Homozygosity for rs738409:G in PNPLA3 is associated with increased mortality following an episode of severe alcoholic hepatitis

Abstract

Background & Aims: Carriage of rs738409:G in PNPLA3 is associated with an increased risk of developing alcohol-related cirrhosis and has a significant negative effect on survival. Short-term mortality in patients with severe alcoholic hepatitis is high; drinking behaviour is a major determinant of outcome in survivors. The aim of this study was to determine whether carriage of rs738409:G has an additional detrimental effect on survival in this patient group. Methods: Genotyping was undertaken in 898 cases with severe alcoholic hepatitis, recruited through the UK Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial, and 1,188 white British/Irish alcohol dependent controls with no liver injury recruited via University College London. Subsequent drinking behaviour was classified, in cases surviving ≥90 days, as abstinent or drinking. The relationship between rs738409 genotype, drinking behaviour and survival was explored. Results: The frequency of rs738409:G was significantly higher in cases than controls (29.5% vs. 18.9%;). Case-mortality at days 28, 90 and 450 was, 16%, 25% and 41% respectively. There was no association between rs738409:G and 28-day mortality. Mortality in the period day 90-450 was higher in survivors who subsequently resumed drinking (Hazard Ratio [HR] 2.77, 95% Confidence Interval [CI] 1.79-4.29; p<0.0001) and individuals homozygous for rs738409:G (HR 1.69, 95% CI 1.02-2.81, p=0.04). Conclusion: Homozygosity for rs738409:G in PNPLA3 confers significant additional risk of medium-term mortality in patients with severe alcoholic hepatitis. Rs738409 genotype may be an additional factor when considering treatment options in these patients.Response to Reviewers: Reviewer statistics 1.Imputing missing drinking behavior at 90 days based on observed values at 1 year is tricky, even in sensitivity analyses. Actually, this corresponds to sort of conditioning on the future, which should be avoided because it may lead to biased results (see works by Terry Therneau, for instance). Since it is a sensitivity analyses, the issue is less severe than for a primary analysis, but the limit should be stated. 2.The authors explain that now they only kept subgroup analyses where a significant interaction was found, but in the manuscript, it remains "Separate models were fitted for clinically relevant features and biochemical parameters", thus without conditioning on a significant interaction. 3.My point on the sentence "Individuals homozygous for rs738409:G had a significantly lower 450-day survival, even if abstinent" has been misunderstood, and it is certainly because I was not clear enough. I did not mean that there was no significant difference in any of the whole population and the subgroup analyses, but that it was not possible to claim that 450 days mortality would be lower in patients homozygous for rs738409:G because this was not analyzed. What the study shows is that among patients still alive at 90 days, the 450 days mortality was different, which is different. Simply stating "450 day...

Patatin‐Like Phospholipase Domain‐Containing Protein 3 I148M and Liver Fat and Fibrosis Scores Predict Liver Disease Mortality in the U.S. Population

“…Multiple studies found relationships of PNPLA3 I148M with NAFLD, but reported associations with mortality from liver disease or all causes are limited. In the Study of Health in Pomerania in North‐Eastern Germany, 148M was associated with a 4‐fold increase in the liver disease mortality hazard for men only, most likely attributable to small sample size, shorter follow‐up time, and fewer events in women . In another report, 148M homozygosity doubled the risk of hepatic decompensation and liver disease mortality in patients with FLD‐associated portal hypertension .…”

Diagnosis and Treatment of Alcohol‐Associated Liver Diseases: 2019 Practice Guidance From the American Association for the Study of Liver Diseases

“…Infection‐related biomarkers like pretreatment serum lipopolysaccharide, bacterial DNA, high‐sensitivity C‐reactive protein, and procalcitonin are associated with the risk of infection and 90‐day mortality . Furthermore, as mentioned previously, the presence of SIRS at admission, with or without infection, predicts multiorgan failure (especially AKI) and early death . Although the recovery of liver function in short‐term prognosis is paramount and captured by the previously discussed prognostic models, in the long term, abstinence from alcohol is the main driver of outcome in patients with severe AH surviving beyond 6 months .…”

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Noncholesterol Sterols as Surrogate Markers in Patients with Severe Alcoholic Hepatitis

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