Potential Treatment Found for Alcoholic Liver Disease
Photo: Marleen Van Den Neste
An anti-inflammatory called hyaluronic acid 35 (HA 35) might one day protect patients from the complications of moderate alcoholic liver disease, said Dr. Laura Nagy at NIAAA’s 24th annual Mark Keller Honorary Lecture in Lipsett Amphitheater on Jan. 28.
“We’re in the planning stage for conducting a pilot clinical trial, to see whether providing HA 35 to healthy adults before a single alcoholic drink can protect the gut,” said Nagy, professor of molecular medicine at the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University and staff member in the departments of inflammation and immunity, and gastroenterology and hepatology at the Cleveland Clinic.
Alcoholic liver disease is a serious health problem resulting from the overconsumption of alcoholic drinks over long periods. The liver’s primary jobs are to make proteins that are essential for blood clotting and to filter blood that comes from the digestive tract and remove toxins from the bloodstream and store energy.
Patients with alcoholic liver disease first develop steatosis, the abnormal retention of fats in the liver. Steatosis is usually reversible if people reduce their consumption of alcohol. They next develop inflammation, then cirrhosis, a condition where scar tissue replaces normal liver tissue.
“Not all heavy drinkers progress along this timeline. There’s likely an association between genetics and environment in the progression of the disease. This is typically a slow progression over 20 to 30 years,” Nagy said.
There are several cell types that play a role in the progression of alcoholic liver disease. One of them is the hepatocyte, “the workhorse of the liver.” Hepatocytes perform key roles in metabolism, detoxification and protein synthesis.
Another is the Kupffer cell, Nagy said. They reside in a capillary called the sinusoid. A type of white blood cell, Kupffer cells are the first line of defense against bacteria and byproducts of digestion that come from the intestines, such as lipopolysaccharides (LPS).
After a person drinks an alcoholic beverage, the liver begins to metabolize and convert ethanol—the chemical name for alcohol—into acetaldehyde and then acetate. Nagy said this process produces reactive oxygen species, which leads to a “perfect storm of damaged macromolecules.” Over time, the liver cannot eliminate the macromolecules.
Photo: Marleen Van Den Neste
Chronic drinking increases the amount of LPS that enter the liver from the intestines. When Kupffer cells are exposed to LPS, they release TNF-α, an inflammatory cytokine. TNF-α spurs an immune system response, which helps clear injured or dead hepatocytes. Repeated LPS exposure increases the inflammatory response.
Nagy guessed that an anti-inflammatory compound—HA 35—might be a good drug candidate for patients with alcoholic liver disease. In one animal study, her lab fed mice the equivalent of several beers per day, along with HA 35. Evidence suggested a “protective effect of HA 35” and a decrease of cytokines.
“HA 35 protects the gut and liver from ethanol” in rodent models, she said. “We’ve completed a safety and tolerance trial and there’s potential therapeutic value, most likely in moderate disease situations.”
Nagy’s lab is also studying death of hepatocytes in patients with severe alcoholic hepatitis. There are several ways hepatocytes can die, including necrosis and apoptosis. Necrosis refers to cell death caused by external factors, such as an alcohol-induced injury, while apoptosis means programmed cell death. They are studying pathways that might prevent necrosis.
The Keller Lecture is a tribute to Mark Keller’s pioneering contributions to the field of alcohol research. The lecture acknowledges the advances scientists are making in a wide range of alcohol-related research.