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Frequently Asked Questions on the Management of NAFLD/NASH

Manal F. Abdelmalek, MD, MPH

Professor of Medicine
Division of Gastroenterology and Hepatology
Duke University
Durham, North Carolina


Manal F. Abdelmalek, MD, MPH, has disclosed that she has received consulting fees from Allergan, Bristol-Myers Squibb, Madrigal, NGM Pharma, Promethera, Prometic, Inventiva, and TaiwanJ; funds for research support from Allergan, Bristol-Myers Squibb, Boehringer-Ingelheim, Conatus, Galmed, Genfit, Gilead Sciences, Intercept, Inventiva, Poxel, Enyo, Durect, Progenity, Target-NASH, Madrigal, NGM Biopharma, Novartis, Novo Nordisk, Viking ; and fees for non-CME/CE services from Alexion and Intercept.


View ClinicalThoughts from this Author

Released: January 16, 2020

This ClinicalThought features key follow-up questions from our symposium in Boston on liver health.

When do you consider bariatric surgery in your patients with nonalcoholic steatohepatitis (NASH)?
I consider bariatric surgery often in patients with NASH when patient otherwise have an indication for bariatric surgery. This includes younger patients with 3 or more risk factors for metabolic syndrome and patients with diabetes for whom trials of lifestyle intervention have failed. Further, bariatric surgery can cure their diabetes and optimize their overall survival and improve NASH.

Bariatric surgery is not advised for patients with cirrhosis, marginal liver synthetic function or portal hypertension. Consideration of bariatric surgery for patients with advanced hepatic fibrosis requires a multidisciplinary  approach and close collaboration with the bariatric surgeon. It should preferably be performed at a tertiary medical center with expertise in hepatology, bariatric surgery, and liver transplantation.

Because NASH is a biopsy-drive diagnosis and current therapies are validated on histology, how are you incorporating noninvasive testing into your management?
I incorporate the use of noninvasive biomarkers to risk stratify patient with risk factors for NAFLD/NASH.  In the absence of an FDA approved therapy, I use these tests to determine who has low probability for hepatic fibrosis vs who has advanced hepatic fibrosis and might therefore require surveillance for hepatocellular carcinoma and/or screening of esophageal varices and targeted treatment approaches as may be available in clinical studies.

For example, if a patient has a liver stiffness value < 5 kPa as measured by vibration-controlled transient elastography (VCTE) and a low FIB-4 score, that patient likely does not have significant hepatic fibrosis and can be managed with lifestyle modification.

By contrast, if a patient’s biomarkers suggest increased risk for advanced hepatic fibrosis, I will implement routine monitoring and surveillance and I may suggest they enroll in a clinical study for an emerging therapy for NASH. 

If a patient falls in the indeterminate range or if I have concerns of a competing diagnosis, such as autoimmune hepatitis or iron overload, I will then order a biopsy to confirm the diagnosis and stage the severity of hepatic fibrosis.

Which is more important, fibrosis improvement or NASH resolution?

The presence and severity of NASH is intimately connected with the development and progression of hepatic fibrosis.

Hepatic fibrosis is the primary predictor for liver-related morbidity and mortality, and decreasing the risk for fibrosis progression, even without fibrosis improvement (ie, maintaining stability), decreases the risk for future hepatic decompensation.

Sustained resolution in necroinflammatory injury, as has been observed with other forms of chronic liver disease for which effective treatments exist, leads to improvement in hepatic fibrosis over time. NASH resolution is a prerequisite for improvement of hepatic fibrosis.

As per the FDA guidance, the question isn’t whether it’s more important to improve fibrosis or resolve NASH. What’s most important is that improvement in either should not be accompanied by worsening of the other: Improvement in fibrosis must not be achieved at the expense of worsening the inflammatory response, and improvement in NASH must not be achieved at the expense of worsening fibrosis.

With the lack of very sensitive measures  for discerning subtle change in hepatic fibrosis, short-term  studies risk missing the primary outcome of fibrosis improvement. But, even in short-term studies, new machine learning models for NASH and hepatic fibrosis may lend higher levels of sensitivity by which to assess the endpoint of NASH resolution. If NASH resolution is achieved (and sustained), fibrosis improvement, with time, will also likely to be achieved.

In the context of a disease that takes decades to progress, I believe it is time for the field to reflect on the stability of fibrosis rather than fibrosis improvement, as a potential meaningful endpoint. Keeping patients stable, despite not being able to readily improve hepatic fibrosis within the timeline set by most clinical studies, may translate into decreased risk of complications such as hepatic decompensation, the need for transplant, or the development of liver cancer, all of which would otherwise occur with fibrosis progression.

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