Fatty liver gives no warning signs

Most of us know that excessive alcohol use is bad for the liver. However, it is much less common knowledge that you can get liver disease even if you don’t consume alcohol at all.  

Text Ulla Kaltiala Photo Raija Törrönen

As much as 30 per cent of the Western population are estimated to be affected by non-alcoholic fatty liver disease (NAFLD), usually linked to obesity.  

A healthy liver contains little or no fat. In NAFLD, extra fat starts accumulating in liver cells. Fatty liver is usually symptomless and may remain harmless, but it can also progress to NASH, non-alcoholic steatohepatitis, where fat accumulation is accompanied by liver inflammation, cell damage and fibrosis – scarring of the liver tissue. The final stage is cirrhosis, a potentially life-threatening condition where the liver functions are irreversibly compromised. In addition, fatty liver increases the risk of liver cancer.

“In three out of four cases, cirrhosis is only found at an advanced state. It is really important to diagnose NAFLD early on and to identify those in whom the disease is likely to progress,” says Ville Männistö, medical doctor and postdoc researcher focusing on the pathogenesis of the disease.  

“Weight loss reduces liver fat effectively, and damage to liver tissue can even be reversed in the early stages. Drugs for NASH are also being tested in numerous trials.”  

“However, at the moment there is no reliable way of predicting who will get NASH and who won’t, and the diagnosis requires a liver biopsy, which can’t be taken from all fatty liver patients.”

 

Fatty liver often goes undiagnosed to begin with. It doesn’t always show in liver function tests or ultrasounds. “Magnetic resonance elastography shows promise in detecting both fat accumulation and scarring, but it’s not widely available yet.”

Männistö works with Professor Jussi Pihlajamäki to investigate how the interactions between genetic and lifestyle factors affect obesity-related diseases like NAFLD and type 2 diabetes. Their unique dataset comprises liver and fat tissue biopsies and clinical data from more than 400 patients that have undergone bariatric surgery for weight loss at Kuopio University Hospital’s Clinical Nutrition and Obesity Centre.

“These patients are massively obese at the starting point and almost all of them have NALFD,” Männistö says.

“One focus of our research is how changes in fatty acid metabolism contribute to the progression of the disease.”

 

Obesity increases the risk of both cardiovascular diseases and type 2 diabetes. These diseases are linked to NAFLD, too. The liver plays an important role in regulating blood sugar and blood lipids, and the accumulation of fat in the liver can disturb these functions. Many risk genes for NAFLD also increase type 2 diabetes and cardiovascular risk.  

Whether or not genetic risk manifests itself may depend on epigenetic mechanisms that regulate gene activity. They in turn are affected by environmental factors like diet and lifestyle. For example, the research group recently found that insufficient folate intake was associated with epigenetic changes in diabetes-related genes in the liver. They have also shown that the diabetes drug metformin exerts its action via epigenetic mechanisms in the liver.  

“Healthy dietary guidelines also apply in the prevention and treatment of NAFLD. Saturated fats and fructose from soft drinks are specifically known to increase the risk.”

Even moderate alcohol use is not recommended for people with NAFLD. Some drugs can also cause more damage to the liver. However, cholesterol-lowering drugs, or statins, don’t seem to be among them, according to the results from a multi-centre study, including Kuopio. Statins have been underused for patients with NAFLD because their use tends to elevate liver values, but the study showed that statins, in fact, may prevent progression to NASH.

 

The most common NAFLD risk gene is a PNPLA3 gene variant carried by 40 per cent of the population in Western countries. Homozygous carriers, who have inherited the risk gene from both parents, make up just five per cent of the population, but they have 70 per cent more fat in their liver than non-carriers.  

The Physical Activity and Nutrition in Children (PANIC) study at UEF showed that, combined with being overweight, the PNPLA3 gene variant is already linked to altered liver metabolism in children.

An example of the genetic complexity behind NAFLD is a TM6SF2 gene variant. It causes fat accumulation in the liver and may promote progression to NASH while decreasing blood lipid levels. Thus, ideal blood lipid levels may conceal the risk of fatty liver and NASH, which was observed in the PANIC study as well.  

“Other gene variants have also been linked to more severe liver disease, but it remains to be seen how genetic information will affect treatment choices in the future.”  

“At present, more awareness is needed of NAFLD and the risks it entails. Diagnostics and follow-ups are just as important in NAFLD as in other obesity-related diseases.”

Photo: Ville Männistö and colleagues study the genetics, epigenetics and pathogenesis of non-alcoholíc fatty liver disease in a unique dataset of more than 400 bariatric surgery patients.

UEF Bulletin 2018