Diseases to Watch: Fatty liver disease and NASH

Diseases to Watch: Fatty liver disease and NASH
by Robert Poolman
Director of Discovery and Pre-Clinical Products, Clarivate Analytics
Life Sciences Connect

With Diseases to Watch, we introduce a new series in Life Sciences Connect providing a profile of a disease or therapeutic area which is currently a “hot topic” in the life sciences industry. The first disease profiled was fatty liver disease and NASH where we outline the disease in general and link to a further discussion about novel and validated target identification using Target Druggability, a new tool from Clarivate Analytics.

Non-alcoholic fatty liver disease and the more severe form of this disease called non-alcoholic steatohepatitis, or NASH, are two increasingly prevalent diseases characterized by the progressive accumulation of fat or triglycerides within the liver. This accumulation occurs in the absence of excessive alcohol consumption. It can lead to inflammation, oxidative damage and the development of scar tissue. The important point is that this disease is a progressive disease that, if untreated, can lead to cirrhosis, fibrosis and even to liver cancer. The good news, however, is that this disease is reversible right up to the point of cirrhosis.

Why should we be concerned about these two diseases? Up until recently fatty liver disease and NASH were considered to be relatively rare and harmless. But due to the growing, global obesity epidemic the prevalence of both fatty liver disease and NASH has grown significantly; fatty liver disease has now become the most prevalent chronic liver disease. It is projected to be the leading indication for liver transplant within the next decade.

“Due to the growing, global obesity epidemic the prevalence of both fatty liver disease and NASH has grown significantly; fatty liver disease has now become the most prevalent chronic liver disease. It is projected to be the leading indication for liver transplant within the next decade.”

While both fatty liver disease and NASH are projected to grow significantly in the U.S. over the next decade, it is important to note that they are not confined to the developed world. By 2017, the presence of fatty liver disease had reached around 25% of the population worldwide, and the more severe form, NASH, was identified in around 4% of the population in the world.

 

Symptoms and risk

In its early phases, the diseases are asymptomatic making them quite difficult to detect. Some patients may suffer with abdominal discomfort and tiredness, but until the disease progresses to NASH, the more severe symptoms like jaundice, abdominal swelling, bleeding and fluid retention would not be seen. Fatty liver disease and NASH are diagnosed using a combination of liver function tests and enzyme tests, as well as imaging, using ultrasound or MRI, and biopsy.

Risk factors for both diseases include obesity and old age; predisposing conditions such as diabetes, hypertension and hyperlipidemia; and ethnicity, with both Asian and Hispanic populations showing an increased predisposition to both diseases. In addition, lifestyle factors such as high-fat diets, smoking and inactivity increase the likelihood of developing both diseases.

There have been a number of genetic polymorphisms that have been identified that put certain individuals at an increased risk of fatty liver disease and NASH, as well as some alterations in the gut microbiome.

 

So what are the potential treatments for the diseases?

Well, first things first: They start with intense lifestyle modifications including weight loss, increased activity and healthy eating. And second line to these modifications are both medical and surgical treatments. But note that at the moment there is no approved drug for NASH on the market.

“… At the moment there is no approved drug for NASH on the market.”

 

Drugs under investigation

There are a number of drugs that are being investigated for both diseases, however. They include standard anti-diabetics, DPP4 inhibitors, statins and even PPAR-α-/γ agonists.

Drugs being investigated for NAFLD and NASH

Drug Category Representative Mode of action
Anti-diabetics Metformin, Pioglitazone Improve insulin sensitivity
GLP1 analogues Exenatide, Liraglutide Suppress appetite, increase weight loss and increase insulin production
DPP4 inhibitors Sitagliptin, Linagliptin Enhances insulin production
Anti-oxidants Vitamin E Reduce oxidative stress
Statins Atorvastatin Lowers plasma lipids
Lipase inhibitors Orlistat Decrease fat absorption from intestine
Farnesoid XR agonist Obeticholic acid Reduce steatosis and inflammation
PPAR-a/g agonist Elafibranor Reduce steatosis, inflammation and fibrosis

Sources: Pappachan, J.M. et al. J Clin and Trans Hepat  (2017) 5: 384-393; Neuschwander-Tetri, B.A. BMC Medicine (2017) 15: 45-50; Incidence and Prevalence Database and Integrity Disease Briefings, Clarivate Analytics.

 

However, the challenge is to identify targets for future drugs for both these diseases. The problem that we have with both diseases is that they are multi-factorial and involve complex genetic factors. There is also a lack of clinical trial endpoints that have been validated for both diseases. Furthermore, information on these diseases is scattered in multiple databases and this makes it quite difficult to identify and prioritize druggable targets.

The impact of these problems is loss of time for researchers spent compiling data from multiple sources, and therefore their potential to pursue targets that lack scientific evidence to link them to the disease.

Part of the solution to these challenges is having access to a database of curated scientific data that can rank targets based on scientific evidence. A solution such as Target Druggability can help.

Please click here for more discussion from the author, who is joined by Sonya Novikova, solution scientist at Clarivate Analytics, for a discussion and demonstration on harnessing the Clarivate Analytics Target Druggability tool to more effectively visualize target disease information for fatty liver disease and NASH and to identify novel targets to pursue. 

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