Alcoholism is a serious problem in Western society and one of the reasons for the increase in liver-related mortality. Among the diseases with the worst prognosis is acute alcoholic hepatitis, a syndrome of subacute liver failure. It is currently estimated that more than half of all deaths from liver disease in the European Union are due to excessive alcohol consumption.

A partnership of the Cima University of Navarra and the University of Pittsburgh (USA), and supported by "la Caixa", has revealed the causes of liver failure in patients with acute alcoholic hepatitis. The results have been published in the latest issue of the scientific journal issue . Nature Communications.

"The only treatment indicated for these patients is corticosteroids, a therapy that has been used since the 1970s and has very limited efficacy," explains Dr. Josepmaría Argemí, first author of work. According to the researcher, trained at the Cima University of Navarra and currently working at the group of Dr. Ramón Bataller, at the University of Pittsburgh (USA), "these patients are not usually candidates for liver transplantation, due to the fact that they have an active addiction to alcohol consumption. programs of study Moreover, this disease has been stigmatized both by society and by academic community and no in-depth study of its biological mechanisms has been carried out".

The work performed by this international team, led by Dr. Bataller, is the first to molecularly characterize the pathways responsible for liver failure in people with acute alcoholic hepatitis. "Specifically, RNA sequencing techniques, DNA methylation analysis, proteomic analysis of plasma and genomic sequence variation analysis (GWAS) have been used to correlate the molecular patterns with the patients' clinical data ," explains Dr. Argemí. 

Drs. Ramón Bataller and Josepmaría Argemí of the University of Pittsburgh.

Piece in the puzzle of liver failure

As Dr. Matías Ávila, director of the Hepatology Program at Cima, researcher of CIBEREHD and co-author of work, points out, "we found that the liver cell (hepatocyte) is transformed into a 'selfish' cell concerned only with its own survival, instead of performing the essential functions for the organism: glucose synthesis, synthesis of coagulation factors, bilirubin secretion, urea metabolization, etc. As a consequence of this change, the patient enters status liver failure, which rapidly leads to multi-organ failure."

This study demonstrates that a central piece in the puzzle of liver failure due to acute alcoholic hepatitis is the transcription factor HNF4A. "In a healthy person, this protein is responsible for coordinating the hepatocyte's own functions. However, in patients with liver failure, there is an alteration in its processing (splicing) and an inhibition of the genes that depend on it," the researchers point out.

"We hope that this molecular information that we offer to academic community will open the door to new treatments that will help us save lives and give our patients a second chance," Drs. Argemí and Ávila conclude.

This is a work coordinated by the most relevant international groups in the study of liver disease associated with alcoholism, in which researchers from CIBEREHD and IdISNA have participated. It has also received funding from the National Institute of Alcohol Abuse and Alcoholism (NIAAA, NIH) of the USA and "la Caixa" (through project Hepacare), among other public and private institutions.

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  Nature Communications volume 10, Article number: 3126 (2019)