most severe cases. Addiction. 2009;104:768–74.
65. Hatton J, Burton A, Nash H, et al Drinking patterns, dependency and life-time drinking history in alcohol-related liver disease. Addiction. 2009;104:587–92.
66. Rothman KJ. Epidemiology. An introduction. 2nd ed. New York, NY: Oxford University Press; 2012.
67. Søgaard M, Heide-Jørgensen U, Norgaard M, et al Evidence for the low recording of weight status and lifestyle risk factors in the Danish National Registry of Patients, 1999-2012. BMC Public Health. 2015;15:1320
68. Sundhedsstyrelsen. Danskernes Sundhed - Den Nationale Sundhedsprofil 2013. 2014. http://proxy.danskernessundhed.dk/SASVisualAnalytics-Viewer/VisualAnalyticsViewer_guest.jsp?reportNameOvervaegt&repor tPath/Danskernes_sundhed/
69. Becker U, Deis A, Sørensen TI, et al Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective population study. Hepatology. 1996;23:1025–9.
70. Whiteford Ha, Degenhardt L, Rehm J, et al Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet. 2013;382:1575–86. http://www.ncbi.nlm.nih.gov/pubmed/23993280
71. Shoreibah M, Raff E, Bloomer J, et al Alcoholic liver disease presents at advanced stage and progresses faster compared to non-alcoholic fatty liver disease. Ann Hepatol. 2016;15:183–9.
72. Sheron N, Moore M, O’Brien W, et al Feasibility of detection and intervention for alcohol-related liver disease in the community: the Alcohol and Liver Disease Detection study (ALDDeS). Br J Gen Pract. 2013;63:698–705. https://doi.org/10.3399/bjgp13X673711
73. Heather N. Can screening and brief intervention lead to population-level reductions in alcohol-related harm?. Addict Sci Clin Pract. 2012;7:15 http://www.ascpjournal.org/content/7/1/15
74. Rösner S, Leucht S, Lehert P, et al Acamprosate for alcohol dependence (Review). Cochrane Libr. 2011.
75. Rösner S, Leucht S, Vecchi S, et al Opioid antagonists for alcohol dependence (Review). Cochrane Libr. 2010.
76. Heather N. Can screening and brief intervention lead to population-level reductions in alcohol-related harm? Addict Sci Clin Pract. 2012;7:15.
77. Zhao J, Stockwell T, Martin G, et al The relationship between minimum alcohol prices, outlet densities and alcohol-attributable deaths in British Columbia, 2002-09. Addiction. 2013;108:1059–69.
78. Wagenaar AC, Maldonado-Molina MM, Wagenaar BH. Effects of alcohol tax increases on alcohol-related disease mortality in Alaska: time-series analyses from 1976 to 2004. Am J Public Health. 2009;99:1464–70.
79. Askgaard G, Leon DA, Kjaer MS, Deleuran T, Gerds TA, Tolstrup JS. Risk for alcoholic liver cirrhosis after an initial hospital contact with alcohol problems: a nationwide prospective cohort study. Hepatology. 2017;65:929–37.
80. Orholm M, Sorensen TI, Bentsen K, et al Mortality of alcohol abusing men prospectively assessed in relation to history of abuse and degree of liver injury. Liver. 1985;5:253–60.
81. Marbet UA, Stalder GA, Thiel G, et al The influence of HLA antigens on progression of alcoholic liver disease. Hepatogastroenterology. 1988;35:65–68.
82. Lambie DG, Whiteside EA, Bell J, et al Mortality associated with alcoholism in New Zealand. N Z Med J. 1983;96:199–202.
83. Higuchi S. Mortality of Japanese female alcoholics: a comparative study with male cases. Jpn J Alcohol Stud Drug Depend. 1987;22:211–23.
84. Lindberg S, Ågren G. Mortality among male and female hospitalized alcoholics in Stockholm 1962-1983. Br J Addict. 1988;83:1193–1200.
85. Ohara KK, Suzuki Y, Sugita T, et al Mortality among alcoholics discharged from a Japanese hospital. Addiction. 1989;84:287.
    86. Lewis C, Smith E, Kercher C, et al Predictors of mortality in alcoholic men: a 20-year follow-up study. Alcohol Clin Exp Res. 1995;19:984–91.
    87. Denison H, Berkowicz A, Oden A, et al The significance of coronary death for the excess mortality in alcohol-dependent men. Alcohol Alcohol. 1997;32:517. http://www.alcalc.oxfordjournals.org/cgi/doi/10.1093/oxfordjournals.alcalc.a008287
    88. Noda T, Imamichi H, Tanaka H, et al Cause-specific mortality risk among male alcoholics residing in the Osaka metropolitan area. Psychiatry Clin Neurosci. 2001;55:465. http://www.ncbi.nlm.nih.gov/pubmed/11555341
    89. Costello RM. Long-term mortality from alcoholism: a descriptive analysis. J Stud Alcohol. 2006;67:694.
    90. Haver B, Gjestad R, Lindberg S, et al Mortality risk up to 25 years after initiation of treatment among 420 Swedish women with alcohol addiction. Addiction. 2009;104:413–9.
    91. Saieva C, Bardazzi G, Masala G, et al General and cancer mortality in a large cohort of Italian alcoholics. Alcohol Clin Exp Res. 2012;36:342–50. http://www.ncbi.nlm.nih.gov/pubmed/22085221.
    92. Park S, Hong JP, Choi SH, et al Clinical and laboratory predictors of all causes deaths and alcohol-attributable deaths among discharged alcohol-dependent patients. Alcohol Clin Exp Res. 2013;37:270–5. http://www.ncbi.nlm.nih.gov/pubmed/23050781
    93. Rivas I, Sanvisens A, Bolao F, et al Impact of medical comorbidity and risk of death in 680 patients with alcohol use disorders. Alcohol Clin Exp Res. 2013;37(Suppl 1):E221–7. http://www.ncbi.nlm.nih.gov/pub-med/23320801
    94. Morandi G, Tomas EP, Pirani M. Mortality risk in alcoholic patients in Northern Italy: comorbidity and treatment retention effects in a 30-year follow-up study. Alcohol Alcohol. 2015;51:63–70.
    95. Sarin SK, Malhotra V, Nayyar A, et al Profile of alcoholic liver disease in an Indian hospital. A prospective analysis. Liver. 1988;8:132–7.
    96. Parrish KM, Dufour MC, Stinson FS, et al Average daily alcohol consumption during adult life among decedents with and without cirrhosis. J Stud Alcohol. 1993;54:450–6.
    97. Stroffolini T, Cotticelli G, Medda E, et al Interaction of alcohol intake and cofactors on the risk of cirrhosis. Liver Int. 2010;30:867–70.

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