Tristan Baldwinson
Tristan Baldwinson
Senior Director, Project Delivery

While obesity and alcoholism are two very different health issues, both can have a similar impact on the liver. Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease far surpassing alcohol-related liver disease. NAFLD is considered to be the hepatic manifestation of the metabolic syndrome, a cluster of closely related clinical features linked to visceral obesity and characterized by insulin resistance, dyslipidemia, and hypertension. As the prevalence of obesity and metabolic syndrome increases in the industrial world, NAFLD is expected to rise as well.

NAFLD is thought to be represented by a spectrum of histological diseases, which progresses from simple steatosis to nonalcoholic steatohepatitis (NASH), and inflammation which causes liver cell damage. Up to one-third of these NAFLD patients go on to develop NASH.

Those who with conditions such as type 2 diabetes, obesity, and metabolic syndrome are more likely to suffer from NAFLD and NASH. It’s estimated 12%- 25% of the US population have NAFLD while 2%-5% are affected by the more serious NASH – which can progress toward cirrhosis and cancer of the liver. Globally, NAFLD through NASH is prevalent in over 20% of the general population in Europe and North America and somewhat higher in the Middle East and South Asia.

Epidemiological studies to assess the genetic component of NASH are important to better understand the condition. For instance, Native American males are more likely to suffer from NAFLD and two genetic mutations for susceptibility have been identified, providing clues to the mechanism of NASH and related diseases. The genes identified (PNPLA3 and TM6SF2 gene variants) are major determinants of hepatic fat accumulation.

In all populations NAFLD and NASH are a growing problem. Looking at the incidence of diabetes (often a comorbid condition), according to the World Health Organization’s Global Burden of Disease report for 2015, the prevalence of diabetes rose from approximately 333 million persons in 2005 to approximately 435 million persons in 2015, a 30.6% increase in a decade alone. Although it is not a given that sufferers of type 2 diabetes will develop liver issues, fatty liver is present in a great number of sufferers. While diabetes and liver issues are often comorbid, diabetes is not the cause of fatty liver, rather the two tend to occur within the same patients due to the same conditions being the root cause of both problems, namely, obesity and insulin resistance. Lifestyle factors – including rising affluence in Middle Eastern and South Asian countries can be attributed to the high incidence of diabetes and NAFLD/NASH alike.

Physicians currently endorse weight loss to treat NAFLD/NASH. Weight loss can reduce fat in the liver, scarring, inflammation, and cirrhosis. Transplant is an option for very advanced cases.

There are currently no approved therapeutics to treat either condition, however some studies suggest that a medicine currently used for type 2 diabetes, pioglitazone, could improve NASH even in patients who don’t suffer from comorbid diabetes.

Clinicaltrials.gov identifies over 70 active or recruiting studies specific to NASH globally. These studies include lifestyle modification, vitamin supplements, investigation into pre-existing therapeutics, and novel drugs. A handful of these studies have promisingly advanced to Phase III.

PRA NASH Study Experience

PRA has worked on numerous NASH trials in recent years, including a global five-study Phase II & III program that enrolled almost 2,000 patients in 2.5 years at over 400 unique sites across nearly 30 countries. The final Phase III study completed enrolment 12 months ahead of schedule, with an enrolment rate that was double that forecasted by the client at the outset - during a time of high competition for this patient population.

PRA worked closely with high-performing sites to identify best practices and shared those across all sites in the program. These efforts, along with others including patient pathway mapping, study branding and streamlined site contracting, helped enable the overall successful program delivery.

Sources:

https://www.niddk.nih.gov/health-information/liver-disease/nafld-nash

Chronic liver disease in Aboriginal North Americans, World Journal of Gastroenterology https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2738784/

Genetic Factors in the Pathogenesis of Nonalcoholic Fatty Liver and Steatohepatitis, BioMed Research International https://www.hindawi.com/journals/bmri/2015/460190/

http://www.who.int/healthinfo/global_burden_disease/en/

Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial. https://www.ncbi.nlm.nih.gov/pubmed/27322798