Jon Jacobs, a biochemist, has examined the blood of people suffering from diseases including Ebola, cancer, TB, hepatitis, diabetes, Lyme disease, brain damage, and influenza.
However, he has never witnessed blood chemistry go so astray as when he and colleagues carefully examined the protein activity in the blood of patients with alcohol-associated hepatitis, an extreme case of liver disease brought on by years of frequent drinking.
The proteins in these patients are more dysregulated than in any other blood plasma that we have analyzed. Almost two-thirds of the proteins we measured are at unusual levels. This is a snapshot of what is going on in the body of a person with this disease and reflects just how severe a disease this is.”
Jon Jacobs, Biochemist, Pacific Northwest National Laboratory, Department of Energy
This “snapshot” is a measurement of the altered proteins in sick individuals. A significant step has been taken toward the development of an easy blood test to detect alcohol-associated hepatitis with this distinct combination of alterations in protein activity.
Recently, Jacobs and associates published their findings in the American Journal of Pathology. These experts came from the Veteran Affairs Long Beach Healthcare System and the University of Pittsburgh. Jacobs and Timothy Morgan, a gastroenterologist at VA Long Beach, who has been treating patients with the condition for more than 35 years, are the study’s corresponding authors.
Alcohol-associated hepatitis: long in the making
Morgan was not surprised by the results.
These individuals are very sick. These patients have been drinking a lot of alcohol, typically more than a six-pack of beer or more than a bottle of wine or more than four shots of liquor per day for more than 10 years.”
Timothy Morgan, Professor, Medicine, UCI Health
The disease is more severe than other liver diseases caused by alcohol, such as cirrhosis and fatty liver. About 10% of individuals with alcohol-associated hepatitis pass away within one month of diagnosis, and about 25% pass away within six months. They are frequently in the last stages of long-term sickness.
Over 400 people with the disease, according to Morgan, have been his patients. Morgan brought together researchers, doctors, and patients from the Southern California Alcoholic Hepatitis Consortium, PNNL, the InTeam Consortium located at the University of Pittsburgh, and other organizations to enhance the treatment he offers patients and learn more about the disease.
Analysis of 106 people’s blood or tissue samples was part of the study. These comprised 49 individuals in good health and 57 patients with alcohol-associated hepatitis, nonalcoholic fatty liver disease, and other alcohol-related liver diseases such as cirrhosis.
The PNNL researchers measured more than 1,500 proteins in the study participants' blood using sensitive mass spectrometry. Although blood proteins are significantly affected by alcohol-associated hepatitis, the PNNL team found a subset of 100 proteins that are changed in patients and appear to be the primary drivers of the disease.
Some proteins were more abundant, whereas others were less abundant, in those patients. The damaged proteins are involved in a wide range of bodily processes, including inflammation, immunity, coagulation, and fundamental liver function.
The findings were in good agreement with earlier liver tissue investigations on alcohol-associated hepatitis in patients. The current study’s author, Ramon Bataller, Chief of Hepatology at the University of Pittsburgh, had previously described the gene activity in the livers of patients with the disease.
His team discovered a clear correlation between the core proteins that were changed in the blood of disease patients and the extensive dysregulation of the genes and proteins in the liver, connecting the expression of disease-specific proteins in the blood to liver function.
Both studies indicate a crucial function for the HNF4A molecule, which serves as the hub of liver gene activity. Diabetes and pancreatic cancer are two more diseases where HNF4A is active.
Goal: biomarker for diagnosis, monitoring
The study is a significant step in the development of a blood-based biomarker, or blood test, that could detect alcohol-associated hepatitis.
Morgan added, “The diagnosis of alcohol-associated hepatitis can be difficult, costly, and sometimes can take several days. Having a blood test for the diagnosis of AH would help physicians make the diagnosis quickly, safely, more accurately, and less expensively than with a liver biopsy.”
The team is undertaking additional research to see whether the same protein alterations could be used to track patients’ treatment responses. Steroids are frequently prescribed by doctors to manage inflammation, but the treatment makes patients more susceptible to infection.
Jacobs concluded, “These data help us understand what’s happening in these patients, and we are hopeful it gives us an additional tool to monitor how patients are responding to treatments.”
Argemi, J., et al. (2023). Integrated Transcriptomic and Proteomic Analysis Identifies Plasma Biomarkers of Hepatocellular Failure in Alcohol-Associated Hepatitis. American Journal of Pathology. doi.org/10.1016/j.ajpath.2022.08.009