Researchers identify factors that contribute to alcoholic liver disease

Results of a novel study may kickstart the development of new diagnostic and therapeutic approaches for a disease with few medical treatment options, researchers report in The American Journal of Pathology


Philadelphia June 13, 2022

The most common form of liver disease, alcohol-associated liver disease (ALD), contributes to half a million cirrhosis deaths worldwide annually. Odds of survival are very low and treatment options are limited. Two manifestations of ALD have a particularly poor prognosis: alcohol-associated hepatitis (AH) and alcohol-associated cirrhosis (AC). A team of researchers investigating the underlying causes of AH and AC observed significant alterations in multiple proteins involved in various biological processes in both diseases that may serve as biomarkers or treatment targets. Their research and dataset appear in The American Journal of Pathology, published by Elsevier.

“Many AC and AH patients are unaware of the severity of their condition, and there are very few medical treatment options available,” explained lead investigators Irina A. Kirpich, PhD, MPH, University of Louisville, Louisville, KY, and Jon Jacobs, PhD, Pacific Northwest National Laboratory, Richland, WA, USA. “This problem has intensified over time, and the COVID-19 epidemic has exacerbated alcohol-related hospitalizations. There is a real necessity for the identification and development of biomarkers and treatments.”

Dr. Kirpich, Dr. Jacobs, and their colleagues conducted the first tandem proteomic and phosphoproteomic analysis on liver tissues from AC and AH patients. Proteomic analysis determines the proteins that are altered under disease conditions. Phosphoproteomic analysis determines the phosphorylation status of these proteins, which plays a role in many cell functions including inflammation, metabolism, proliferation, and cell death. They analyzed liver samples from two independent groups of AH patients and one subset of AC patients to identify novel protein and phosphoprotein signatures of AC and AH as well as AH severity. AH patients were divided into four groups based on their Model for End-Stage Liver Disease (MELD) score, which ranks the severity of a patient’s disease, with higher scores for more critical illness.

This research identified metabolic defects that are likely to lead to the development and progression of AH and AC, including impaired liver protein secretion, impaired neutrophil function, and impaired liver regeneration. They found that protein synthesis, a critical function commonly compromised in chronic liver disease, was altered in AH and AC. They identified elevated albumin protein expression in the liver, but with reduced phosphorylation, which may prevent the release of albumin to the blood. This could contribute to severe hypoalbuminemia (low levels of albumin in blood) seen in these patients, which is a hallmark of liver failure. They also identified multiple pro-fibrotic transcription factors that were associated with AH severity.

Another finding was that hepatic neutrophil markers and chemoattractants follow a bell-shaped curve according to AH severity – they were elevated in patients with MELD scores between 17 and 25 but were decreased in patients with MELD scores greater than 25. This may have implications for when to administer immunomodulatory drugs such as prednisolone. Finally, synthesis of hepatic cardiolipin was compromised in AC and AH, which could impact mitochondrial function and liver repair and regeneration.

Kirpich

“This one-of-a-kind study and its novel proteomic dataset will provide a roadmap for the development of novel biomarkers and therapies for AH and AC and,” said Dr. Kirpich and Dr. Jacobs. “We are optimistic that findings from this study will be utilized by many investigators in the field for years to come and could therefore help finetune current treatment strategies to improve patient outcomes and open the door to new paradigms and ideas to improve patient care.

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Notes for editors

The article is “Hepatic Protein and Phosphoprotein Signatures of Alcohol-Associated Cirrhosis and Hepatitis,” by Josiah Hardesty, Le Day, Jeffrey Warner, Dennis Warner, Marina Gritsenko, Aliya Asghar, Andrew Stolz, Timothy Morgan, Craig McClain, Jon Jacobs,and Irina Kirpich (https://doi.org/10.1016/j.ajpath.2022.04.004). It appears online in advance of The American Journal of Pathology, volume 192, issue 7 (July 2022), published by Elsevier.

The article is openly available at https://ajp.amjpathol.org/article/S0002-9440(22)00121-3/fulltext.

The study was supported by NIH grants R01AA024102, F32AA027950, F31AA028423, T32ES011564, U01AA026934, U01AA026926, U01AA026980, R01AA023681, U01AA021886, U01AA021918, P50AA11999 and the Department of Veterans Affairs I01BX000350. This work was also supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the NIH under grants P20GM113226 and P41GM103493; and the National Institute on Alcohol Abuse and Alcoholism of the NIH under Award P50AA024337.

Full text of the article is also available to credentialed journalists upon request. Contact Eileen Leahy at +1 732 238 3628 or ajpmedia@elsevier.com to request a PDF of the article, additional information or an interview with the authors.

About The American Journal of Pathology

The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. https://ajp.amjpathol.org.

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Eileen Leahy
Elsevier
+1 732 238 3628
ajpmedia@elsevier.com