Searching for effective ways to diagnose non-alcoholic fatty liver disease

23 January 2020

Around 20 million people in Germany suffer from non-alcoholic fatty liver disease (NAFLD). It can cause severe inflammation, cirrhosis of the liver, and even cancer. At present, there is no simple technique to detect NAFLD reliably at an early stage. But this is essential for the development of appropriate new drugs and therapies. The LITMUS research project seeks to make a major contribution in this field: Involving an international consortium, with the Mainz University Medical Center being a key player, the LITMUS network is developing biomarkers that open up new horizons.

"We take blood samples to determine the status of subject's liver." This is how Professor Jörn Schattenberg summarizes the main purpose of the LITMUS research project, which receives funding to the tune of EUR 34 million. "One in three of us suffers from fatty liver," adds Schattenberg, head of the Metabolic Liver Research Program at the Department of Internal Medicine I at the University Medical Center of Johannes Gutenberg University Mainz (JGU). "One of the reasons why so many people are affected today is the fact that our lifestyle has changed. We eat more nutritious food and we do more sedentary work. That is bad for the liver because it accumulates fat." This process with its often serious consequences can today at best be diagnosed by means of a biopsy, i.e, the removal of a sample of tissue. For two years now, however, experts in an international network have been searching for some form of alternative method.

The LITMUS project, short for Liver Investigation: Testing Marker Utility in Steatohepatitis, was launched in late 2017. The international consortium behind LITMUS aims to identify biomarkers with which it is possible to diagnose NAFLD. "Various universities and 20 large pharmaceutical companies jointly applied for funding from the European Union for the project, which had been in development for many years," points out Schattenberg. "They all recognized the urgent need for a simple and safe diagnostic tool to help develop effective drugs for NAFLD." The EU is contributing half of the research funding, with the other half coming from the private sector. "We have since been joined by other partners who also recognize the potential of our research."

International consortium investigating potential biomarkers

The consortium now comprises a total of 50 research institutions in addition to various pharmaceutical and biotech companies. The Mainz University Medical Center is an important partner in this international research network. Both Professor Jörn Schattenberg and the Director of the Institute of Translational Immunology (TIM), Professor Detlef Schuppan, are members of the LITMUS Executive Committee. "We collaborate on this project here at the University Medical Center and complement each other very well," says Schattenberg.

Schattenberg has just finished a patient's treatment and can now take a short break between consultations. He starts giving a short overview of what happens in NAFLD. "If fat accumulates in your liver, more cells die off. The liver can recover by regenerating, but this causes fibrous tissue to accumulate. The problem is that if cells are continuously being destroyed, the fibrous tissue will continue to build up. This fibrous tissue represents scarring of the liver, and if too much accumulates there can be a complete remodeling of the liver, resulting in cirrhosis. This also increases the risk of liver cancer."

Having a fatty liver doesn't necessarily result in such serious problems, but it can be the starting point for these. "That is why we need to identify NAFLD early on. But we do not yet have the diagnostic tools to do so." The only option available is biopsy, but as this is an invasive procedure the pros and cons always need to be considered very carefully. "You do not just do that," stresses Schattenberg.

The consortium is looking for markers in the blood that provide insights into liver status. These, on the other hand, would be of major interest and importance in the development, testing, and authorization of new medications. Rather than having to perform a biopsy, physicians would simply need to take a blood sample to test a drug's effectiveness. But the situation at the moment is uncertain: "There is still not a single drug on the market that has been approved," says Schattenberg.

Worldwide unique results

Schattenberg doesn't just remain in contact with his patients in Mainz, he also manages the ethical issues associated with handling the cases of the approximately 5,000 subjects in the LITMUS project, all of whom are suffering, to a varying degree, from liver disease. "We aim to, and need to, keep each patient fully informed. I myself take the time to talk at length with my patients. EU-wide data protection guidelines do exist, but procedures in France and the UK differ from those in Germany."

Coordination between the different countries and partners has always been challenging, especially at the beginning of the project. "In the meantime, however, an enormous dynamic has developed," concludes Schattenberg. He glances at his watch and takes his leave as he has patients waiting for him.

Professor Detlef Schuppan's office is just a few hundred meters away. In cooperation with the Danish company Nordic Bioscience, he is working on identifying such blood biomarkers: "Getting results from studies testing the effectiveness of novel NAFLD or antifibrotic drugs takes a very long time," he explains. "Proving their efficacy is very time-consuming and costly, and onerous on patients. If we knew what blood markers we could use, we could directly monitor the progress of the disease, from inflammation to liver cirrhosis – and naturally also the effects of any medication we administer. This would enable us to see very rapidly what effect treatment was having, and we would no longer need to take tissue samples."

In his opinion, discovering blood and biomarkers will not just be important in connection with NAFLD. "They could help us to diagnose and treat many chronic diseases as well as to develop and test cancer drugs." Schuppan is optimistic about the LITMUS project: "We have already discovered some very promising markers that are close to being approved. These can reveal how active fibrosis is and whether it is progressive or not. We are the first in the world to achieve that." His many years of scientific and clinical experience in fibrosis research and as a hepatologist have played a major role in this world-class achievement.

Side effects: Effective treatments with known drugs

It goes without saying that pharmaceutical companies have a considerable interest in developing new drugs. Schuppan, however, adds another focus: "As physicians, the health of our patients is our chief concern. In certain cases a combination of very simple, existing drugs will be effective. Five years ago, we published a high-ranking paper with evidence that aspirin, for example, can inhibit liver fibrosis. There are also other inexpensive drugs that have been shown to have similar effects. The pharmaceutical industry is, understandably, not as interested in such research nor in the testing of combinations of such drugs, which, in all likelihood, could turn out to be both very effective and associated with few undesirable effects.

"Using blood markers would allow us to investigate such therapeutic approaches much more easily and with drugs that cost only a few euros per day. Blood markers would also help us to tailor such drug combinations to the needs of individual patients. This would represent further progress towards the development of genuinely personalized medicine."

New blood markers have the potential to drive such developments in a wide range of areas. "We would be able to treat a whole range of common diseases with innovative methods," asserts Schuppan, venturing a look into the future. "Treatment based on markers will open up completely new and often inexpensive opportunities. The pharmaceutical industry may not be particularly excited at the prospect, but we physicians and our patients certainly are."