Target Audience and Goal Statement: Hepatologists, weight loss specialists, endocrinologists, hematologists, primary care physicians
The goal was to estimate the association of weight loss interventions with biomarkers of liver disease in non-alcoholic fatty liver disease (NAFLD).
Question Addressed:
- Were weight loss interventions associated with changes in biomarkers of liver disease in people with NAFLD?
Synopsis and Perspective:
About 25% of adults worldwide and two-thirds of those with obesity have NAFLD. This disease is diagnosed when more than 5% of a person’s liver is comprised of fat. NAFLD encompasses a histological spectrum of conditions ranging from excess fat deposits in the liver (steatosis, non-alcoholic fatty liver) to non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Beyond the liver, NAFLD is associated with heightened risks for cardiovascular morbidity, hepatocellular carcinoma, and mortality. Obesity remains the most common risk factor for this condition.
Action Points
- Weight loss interventions were associated with clinically meaningful improvements in biomarkers of liver disease, but not a change in fibrosis, based on a systematic review and meta-analysis of 22 randomized clinical trials (n=2,588) of nonalcoholic fatty liver disease (NAFLD).
- Note that the evidence appeared to support changing the current clinical guidelines and recommending formal weight loss programs to treat people with nonalcoholic fatty liver disease.
Data published in JAMA Internal Medicine on 2,588 participants with NAFLD across 22 randomized clinical trials (RCTs in 12 countries) have now confirmed that, when compared with too little or no weight loss support, various weight loss interventions were associated with improvements in NAFLD biomarkers and greater weight loss.
“The accumulated evidence supports changing the clinical guidelines and routine practice to recommend formal weight loss programs to treat people with NAFLD,” Koutoukidis’ group wrote.
Multiple inclusion criteria were used in this systematic review and meta-analysis, including the need to report at least one biomarker of liver disease, 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).
A total of 22 studies (20 full-text articles and 2 conference abstracts) included 26 interventions. Of the included trials, 6 were conducted in middle-income countries and the remaining trials were conducted in high-income countries. Behavioral weight loss programs were used as interventions in 15 trials, pharmacotherapy in 6 trials, and surgery in 1 trial. Pharmacotherapies included orlistat (Xenical), liraglutide (Victoza), or sibutramine hydrochloride (Meridia), and the 1 surgical trial examined the implications of placing a gastric balloon. The median intervention duration was 6 months. Intensity was defined by the extent of behavioral support, prescribed energy deficit, or pharmacotherapy dose.
Two-thirds of participants were male (mean age of 45; mean BMI of 33.7) and about 7% had type 2 diabetes. Three studies did not report on sex and 4 studies did not report on diabetes status.
Compared with no or lower weight-loss interventions, formal weight loss interventions were associated with greater weight change (–3.61 kg; 95% CI –5.11 to –2.12, I2=95%). Difference in weight loss varied considerably across studies by intervention intensity, ranging from –14.5 kg in a 2013 study of diet and exercise versus no intervention to a 0 kg difference in a 2017 comparison of liraglutide versus lifestyle modification.
Weight loss was significantly associated with the following improvements in :
- Alanine aminotransferase (ALT): –9.81 U/L (95% CI –13.12 to –6.50, I2=97%)
- Histologically or radiologically measured liver steatosis: standardized mean difference –1.48 (95% CI –2.27 to –0.70, I2=94%)
- Histologic NAFLD activity score: –0.92 (95% CI –1.75 to –0.09, I2=95%)
- Presence of nonalcoholic steatohepatitis: (OR, 0.14; 95% CI 0.04-0.49, I2=0%)
However, researchers did not observe a histologically significant change for liver fibrosis (–0.13; 95% CI –0.54 to 0.27, I2=68%). They stated that 12 studies were at high risk of bias in at least 1 domain. But estimates and precision of most outcomes did not materially change, based on a sensitivity analysis of 3 trials at low risk of bias.
Because most studies were short to medium-term duration, the long-term association of these interventions with the liver were unclear, the researchers said. Although sibutramine is no longer licensed, removal of this trial from the analysis did not materially affect the results, they added. Steatosis results might have been affected by different methods of assessing the outcome, but the researchers felt that there was “no basis for assuming the different methods would bias the findings by trial arm.”
Other study limitations included that results were limited by statistical heterogeneity and that fewer studies reported biomarkers other than ALT. Only a minority of the trials reported on histologic outcomes.
Source Reference: JAMA Internal Medicine 2019; DOI: 10.1001/jamainternmed.2019.2248
Editorial: JAMA Internal Medicine 2019; DOI: 10.1001/jamainternmed.2019.2244
Study Highlights: Explanation of Findings
Koutoukidis and colleagues looked at the relationship of weight loss interventions with relevant biomarkers among 2,588 participants with NAFLD across 22 RCTs. Compared with little or no weight loss interventions, they found statistically and clinically significant improvements in biomarkers of liver disease in people with NAFLD in the short term. However, there was no change in histologic liver fibrosis after 6 months.
In keeping with European guidelines, the 2018 Practice Guidance of the American Association for the Study of Liver Diseases (AASLD) did not offer specific recommendations to refer to or provide formal weight loss programs for treating NAFLD. Hepatologists often advised participants to lose 5% to 10% of excess weight, but referral to a formal weight loss program was uncommon, according to the researchers. They noted that the mean weight loss difference in the current study was equivalent to weight loss of more than 4 kg in one year reported for patients offered access to typical weight loss programs, compared with a 1 kg loss after one year for patients who were only given advice to lose weight from a physician.
In an invited commentary, Elizabeth Adler, MD, and Danielle Brandman, MD, both of the University of California San Francisco, commended the authors on their clear summary of existing evidence that weight loss is an effective treatment for NAFLD.
The editorialists also commented on the finding that steatosis improved with behavioral weight loss programs, but not with pharmacotherapy-centered weight loss programs (including orlistat, sibutramine, and liraglutide). Evidence on the impact of many pharmacotherapeutic options for NAFLD were inconclusive.
Only patients with biopsy-proven NASH should receive pharmacotherapy, based on the AASLD guidelines. But there was no evidence for metformin and statins — therapies that form part of the treatment for metabolic syndrome (commonly seen in NAFLD patients) — as sole treatments of NAFLD. Although several drugs were in development to target a variety of mechanisms, “cost and risk of long-term adverse effects may limit the adoption of pharmacotherapy for NAFLD,” the editorialists wrote.
Adler and Brandman provided their own possible explanations for why the authors did not see an association between weight loss interventions and changes in histologic scores for inflammation or fibrosis, such as the NAFLD fibrosis score. Few studies reported histologic outcomes and there was a lack of long-term follow-up in all but 2 RCTs. In addition, weight loss was not maintained in the 2 studies that did report long-term follow-up (6 months and 5 years).
However, other evidence from the literature showed that sustained weight loss held promise for stopping fibrosis in NAFLD and thereby improving liver-related mortality. A loss of at least 7% of body weight over 48 weeks improved liver histologic findings in patients with NASH, according to one study. Significant improvements were observed in steatosis, lobular inflammation, and ballooning — all key components of NASH.
“Overall, this study should encourage clinicians — hepatologists and primary care physicians alike — to incorporate weight loss programs into their treatment of NAFLD. In addition, large-scale support for interventions focused on maintenance of weight loss will be key in trying to curb the impending epidemic of advanced liver disease due to NAFLD,” they concluded.
Reviewed by Henry A. Solomon, MD, FACP, FACC Clinical Associate Professor, Weill Cornell Medical College
Primary Source
JAMA Internal Medicine
Secondary Source
JAMA Internal Medicine
Additional Source
MedPage Today
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