Weight Loss is Key to Improving Non-Alcoholic Fatty Liver Disease

Patients who attend structured weight loss programs appear most successful at reverseing NAFLD but cost and lack of insurance reimbursement remain prohibitive obstacles.

With Dimitrios A. Koutoukidis, PhD, RD, and Kenneth Cusi, MD 

Non-alcoholic fatty liver disease (NAFLD) remains a common and costly condition associated with a range of serious health consequences, including liver- and cardiovascular disease-related morbidity and mortality.1

Patients with NAFLD develops as subtypes reflecting a range in clinical disease—from recent fat accumulation in the liver to inflammation and fibrosis to end-stage, non-alcoholic steatohepatitis (NASH)— with an increasing prevalence anticipated. In addition, advanced fibrosis and cirrhosis typically develop as the condition advances.

Structured weight loss programs lead to greater weight loss in people with NAFLD.

Obesity is a Key Contributor to NonAlcoholic Fatty Liver Disease

Appreciating the role that obesity plays in the onset and progression of non-alcohol fatty liver disease has become a clinical necessity given that half to three-quarters of people with obesity develop NAFLD.1 And about 50% of individuals with type 2 diabetes (T2D) are at risk of developing NFALD, based on separate reporting.2

The urgency is heightened given the increased incidence of cardiovascular disease that more than doubles, rising 2.5 times, in patients with severe NAFLD as compared with matched controls.3 And, the complications of NAFLD are also associated with hepatocellular carcinoma, which has seen a 10-fold rise over the past few decades introducing NASH as the second most common reason to need a liver transplant.4,5

Despite the burgeoning prevalence of non-alcoholic fatty liver disease, there are no approved drugs earmarked to treat either NAFLD or NASH, so the standard of care remains a focus on advocating lifestyle modification, specifically weight loss achieved with changes to diet and physical activity.6

Weight Loss Present Best Opportunity to Improve NAFLD  Outcomes

The good news arising out of a systematic review of the literature and meta-analysis of 22 studies—weight loss remains the recommended standard of care to inhibit progression of nonalcoholic fatty liver disease.1  In particular, patients who attend formal weight loss programs have the most success at sufficient abdominal weight to reverse the accumulation of fat in the liver, as highlighted in the most recent clinical recommendations.6

 "We found consistent evidence that referring people with non-alcoholic fatty liver disease to weight loss programs improves their liver disease status compared with simply advising people to lose weight," says study leader Dimitrios A. Koutoukidis, PhD, a researcher at the University of Oxford in the United Kingdom. And, patients should be advised that there is no evidence that liquid diets, diet pills and supplements, and popular do-it-yourself diets offer any lasting benefit.1

When the researchers looked more closely at the studies, they found that the key to significant improvement in liver function is not to simply tell patients to lose weight, but to provide an actual referral to a dedicated, structured weight loss program. Doing so, the studies suggest, improved several biomarkers of NAFLD.1

Exactly how the weight loss helps to restore liver health remains unknown, Dr. Koutokidis says. "The review demonstrates that weight loss improves the reverse the issues of fatty liver, but the findings not set out to specifically look at the mechanisms by which this might occur," he says. "We did, however, find some evidence that weight loss improved NAFLD through improvements in the control of blood glucose levels and reductions in insulin resistance, but we need more research to understand the underlying pathways."

However, so strong are the findings, he tells EndocrineWeb, that his team believes the clinical guidelines should be strengthened to have health care providers recommend formal weight loss programs for those with NAFLD.

Evaluating Cumulative Data on Weight Loss and NAFLD

In this new meta-analysis and systematic review, the researchers looked at a key question:  Are weight loss interventions associated with changes in biomarkers of liver disease in people with NAFLD?

The randomized clinical trials that were examined accounted for 2,588 NAFLD patients with a mean age of 45 years.1 The researchers looked at blood, radiologic and histologic biomarkers of liver disease.

The studies looked at a range of interventions for weight loss. Fifteen tested behavioral weight loss programs, 6 tested pharmacology-based ones and one looked at surgery. The median intervention time was 6 months.

Compared to no or lower-intensity weight loss intervention, the more-intensive interventions were linked to greater weight change (-3.61kg; 95% CI, -5.11 to -2.12).

The weight loss interventions were also statistically significantly associated with improvement in biomarkers:1

  • Alanine aminotransferase (-9.81 U/L; 95% CI, -13.12 to -6.50).
  • Histologically or radiologically measured steatosis (mean difference -1.48; 95% CI, -2.27 to -0.70)
  • Histologic NAFLD activity score (-0.92; 95% CI, -1.75 to -0.09)
  • Presence of nonalcoholic steatosis (OR, 0.14; 95% CI, 0.04-0.49).

No change in histologic liver fibrosis was found of significance.1

The authors did indicate that there were limitations in the data gathering: 12 studies had risk of bias in at least one domain; however, a sensitivity analysis of the three trials at low risk resulted in no material change in the estimates and precision of most outcomes.1

Is Treatment for NAFLD All About Weight Loss Programs? Which Ones?!

Current guidelines from the American Association for the Study of Liver Diseases advise that weight loss typically reduces steatosis; but as is the case with the European guidelines, there is a gentle mention but no specific recommendation for referring patients to a formal weight loss program.6-8

However, the UK authors point out that those referred to typical weight loss programs can expect a loss of more than 4 kilograms in a year; compared to only a 1 kg loss per year if a physician tells the patient to lose weight.9,10 Did some structured programs work better than others?

"We found mixed evidence regarding the type of programs patients were referred to," Dr. Koutoukidis says. "In one subgroup analyses, there were no differences in liver transaminases reported between the program. However, we found that behavioral weight loss programs improved liver steatosis whereas programs featuring weight loss pharmacotherapy did not."

Despite the mixed evidence,1 he says that health care providers should refer patients who need it to a weight loss program immediately after the diagnosis of NFALD.

Weight Loss Programs Must Be Accessible and Affordable to Help

The analysis is thorough and needed, says Kenneth Cusi, MD, FACP, FACE, chief of the division of endocrinology, diabetes and metabolism at the University of Florida, Gainesville, who reviewed the study for EndocrineWeb.

And structured programs, in general, he agrees, are more effective for weight loss than simply telling a patient to lose weight. "It is well known in the obesity world that people achieve more weight loss from attending a structured programs," Dr. Cusi says.

However, he says, there is limited evidence about this relationship specifically in patients with NASH, and ''there have not been large and carefully crafted studies in NASH patients who were prescribed weight loss medications." 

Dr. Cusi indicates another limitation of this meta-analysis: the researchers looked at biomarkers of liver disease in those with NAFLD in the short term, yet biomarkers, ''do not always reflect what is happening in the liver. Since only 6 of the studies looked at histology, which is important to know about liver function, and the studies need to be longer than six months, really longer than 12 months. None of the trials showed a huge impact on fibrosis."

The authors did not include the largest study—by Vilar-Gomez, although not controlled, was impressive as to the role of structured lifestyle intervention—he says, "many structured programs for weight loss are pricey and not covered by insurance so patients often indicate that they cannot afford to enroll in these physician-led programs."

One benefit of paying greater attention to mention of the value of structure weight loss programs, would to assure wider implementation of the recommendation "to refer patients to a structured program, as approproate, and to advocate for the need to gain consistent reimbursement from insurance companies, Dr. Cusi says, and that policy change would be very welcome. After all, health insurers are fully aware of the benefits of weight loss and it is time they assume this social responsibility," 

Dr. Koutoukidis and Dr. Cusi have no relevant disclosures. Other coauthors of Dr. Koutoukidis' report receiving grants from Cambridge Weight Plan, but outside the submitted work published in this report.

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