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Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases in which excess fat deposits in the liver (steatosis, NAFL) are separate from but can progress to inflammation and fibrosis (nonalcoholic steatohepatitis, NASH), fibrosis, and cirrhosis. Nonalcoholic fatty liver disease has become a major public health issue, affecting about 25% of adults worldwide and two-thirds of adults with obesity.1 Hepatocellular carcinoma associated with NAFLD increased 10-fold between 2000 and 2010, and trends suggest that NAFLD will emerge as the leading cause of end-stage liver disease in the coming decades.2 Beyond liver disease, patients with NAFLD are at significant risk of cardiovascular morbidity and mortality.3
Approximately 20% of patients with NAFLD progress to NASH, which is associated with more rapid rates of fibrosis and liver-related mortality. Liver biopsy is the gold standard for classification of NAFLD. However, owing to cost and risk for morbidity, biopsy is often reserved for cases of clinical suspicion for NASH or advanced fibrosis. Noninvasive assessment of fibrosis stage such as clinical prediction rules (eg, NAFLD Fibrosis score, FIB-4) and/or imaging (ultrasonography or magnetic resonance–based elastography) are also helpful for diagnosing and staging of NAFLD. Obesity is the most common and well-documented risk factor for NAFLD.
The link between obesity and NAFLD has prompted investigation of weight loss interventions as a potential treatment for NAFLD. However, there has been considerable variability in intervention types and outcome measures. The meta-analysis by Koutoukidis et al4 in this issue of JAMA Internal Medicine better characterizes the impact of weight loss interventions and builds a compelling case for implementing formal weight loss programs as a mainstay in the treatment of NAFLD. In their systematic review of 22 randomized clinical trials that included 2588 participants with NAFLD, Koutoukidis et al4 found that weight loss interventions were associated with improvements in blood biomarkers of liver disease, as well as radiologic and histologic markers.4
This study confirms the importance of weight loss interventions in the treatment of NAFLD. Koutoukidis et al4 specifically observed the association between weight loss by various intervention types and improvement in liver blood biomarkers, such as alanine transaminase (ALT) and aspartate transaminase (AST), and improvement in steatosis based on a collection of outcome measures from various studies—including histologic analysis, magnetic resonance imaging, ultrasonography, and NAFLD activity score. Whereas AST and ALT are surrogate markers for steatosis and NASH, they are clinically meaningful because several studies have demonstrated good correlation with liver histologic findings. Nonalcoholic fatty liver disease with normal ALT has been shown to confer lower risk of hepatocellular carcinoma and cirrhosis compared with NAFLD and elevated ALT.5 This phenomenon likely accounts for higher likelihood of NASH with elevated liver enzymes, with a reduction in ALT reflecting improvement in NAFLD disease activity in response to weight loss.
The efficacy of lifestyle interventions focused on weight loss in the treatment of NAFLD is especially important given limited pharmacotherapy options. In a subgroup analysis, Koutoukidis et al4 found that steatosis improved with behavioral weight loss programs but not with pharmacotherapy-centered weight loss programs (including orlistat, sibutramine, and liraglutide). This is consistent with a body of literature that has shown inconclusive evidence on the impact of many pharmacotherapeutic options for NAFLD.3 American Association for the Study of Liver Diseases guidelines currently recommend that only patients with biopsy-proven NASH receive pharmacotherapy; the only medications that have been shown to be of benefit on liver histologic analysis are vitamin E in nondiabetic patients and pioglitazone (with most clinical trials among nondiabetics, without long-term safety and efficacy data).3 Importantly, both metformin and statins—key therapies for the metabolic syndrome (commonly seen in NAFLD patients)—are safe to use in NAFLD. However, there are no conclusive data supporting their use for the sole purpose of treatment of NAFLD. Many drugs targeting a variety of mechanisms are currently in development, though cost and risk of long-term adverse effects may limit the adoption of pharmacotherapy for NAFLD. Overall, as Koutoukidis et al4 have clearly shown, behavioral weight loss programs are the most effective intervention in treating all-comers with NAFLD. Weight loss is an intervention that is likely to have a favorable impact on morbidity related to the metabolic syndrome and mortality due to cardiovascular disease, the leading cause of death in this patient population.
In the long-term, our goal in treating NAFLD centers on preventing progression of fibrosis and its complications: cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Several studies have demonstrated that fibrosis stage is the most important predictor of liver-related mortality in patients with NAFLD.6 Although Koutoukidis et al4 did not find a significant association between weight loss interventions and changes in histologic scores for inflammation or fibrosis, such as the NAFLD fibrosis score, their analysis was limited by the fact that few studies reported histologic outcomes, as well as a lack of long-term follow-up in all but 2 randomized clinical trials. In the 2 studies that did report long-term follow-up (6 months and 5 years), improvement of weight was not maintained. To stop the progression of fibrosis or reverse it, removal of the causative factor must be sustained over time. Thus, it is expected that both short-term studies and long-term ones without weight loss maintenance would not show meaningful change in liver fibrosis. However, sustained weight loss does show promise for stopping fibrosis in NAFLD and thereby improving liver-related mortality. For example, Promrat et al7 found that reduction of at least 7% of body weight over 48 weeks improved liver histologic findings in patients with NASH, with significant improvement in steatosis, lobular inflammation, and ballooning, all key components of NASH.
The study by Koutoukidis et al4 clearly summarizes the existing evidence that weight loss is an effective treatment for NAFLD. Their detailed analysis highlights that behavioral weight loss programs hold particular promise for improving liver blood biomarkers and markers of steatosis. They did not observe changes in liver fibrosis, a key predictor of liver-related mortality; this will require future studies to complete long-term follow-up with histologic measurements. 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.
Corresponding Author: Danielle Brandman, MD, MAS, Division of Gastroenterology, Department of Medicine, University of California, San Francisco, 513 Parnassus Ave, S357, San Francisco, CA 94143 (email@example.com).
Published Online: July 1, 2019. doi:10.1001/jamainternmed.2019.2244
Conflict of Interest Disclosures: Brandman reports research funding (clinical trials) from Gilead, Conatus, Allergan. No other conflicts were reported.
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Adler E, Brandman D. Treatment of Fatty Liver Disease—Time to Implement Common Sense Measures. JAMA Intern Med. Published online July 01, 2019. doi:10.1001/jamainternmed.2019.2244
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