NASH, NAFLD, & NIS4: Ask an Expert with Marge Connelly

Dr. Margery Connelly is the lead scientist behind several Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) tests at Labcorp, as well as testing for other metabolic disorders. Dr. Connelly discusses the clinical significance of NASH and what positive NASH and liver fibrosis test results mean for patients. Read her bio >>

What are NAFLD and NASH?

Dr. Marge Connelly: Nonalcoholic fatty liver disease (NAFLD) is defined by the accumulation of lipids in hepatocytes, in the absence of significant alcohol intake, viral infection, or other etiologies of fatty liver disease. Within NAFLD there is a spectrum of histopathologic features that includes hepatic steatosis or fatty liver, steatosis accompanied by liver inflammation and liver cell injury (ballooning) which is referred to as nonalcoholic steatohepatitis (NASH), liver fibrosis and NASH-related cirrhosis.

Furthermore, patients with at-risk NASH, which is defined by the presence of NASH and significant or advanced fibrosis with a NAFLD activity score ≥ 4, and liver fibrosis stage ≥ 2 as assessed by histological evaluation of a liver biopsy, have a higher risk of progression to more severe liver disease.

Who is at risk for NAFLD and NASH?

MC: People with metabolic syndrome, prediabetes, type 2 diabetes, obesity, dyslipidemia, and/or hypertension. However, NASH is often a silent disease and patients with NASH do not show definitive symptoms until the disease has progressed. Early signs of NASH such as elevated liver enzymes such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) can be found in many other diseases which makes early detection of NASH challenging.

How common is NAFLD and NASH?

MC: NAFLD has a high prevalence worldwide, estimated to affect more than 25% of the general population. Obesity is a common cause of the disease, and it is estimated that as many as 20% of obese adults have the most severe form of NAFLD, NASH. NASH is projected to become the leading cause of liver transplantation in the U.S., where it already is the primary cause among women and the secondary cause overall. NASH, however, remains a highly underdiagnosed disease due to its asymptomatic nature and the limitations of existing diagnostic approaches.

Historically it has been difficult to definitively identify patients with NASH and liver fibrosis. [I]t is important that new diagnostic tools are employed in order to clearly identify patients with NASH and liver fibrosis.

Dr. Marge Connelly, Labcorp

What is NIS4?

MC: NIS4 is GENFIT’s non-invasive, multi-biomarker based algorithm specifically developed to identify patients with at-risk NASH.

Labcorp is committed to developing and distributing NIS4 to specialty and primary care physicians across the U.S. and Canada to support the diagnosis of patients with NASH. That's why the launch of NASHnext^TM is such an important milestone in helping inform decisions and implement strategies to monitor or slow the progression of NASH.

What is NASHnext™?

MC: NASHnext is a blood-based diagnostic test that quantitatively measures four independent biomarkers to produce a NIS4 score, which identifies, among patients with metabolic factors, those with at-risk NASH, who are at higher risk of disease progression.

How is a NIS4 score calculated?

MC: The NIS4 scores range from 0 to 1 and are calculated by combining the results of four individual biomarker assays [miR34a-5p, α2-macroglobulin (A2M), YKL-40 and HbA1c] each of which contributes to the test’s ability to detect liver inflammation and/or fibrosis.

Why is the addition of NASHnext important to Labcorp’s offerings for NASH?

MC: Many of the tests on the market for evaluation of patients for NASH and liver fibrosis are only capable of identifying later stage or advanced fibrosis. For example, the AST-to-Platelet Ratio Index (APRI), Fibrosis-4 (FIB-4), and Enhanced Liver Fibrosis test (ELF^TM) tests and are able to identify most patients with advanced or severe liver fibrosis but not necessarily in the context of NASH. The NASH FibroSure test produces three separate results for identifying steatosis, NASH and fibrosis. 

NASHnext produces a single score for identifying patients with both NASH and significant or advanced liver fibrosis.

We have already seen success within our drug development business where pharmaceutical customers have included NIS4 in their clinical studies. Our agreement with GENFIT allows us to add to our current NASH test menu by adopting this great technology, enabling widespread access to healthcare providers.

Which patients may benefit from getting a NASHnext test?

MC: Patients with one or more of the metabolic risk factors, as well as those with metabolic syndrome, prediabetes, type 2 diabetes, obesity, dyslipidemia, hypertension and/or elevated ALT or AST are at higher risk of having NASH and may benefit the most from this type of testing.

How will physicians and healthcare providers be able to use NASHnext to optimize care for their patients?

MC: Physicians will be able to use NASHnext as a means to assist in identifying patients who may need early intervention (including lifestyle modification) in order to reduce progression of NASH. Liver disease due to etiologies other than metabolic disease – including viral hepatitis, hepatitis due to excessive alcohol consumption, drug induced hepatitis, genetic liver diseases, autoimmune hepatitis and/or extrahepatic cholestasis – should be ruled out by the use of appropriate testing. Fatty liver disease can be identified by the use of ultrasound imaging.

Patients whose NIS4 scores fall into the >0.63 category have a higher risk for at-risk NASH or advanced fibrosis and treatment with aggressive lifestyle or therapeutic interventions may be considered. For patients whose NIS4 scores fall into the moderate risk category, 0.37-0.63, physicians might consider additional testing for NASH and liver fibrosis, such as FIB-4 or the NASH FibroSure test, to provide assurance that the patient’s disease is not advanced. Alternatively, physicians may want to repeat NASHnext testing in 6-12 months to ensure a patient’s liver disease is not progressing.

In addition, NIS4 technology has shown reliable diagnostic performance across multiple clinically-relevant subpopulations, including those with type 2 diabetes. Unlike other diagnostic tests, the performance of NIS4 was not impacted by age, sex, body mass index (BMI), ALT or AST, or metabolic comorbidities such as type 2 diabetes or obesity.

How will NIS4 scoring change therapeutic decision making and patient care?

MC: Historically it has been difficult to definitively identify patients with NASH and liver fibrosis. Given that NASH can be silent while progressing to end stage liver diseases, such as NASH-related cirrhosis and hepatocellular carcinoma (HCC), it is important that new diagnostic tools are employed in order to clearly identify patients with NASH and liver fibrosis. NASHnext is a promising new diagnostic tool that Labcorp is excited to begin offering to healthcare providers to help inform the best course of intervention, from early treatment and prevention of progression to later stage disease where liver transplant may be the only treatment option.