Key Publication

Reviewer: Manpreet S. Mundi, MD; Associate Professor of Medicine, Division of Endocrinology, Diabetes, Metabolism, and Nutrition; Mayo Clinic, Rochester, MN.

Reference: Koutoukidis DA, Astbury NM, Tudor KE, et al. Association of Weight Loss Interventions With Changes in Biomarkers of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. JAMA Intern Med. July 2019. doi:10.1001/jamainternmed.2019.2248

Why is this paper important? This meta-analysis reveals the beneficial impact of weight loss through any intervention on non-alcoholic fatty liver disease (NAFLD). 

Summary: The currently reviewed manuscript is a meta-analysis that included randomized control trials (RCTs) focused on treatment of adult patients with NAFLD through weight loss.  They included trials focused on lifestyle modification through behavioral weight loss programs (BWLP), pharmacotherapy, bariatric surgery, or the combinations of these modalities.  The following outcome variables were assessed; alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), the Enhanced Liver Fibrosis score, the NAFLD fibrosis score, the Fatty Liver Index, liver stiffness, radiologically or histologically measured steatosis, inflammation, ballooning, fibrosis, and the NAFLD Activity Score (NAS). Additional outcomes evaluated included body weight and insulin-resistance markers (hemoglobin A1c, fasting glucose, fasting insulin, and the homeostatic model assessment for assessing insulin resistance [HOMA-IR] or equivalent). 

After screening 2096 titles, 22 studies (20 full text articles and 2 abstracts) were including consisting of 2588 participants.  15 studies tested BWLP, 6 tested pharmacotherapies (including liraglutide – 2 studies, Orlistat – 3 studies, and Sibutramine – 1 study), and one study tested intragastric balloon.  The median (IQR) intervention duration was 6 (3-8) months and resulted in in significant weight loss (-3.61 kg; 95% CI, -5.11 to -2.12).   Weight loss interventions were statistically significantly associated with improvements in biomarkers, including alanine aminotransferase (–9.81 U/L; 95% CI, –13.12 to –6.50), histologically or radiologically measured liver steatosis (standardized mean difference: –1.48; 95% CI, –2.27 to –0.70), histologic NAFLD activity score (–0.92; 95% CI, –1.75 to –0.09), and presence of nonalcoholic steatohepatitis (OR, 0.14; 95% CI, 0.04-0.49). No statistically significant change in histologic liver fibrosis was found (–0.13; 95% CI, –0.54 to 0.27).

Commentary: As the obesity epidemic continues to increase in prevalence worldwide, the health care community is underprepared for its full impact given association with a number of co-morbidities ranging from diabetes to endometrial cancer. One of these comorbidities is a spectrum of diseases categorized as non-alcoholic fatty liver disease (NAFLD) which ranges from fatty liver (steatosis) to inflammation and fibrosis (steatohepatitis; NASH) and can also progress to liver cirrhosis.  NAFLD is a manifestation of metabolic syndrome with insulin resistance playing a key pathogenic role.  As individuals gain weight and develop insulin resistance through consumption of excess calories and decrease caloric expenditure, there is increased free fatty acid (FFA) delivery to the liver.  Key isotope labeled trials have shown that these FFA arrive from three distinct sources including release from adipose tissue, dietary fat, and de novo lipogenesis from excess carbohydrates.  As FFA arrive, they are taken up by the liver in proportion to their rate of deliver and stimulate hepatocyte very low density lipoprotein (VLDL) triglyceride synthesis.  Unfortunately, as the delivery of these energy substrates exceeds the liver’s capacity to handle them, the storage pool continues to grow, and their metabolites begin to cause liver injury.  In addition to simply excess calories, certain combinations often found in fast food (red meat, trans-fat, high fructose corn syrup, highly refined carbohydrates, low fiber, and high energy density) may be the most deleterious when combined with sedentary behavior.  

It is due to this direct correlation of NAFLD with weight gain and insulin resistance, that weight loss is the treatment of choice.  Key studies like the one reviewed here are highlighting the benefits of even modest weight loss (5-10%) in reversing NAFLD.  However, it is important to highlight that this level of weight loss cannot be achieved through simple advice from a clinician during one visit.  Instead, intensive behavior therapy that typically consists of weekly visits for 3-6 months and focuses on improvement in diet (especially avoiding “fast-food”) and increase in activity level is needed to achieve 5-10% in most patients.  Even despite the use of these intensive BWLP such as those offered by the LOOK Ahead trial and the Diabetes Prevention Program (DPP), not all patients will respond.  Therefore, it is key for the clinical to follow their patients closely and if they are not losing weight to escalate the intensity by adding weight loss medications and/or proceed to endoscopic or surgical intervention.  Additionally, even patients who respond initially may have weight regain over the long run.  These patients often feel quite discouraged and may not seek additional care. It is important to follow these patients long-term as with weight regain, there is often return of weight related co-morbidities.  


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