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 these disease are progressive diseases that, if untreated, can lead to cirrhosis, fibrosis and even to liver cancer. The good news, however, is that they are 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.
A 2018 study reported that the prevalence of fatty liver disease and NASH in the U.S. are projected to grow by 21% and 63% respectively by 2030.1 However, it is important to note that these diseases are not confined to the developed world. By the end of 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, according to the Incidence and Prevalence Database, from Clarivate Analytics.
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 currently approved drug for NASH on the market.
Drugs under investigation
There are a number of drugs that are being investigated for both diseases, however (See Table 1). They include established anti-diabetics, anti-oxidants and statins, as well as novel therapies including PPAR-α-/γ agonists, SGLT2, Caspase and ASK1 inhibitors.
|Drug category||Representative||Mode of action|
|Anti-diabetics||Metformin||Improve insulin sensitivity|
|GLP1 analogues||Exenatide, Liraglutide||Suppress appetite, increase weight loss and increase insulin production|
|DPP4 inhibitors||Sitagliptin, Linagliptin||Enhance insulin production|
|Anti-oxidants||Vitamin E||Reduce oxidative stress|
|Statins||Atorvastatin||Lower plasma lipids|
|Lipase inhibitors||Orlistat||Decrease fat absorption from intestine|
|Farnesoid XR agonists||Obeticholic acid||Reduce steatosis and inflammation|
|PPAR-a/g agonists||Elafibranor, Pioglitazone||Reduce steatosis, inflammation and fibrosis|
|SGLT2 inhibitors||Canagliflozin, Ipragliflozin, Luseogliflozin||Reduce steatosis, apoptosis and fibrosis|
|Caspase and ASK1 inhibitors||Emricasan, Selonsertib||Reduce steatosis, apoptosis and fibrosis|
Table 1: Novel therapies including PPAR-α-/γ agonists, SGLT2, Caspase and ASK1 inhibitors have joined more established agents under investigation for NASH and fatty liver disease such as anti-diabetics, anti-oxidants and statins. Source: Cortellis Competitive Intelligence.
Identifying targets for future drugs for these diseases, which are both multi-factorial and involve complex genetic factors, is a challenge. There is also a lack of clinical trial endpoints that have been validated for both diseases.
As both diseases surge in prevalence around the world, compounded by the global obesity epidemic, so too does the search for effective agents to treat them.”
Currently, 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 the loss of time for researchers spent compiling data from multiple sources and therefore the potential to pursue targets which 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 helps researchers effectively visualize target disease information for fatty liver disease and NASH and to identify novel targets to pursue and rank them based on the scientific evidence.
As both diseases surge in prevalence around the world, compounded by the global obesity epidemic, so too does the search for effective agents to treat them.
- Estes, C. et al. Hepatology (2018) 67;1 123-133
For more information on preclinical workflow tools using analytics, visualizations and insight to drive target identification, visit: clarivate.com/products/drug-research-advisor/