Identification of optimal therapeutic window for steroid use in severe alcohol-associated hepatitis: A worldwide study

Abstract

Background & aims: Corticosteroids are the only effective therapy for severe alcohol-associated hepatitis (AH), defined by a model for end-stage liver disease (MELD) score >20. However, there are patients who may be too sick to benefit from therapy. Herein, we aimed to identify the range of MELD scores within which steroids are effective for AH.

Methods: We performed a retrospective, international multicenter cohort study across 4 continents, including 3,380 adults with a clinical and/or histological diagnosis of AH. The main outcome was mortality at 30 days. We used a discrete-time survival analysis model, and MELD cut-offs were established using the transform-the-endpoints method.

Results: In our cohort, median age was 49 (40-56) years, 76.5% were male, and 79% had underlying cirrhosis. Median MELD at admission was 24 (19-29). Survival was 88% (87-89) at 30 days, 77% (76-78) at 90 days, and 72% (72-74) at 180 days. A total of 1,225 patients received corticosteroids. In an adjusted-survival-model, corticosteroid use decreased 30-day mortality by 41% (hazard ratio [HR] 0.59; 0.47-0.74; p <0.001). Steroids only improved survival in patients with MELD scores between 21 (HR 0.61; 0.39-0.95; p = 0.027) and 51 (HR 0.72; 0.52-0.99; p = 0.041). The maximum effect of corticosteroid treatment (21-30% survival benefit) was observed with MELD scores between 25 (HR 0.58; 0.42-0.77; p <0.001) and 39 (HR 0.57; 0.41-0.79; p <0.001). No corticosteroid benefit was seen in patients with MELD >51. The type of corticosteroids used (prednisone, prednisolone, or methylprednisolone) was not associated with survival benefit (p = 0.247).

Conclusion: Corticosteroids improve 30-day survival only among patients with severe AH, especially with MELD scores between 25 and 39.

Lay summary: Alcohol-associated hepatitis is a condition where the liver is severely inflamed as a result of excess alcohol use. It is associated with high mortality and it is not clear whether the most commonly used treatments (corticosteroids) are effective, particularly in patients with very severe liver disease. In this worldwide study, the use of corticosteroids was associated with increased 30-day, but not 90- or 180-day, survival. The maximal benefit was observed in patients with an MELD score (a marker of severity of liver disease; higher scores signify worse disease) between 25-39. However, this benefit was lost in patients with the most severe liver disease (MELD score higher than 51).

Keywords: MELD; Maddrey discriminant function; alcohol; alcohol-associated liver disease; alcoholic hepatitis; alcoholic liver disease; cirrhosis; corticosteroids; steroids.

Fig. 1.. Impact of steroid use in terms of severity at 30, 90 and 180 days.

(A), Changes in MELD score between admission and 30, 90 and 180 days according to steroid use. (B), Change in serum bilirubin between admission and by day 7 according to steroid use. The groups were compared with the Mann-Whitney U test, and a p value <0.05 was considered significant. MELD, model for end-stage liver disease; n.s., not significant.

Fig. 2.. Predictive model of 30-day survival adjusted by age, gender, ethnicity, cirrhosis, dialysis, and MELD score.

The curves represent mortality per use of steroids and severity (MELD score). A discrete-time hazard was estimated at 30 days using an adjusted multivariable logistic regression. We added an interaction term between the time and the MELD score. Efficacy was defined based on the upper limit of the 95% CI of the hazard ratio. The hazard ratio was 0.59, 95% CI 0.47–0.74, p <0.001. MELD, model for end-stage liver disease.

Fig. 3.. Forest plot of the predictive model of 30-day survival adjusted by age, gender, ethnicity, cirrhosis, dialysis, and MELD score.

A hazard ratio less than 1 represents a survival benefit with corticosteroids treatment. The transform-the-endpoints method was used to estimate the hazard ratio for different MELD scores. A p value <0.05 was considered statistically significant. MELD, model for end-stage liver disease.

Fig. 4.. Principal causes of death according to corticosteroid use at 180 days of follow-up.

Comparisons were performed using the chi-square test. A p value <0.05 was considered statistically significant. AKI, acute kidney injury; GI bleeding, gastrointestinal bleeding; MOF, multiple organ failure.