PRO: Should patients with nonalcoholic steatohepatitis fibrosis undergo bariatric surgery as primary treatment?

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INTRODUCTION

The worldwide obesity epidemic has resulted in an increase in metabolic diseases, including nonalcoholic fatty liver disease (NAFLD) and its most severe form, nonalcoholic steatohepatitis (NASH). In fact, NAFLD is the most common liver disease in the world, with a prevalence rate of 25%. ¹ , ²

According to the largest US‐based prospective study by Harrison et al. ³ that was done to establish the prevalence of NAFLD and NASH, the prevalence rate of NAFLD was 38%, NASH was 14%, and significant liver fibrosis was found in 6% of asymptomatic middle‐aged Americans. The highest prevalence was in Hispanics (55%) and those with obesity (57%) and diabetes (70%). ³

For this reason, it is important to have a durable and predictable treatment of NASH fibrosis associated with obesity.

KEY POINT 1: BARIATRIC SURGERY SHOULD BE CONSIDERED PRIMARY THERAPY IN THOSE WITH MODERATE TO ADVANCED (F2‐F4) NASH‐RELATED FIBROSIS WHO ARE OTHERWISE QUALIFIED

NAFLD is the hepatic manifestation of metabolic syndrome and is a direct result of obesity with associated diseases, including hypertension, type 2 diabetes, and hyperlipidemia.

A recent prospective cohort study that examined paired liver biopsies in 261 patients found that all patients who lost more than 10% of their weight had reductions in their NAFLD activity score, and 90% had complete resolution of their NASH. The same study also suggested that weight loss greater than 10% can be associated with fibrosis regression and was seen in as many as 45% of patients. Even modest weight loss of 5% was shown to at least stabilize fibrosis. ⁴

Weight loss is the gold standard of treatment for NAFLD/NASH, and regardless of how it is achieved has the strongest association with histological improvement. Although it is important to recognize that in certain populations, structured multidisciplinary weight loss programs are successful in improving NASH fibrosis as compared with general medical advice in the clinic, and the degree of weight loss required typically is difficult to achieve and even harder to sustain. ⁵ Retrospective reviews have shown that less than 50% of patients are able to meet their weight loss goal through intensive lifestyle modification, even in well‐monitored clinical trial settings. ⁶ Similarly, a meta‐analyses demonstrated an adherence rate to structured weight loss programs will often reach only around 60%, and those who are adherent lose only about 3% of their overall body weight. ⁷

As an alternative, patients and clinicians may turn to prescription antiobesity medication. However, the majority of medications offered have prohibitive side effects and are, in fact, not US Food and Drug Administration approved for long‐term use or for use in NASH, as shown in Figure 1. The exception is orlistat, which is US Food and Drug Administration approved for longer‐term weight management; however, it often has distressing side effects for patients, leading to premature discontinuation. ⁸ Although many drugs target improvement in histological features of NASH in development, no drug therapy for NASH currently has been approved by regulatory institutions.

FIGURE 1.

Mean change in metabolic markers after bariatric surgery. Adapted with permission from Obesity Surgery. ¹⁴ Copyright 2019, Springer Science+Business Media

Because obesity is the main pathophysiological driver of NASH and bariatric surgery is the most effective therapy available for obesity, for those in which these conservative measures are ineffective, bariatric surgery should be strongly considered. Even though sustained weight loss is the most visible effect of bariatric surgery, its most important goal is the treatment of life‐threatening, obesity‐related comorbidities, which includes NASH‐related fibrosis. ¹ A prospective study of 109 patients found that 85% of patients no longer had NASH on liver biopsy at 1 year after bariatric surgery, and up to 33% of patients had some degree of fibrosis regression. ⁹

Criteria set forth from the European Association for the Study of Obesity specifically highlight NAFLD as an indication for surgery in those who have a body mass index (BMI) ≥ 35. Relevant to our position, we support the use of bariatric surgery for the treatment of NASH and F2‐F4 fibrosis in those patients who meet criteria otherwise. ¹⁰ This includes patients carefully selected by a multidisciplinary team of specialists, including bariatric surgeons and hepatologists, with ideally Child‐Pugh class A and Model for End‐Stage Liver Disease score < 12 with no significant portal hypertension.

It is important to highlight that it may be premature to consider bariatric surgery as an established option to specifically treat NASH or lean NASH given the lack of prospective data in this area that are needed to draw valid conclusions.

KEY POINT 2: THERE IS EVIDENCE THAT BARIATRIC SURGERY FOR THE TREATMENT OF NASH IMPROVES HISTOLOGY, METABOLIC RESPONSE, AND SYSTEMIC INFLAMMATION AND DECREASES THE RISK FOR HEPATOCELLULAR CARCINOMA

A study by Lassailly et al. ¹¹ in 2020 demonstrated that after bariatric surgery, histological improvement is sustained up to at least 5 years. Thereafter, NASH was resolved without worsening fibrosis in 84% of patients, fibrosis decreased in 70.2% of patients, and fibrosis completely resolved in 56% of all patients. Improvement in fibrosis was seen as soon as 1 year after surgery. ¹¹

In a retrospective study evaluating clinical and histological data of 895 obese patients undergoing bariatric surgery, biopsies were evaluated 3 to 82 months postsurgery. Their findings note that periportal and perivenular changes significantly improved, with evidence of fibrosis regression on histological analyses of patients’ liver biopsies. ¹²

Furthermore, major improvements in the metabolic parameters involved in the pathophysiology of NAFLD, including BMI, basal metabolic rate, low‐density lipoprotein (LDL)‐cholesterol, and hemoglobin A1c (HbA1c), and improved insulin resistance parameters (described as homeostasis model assessment of insulin resistance [HOMA‐IR]) have also been reported, as illustrated in Figure 1. ¹³ , ¹⁴ These results have been shown to be sustained for 5 years.

A recent retrospective cohort study conducted by Aminian et al. ¹⁵ was the first to demonstrate that among patients with biopsy‐proven NASH and obesity, bariatric surgery compared with nonsurgical management was associated with a significantly lower risk for major adverse liver outcomes and major adverse cardiac events. The findings of this study suggest that bariatric surgery can be considered as a therapeutic option for patients with NASH and obesity. Specifically, the cumulative incidence of major adverse liver outcomes at 10 years was 2.3% in the bariatric group versus 9.6% in the nonsurgical group. Regarding major adverse cardiac events, cumulative incidence at 10 years was 8.5% in the bariatric surgery group and 15.7% in the nonsurgical group. ¹⁵

Another aspect to consider is the development of NAFLD‐related malignancies. Retrospective cohort studies have shown that the adjusted cumulative incidence of NAFLD‐related malignancy (which includes hepatocellular carcinoma [HCC]) is lower in patients who undergo bariatric surgery versus not. These findings make physiological sense because insults of increased steatosis, oxidative damage, recurring inflammation, fibrotic changes, and other metabolic irregularities are improved with bariatric surgery, which in turn leads to lower event risks for HCC. ¹⁶

Lastly, the benefits of bariatric surgery extend beyond the liver to affect diseases of other organ systems, specifically the risks for cardiovascular disease, stroke, and renal failure. ¹⁷

KEY POINT 3: BARIATRIC SURGERY IS SAFE IN THOSE WITH ADVANCED FIBROSIS AND WELL‐COMPENSATED CIRRHOSIS

In terms of safety, bariatric surgery is safe and clinically acceptable in select patients with moderate to severe advanced liver fibrosis and selected patients with cirrhosis: Child‐Pugh class A, Model for End‐Stage Liver Disease score < 12, and no portal hypertension.

Singh et al. ¹⁸ examined varying degrees of fibrosis (advanced vs. mild fibrosis) in those who underwent bariatric surgery between 2005 and 2014, and demonstrated that there is no significant difference in surgical complication rates, except those with advanced fibrosis had greater length of hospital stay compared with minimal fibrosis (4 vs. 3 days with p = 0.002). ¹⁸ There is also no difference in pulmonary, cardiovascular, or surgical complications from bariatric surgery based on NAFLD activity score, which was used as a marker of disease severity. ¹⁹

Furthermore, in patients with compensated cirrhosis, meta‐analyses show that there is no significant difference in 90‐day all‐cause mortality or liver‐related mortality after bariatric surgery. One important point to note is that the majority of patients in this study had Child‐Pugh class A cirrhosis, thus highlighting the need for well‐selected surgical candidates. ²⁰

CONCLUSION

The major impact of NASH on the risk for cirrhosis highlights the urgent need for effective therapy to reverse the disease, which is an objective rarely obtained with available therapy. Although current US guidelines do not take an established stance for or against bariatric surgery in obese individuals with NASH fibrosis, we recommend NASH with fibrosis be the primary indication for the use of bariatric surgery in obese individuals who otherwise meet criteria. There is evidence that bariatric surgery is safe, improves histopathology and fibrosis scoring, improves metabolic response and systemic inflammation, and reduces the risk for mortality from cardiovascular disease and NAFLD‐associated HCC. Although we understand that bariatric surgery improves metabolic parameters involved in the pathophysiology of NASH, there are insufficient data to support the use of bariatric surgery in patients with lean NASH at this time.

CONFLICT OF INTEREST

Nothing to report.

Orekondy N, Lee D, Malik R. Should patients with nonalcoholic steatohepatitis fibrosis undergo bariatric surgery as primary treatment? Clinical Liver Disease. 2022;20:5–8. 10.1002/cld.1224