Worldwide, 75 million people have been diagnosed with an alcohol use disorder that puts them at risk of developing alcohol-related liver disease. About 1 million of these people die each year from liver disease. Although consuming alcohol is closely linked with the risk of liver disease, researchers have had difficulty understanding why some of these people develop severe liver disease and die and others do not. A new study suggests that genetics and insulin resistance determine whether these people develop liver disease. The new knowledge can be used to identify those who should definitely consume less alcohol.
The liver is the body’s processing and filtering organ, metabolizing carbohydrate, fat and protein and degrading and filtering out foreign substances. People who consume excessive alcohol develop an inflammatory condition in the liver that eventually can lead to the formation of fibrosis (scar tissue). However, people differ in the rate at which this happens. A new large study of people with a history of excessive alcohol use has enabled researchers to identify the people whose livers will be most severely affected by this excessive drinking.
“We investigated people with a history of excessive drinking to determine which risk factors most strongly affected whether liver fibrosis developed and thereby eventually caused cirrhosis. Although insulin resistance is the strongest indicator that alcohol-related fibrosis is underway, genetic factors play a significant role in developing liver disease. The new knowledge improves the opportunities to understand the development of this disease and to convince people who drink excessively to stop in time,” explains Mads Bastrup Israelsen, a postdoctoral fellow at the FLASH Liver Research Centre, Odense University Hospital and University of Southern Denmark.
Indicating the stage of liver damage
The researchers examined 325 people with a history of excessive alcohol use based on the guidelines on safe alcohol consumption of the Danish Health Authority. The participants therefore did not necessarily have an alcohol use disorder or have developed symptoms of liver disease yet.
“Previous studies of this kind typically focused on people who developed cirrhosis, comparing them with a healthy control group. We wanted to examine liver disease while it is asymptomatic to understand how it develops and to determine whether we can identify which people are predisposed for alcohol-related liver disease and how to avoid it,” says Mads Bastrup Israelsen.
The researchers analysed participants’ blood to measure their glucose and fat metabolism and to examine their genes for various genetic variants known from other liver diseases such as nonalcoholic steatohepatitis. All the participants then had a liver biopsy to determine the stage of fibrosis to indicate the extent of liver damage.
“This enabled us to compare the various risk factors with the stage of fibrosis. In particular, the homeostatic model assessment of insulin resistance was clearly linked to the stage of liver fibrosis, but the concentration of low-density lipoprotein (LDL) and a genetic variant of the PNPLA3 gene (encoding patatin-like phospholipase domain-containing protein 3) were also clearly associated,” explains Mads Bastrup Israelsen.
A message that can change lifestyle
The new study cannot determine that insulin resistance and the genetic variant cause more severe alcohol-related liver disease but shows that they are associated. Future studies therefore aim to understand these associations.
“The genetic variant of PNPLA3 and insulin resistance are also associated with nonalcoholic steatohepatitis, with both increasing the risk of developing cirrhosis, so the evidence indicates that, although we currently differentiate between alcoholic and nonalcoholic liver diseases, the mechanisms that lead to these diseases probably overlap,” says Mads Bastrup Israelsen.
The latest research suggests that the genetic variant of PNPLA3 also changes the bacteria in the gut, which is extremely interesting since this study is one element in two major research projects: MicrobLiver, led by Torben Hansen; and GALAXY, led by Aleksander Krag. Both projects seek to understand the interaction between the gut and the liver.
“Only 6% of the participants were metabolically healthy, which emphasizes the strong association between alcohol consumption, the liver, gut flora and people’s general energy metabolism. The message is clear for preventing both alcoholic and nonalcoholic liver disease. In both cases, people need to drink less alcohol and consume fewer calories,” explains Mads Bastrup Israelsen.
The new knowledge now provides an even better basis for assessing who should especially watch their alcohol consumption. In the future, people can be screened for the genetic variant of PNPLA3. In combination with a blood test for insulin resistance, this is an effective tool to assess whether an individual has higher risk.
“These people often do not have a complex alcohol use disorder but drink an extra glass of wine or beer. Therefore, dialogue often succeeds for them. The message that excessive drinking risks their liver is usually enough to make them change their lifestyle,” says Mads Bastrup Israelsen.