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