NAFLD and Weight Loss: Study Quantifies Dose-response Relationship

In patients with nonalcoholic fatty liver disease (NAFLD), even modest weight loss results in clinically significant improvements, according to findings of a meta-analysis published in Metabolism Clinical and Experimental.

Estimates are that approximately half of individuals with NAFLD also have obesity, placing them at risk for disease progression, the authors note. There are currently no pharmacologic treatments for management of NAFLD but current guidelines do recommend weight loss and other lifestyle changes as “cornerstones” for management, although these recommendations are based on only “moderate quality” evidence.

The authors cite previous meta-analyses of weight loss intervention trials that, taken together, suggest greater improvements in a range of biomarkers of liver disease with greater reductions in weight but it is unclear if there is a dose-response relationship. Their analysis sought to quantify that relationship between magnitude of weight loss and improvements in NAFLD.

Nine databases and trial registries were searched until October 2020. Studies eligible for inclusion were single-arm, nonrandomized comparative, or randomized trials of weight loss interventions in people with NAFLD that reported an association between changes in weight and changes in blood, radiologic, or histologic biomarkers of liver disease. Interventions included were behavioral weight loss programs (BWLPs), pharmacotherapy, or bariatric surgery. Standard methods of review and a validated assessment for risk of bias were used. Pooled unstandardized b coefficients were calculated using random-effect meta-analyses.

A total of 43 studies (BWLPs, 26; pharmacotherapy, 9; bariatric surgery, 8) with 2809 participants were included. Most studies were conducted in high- or middle-income countries. Diabetes and hypertension were prevalent in studies that reported the characteristics. NAFLD was diagnosed by biopsy, MRI, CT, ultrasound, or liver function tests. Overall, 44% of participants were women, average age was 46.8 years, and BMI, 32.8 kg/m^2. Median follow-up was 6 months with bariatric surgery generally longer (median, 17 months). Direction of effect was overall consistent, but estimates were imprecise.

According to the authors, the results suggest that:

• Initial weight loss of ~5kg is associated with a minimal clinically meaningful improvement in steatosis of 5%, on average.
• An additional 5% reduction in steatosis was seen with each additional 6 kg of weight loss.
• Initial loss of 4 kg and 2 kg saw clinically meaningful improvements in ALT (12 U/L) and AST (7 U/L), respectively. The authors note that weight loss programs typically offered in routine care, ie, community-based groups, show similar mean reductions in weight at one year.
• Bariatric surgery led to greatest weight loss with proportional larger benefits in liver outcomes, but the dose-response relationship was weaker than with other treatments.

Evidence of a dose-response relationship was observed with liver inflammation, ballooning, and resolution of NAFLD or nonalcoholic steatohepatitis but there was only limited evidence of the relationship with fibrosis or NAFLD activity score.

The authors suggest that physicians could use the results in conversations with patients to help support recommendations for weight loss. They also emphasize in their comments that offering patients structured support, such as would be found in a community or other type of weight loss program, is far more likely to be successful than “simply advising weight loss.”

“If greater weight loss leads to greater improvements, weight loss programs that are more effective should be considered as the first-line option for the treatment of NAFLD," they state.

Strengths and weaknesses

The authors point to several strengths of the study including an initial search limited to interventions intended for weight loss, inclusion of studies that included bariatric surgery, and, given the absence of an ideal biomarker for NAFLD/NASH the concordance of a dose response relationship between weight loss and various liver biomarkers minimized risk of false positive findings.

Limitations include an assumption of a linear relationship between changes in weight loss and biomarkers of liver disease and a high level of heterogeneity among studies.