Alcohol-related ACLF often results in multiple organ failure, leading to high mortality. In this study, the 28-day and 90-day mortality rates in alcohol-related ACLF patients were 33% and 52%, respectively, consistent with previous studies [2, 3]. No specific treatment except alcohol abstinence is available for patients with alcohol-related ACLF. Although corticosteroids, pentoxifylline and N-Acetylcysteine are reported as treatment options for ACLF, the efficacy of these treatments is limited [7]. Liver transplantation is an effective treatment for ACLF patients [16] and considerably improved the prognosis of patients with severe alcoholic hepatitis who were not responding to medical therapy [17]. In Japan, a 6-month alcohol abstinence is recommended prior to living donor liver transplantation for patients with alcoholic liver cirrhosis because alcohol abstinence might result in an improvement of liver function. However, 95% of the deceased patients with alcohol-related ACLF had died within 6 months of diagnosis in this study. In addition, a previous study also revealed high near-term (less than six months) mortality among patients with severe alcoholic hepatitis [18]. Interestingly, Mathurin et al. reported that early liver transplantation could improve survival in patients with a first episode of severe alcoholic hepatitis who do not respond to medical therapies [19]. In our institution, the indication for living donor liver transplantation for alcoholic cirrhosis is generally based on the 6-month rule. However, for patients with severe alcoholic hepatitis who do not respond to medical therapy, liver transplantation is indicated if there has been no episode of alcohol dependence, family cooperation, determination to abstain from alcohol, and approval by the hospital's Indication Evaluation Committee.
Various markers have been developed to predict the prognosis of ACLF. White blood cell count is an independent factor contributing to mortality that has been incorporated into the CLIF-C ACLF score [1]. The neutrophil/lymphocyte ratio [20, 21] and CRP reduction [22] are also associated with mortality in ACLF patients. A sub-analysis of the CANONIC study showed that ACLF grades from day 3 to day 7 after ACLF diagnosis were more accurate predictors of short- and medium-term prognosis than initial grades [23]. A multicenter study in Japan showed age and organ failure as prognostic factors in ACLF patients [6]. Consistent with this multicenter study, older patients with ACLF showed an unfavorable prognosis compared to younger patients. In our cohort, not MELD score at admission, but MELD score at day 4 of admission was identified as a prognostic factor within 6 months for alcohol-related ACLF, suggesting that early response to intensive care could determine the prognosis of the patients because multiple pathologies, such as infection, dehydration, and nutritional disorders were related to the pathogenesis of alcohol-related ACLF.
In the present study, serum concentrations of inflammatory cytokines such as IL-1β, IL-8, IL-10, IL-12p70 and TNF-α were significantly elevated in alcohol-related ACLF patients. Among these inflammatory cytokines, higher IL-6 concentration was particularly associated with poor prognosis. Some studies have shown that inducing systemic inflammation is a feature of ACLF and is more prominent in alcohol-related ACLF [4, 24]. In a sub-analysis of the CANONIC study, elevation of serum IL-8 and IL-6 levels was associated with heavy alcohol drinking and bacterial infection in ACLF patients, respectively [13]. In the liver, IL-6 is an important inducer of the acute phase response and infection defenses [25] and is crucial for hepatocyte homeostasis. It is also involved in liver regeneration as well as in metabolic functions of the liver [26]. Recently, several reports showed that serum and ascitic IL-6 levels were elevated in ACLF patients [14, 15, 27, 28]. Dynamics of serum IL-6 levels were analyzed in three patients in our cohort. Serum IL-6 levels elevated at the time of ACLF development and decreased with recovery from the disease in all three patients (Supplementary Fig. 1). Taken together, serum IL-6 could be a useful marker to predict prognosis for patients with alcohol-related ACLF.
The present study has several limitations. First, this study was a retrospective analysis from a single facility, and include the patients diagnosed as ACLF not only fulfilled, but with extended, probable, and extended/probable cases. Further analysis is needed to clarify the prognosis and predictive factors for mortality in a prospective multicenter study using patients diagnosed as fulfilled ACLF. Second, although serum cytokine concentrations were associated with the prognosis of alcohol-related ACLF, only six cytokines were analyzed in this study. Increasing the number of cases within multiple centers and including more detailed cytokine measurements will be necessary in the future to evaluate the potential of serum IL-6 as a predictive marker for prognosis in alcohol-related ACLF patients.
In conclusion, serum IL-1β, IL-8, IL-10, IL-12p70 and TNF-α levels were elevated in patients with alcohol-related ACLF. Among these inflammatory cytokines, higher IL-6 concentration was particularly associated with poor prognosis. Serum IL-6 concentration and MELD score 4 days after admission were prognostic factors for patients with alcohol-related ACLF. Early liver transplantation may be a treatment option for patients whose prognosis is expected to be poor.