Nonalcoholic Fatty Liver Disease and Bariatric Surgery

Sindu Stephen; Ancha Baranova; Zobair M Younossi

Disclosures

Expert Rev Gastroenterol Hepatol. 2012;6(2):163-171. 

In This Article

Lifestyle Modifications & Antiobesity Medications

Lifestyle modifications, such as diet and exercise, remain a mainstay for the therapy for obesity. A number of current studies evaluated the effects of lifestyle modifications on the progression of NAFLD. For example, one study assessed the effect of nutritional counseling on liver histology in patients with biopsy-proven NASH. Nine out of 15 patients in the study demonstrated relatively moderate weight loss and an improvement of NASH scores on repeat biopsy after 1 year.[29] Another study showed an average decrease of 2.25 NAS score units in 30 patients who received a supervised hypocaloric diet and exercise for 6 months.[30]

However, not every study of lifestyle modifications produced such impressive results. For example, in a Japanese study, patients placed on a restricted diet and exercise program for 3 months revealed a reduction in aminotransferases, cholesterol, fasting glucose and BMI compared with the control group.[31] However, liver biopsy revealed no change in fibrosis or inflammation, but only an improvement in steatosis.[31] Another study demonstrated actual worsening of the NAFLD scores after low-calorie, low-fat diet;[32] an increase of inflammation was attributed to increased carbohydrate intake not compensated by decrease in inflammation associated with reduced intake of fat.[32]

Currently, two antiobesity medications have been used in the USA. Orlistat inhibits gastric and pancreatic lipase, blocking fat absorption. Sibutramine inhibits serotonin and norepinephrine reuptake, enhancing satiety. In Europe, rimonabant, a cannabinoid receptor type 1 antagonist, has also been used. Recent meta-analysis of 30 randomized controlled trials evaluated all three approved antiobesity medications from 2002 to 2006.[33] Rimonabant decreased weight by 4.7 kg (95% CI: 4.1–5.3 kg), sibutramine by 4.2 kg (95% CI: 3.6–4.7 kg) and orlistat by 2.9 kg (95% CI: 2.5–3.2 kg).[33] Experimental therapies of obesity include lorcaserin, a selective agonist for a subtype of 5-HT receptors important in appetite regulation; topiramate, a sulfamate-substituted monosaccharide derivative of the naturally occurring sugar monosaccharide D-fructose with a weight reduction side effect of unclear mechanism; and a combination of topiramate with phentermine, a nonaddictive analog of amphetamine.

From a biochemical perspective, rimonabant's potential as an anti-NAFLD medication was high. Endogenous activation of peripheral CB1 receptors seems to be a key mediator of insulin resistance and enhances liver lipogenesis. Moreover, tonic activation of CB1 receptors is responsible for progression of liver fibrosis.[34] However, despite the fact that preliminary data derived from clinical trials strongly suggest that selective CB1 antagonism improves insulin resistance and reduces liver fat, the increased side effects associated with mood disorders moved rimonabant out of the list of compounds considered for clinical trials in NAFLD.

Another medication, sibutramine, acts in part through a primary amine metabolite, M2, which was shown to affect glycemia and hepatic gluconeogenesis independently of satiety and weight loss.[35] There was an interesting bariatric surgery-associated study that compared 20 patients who received 15 mg of sibutramine prior to laparoscopic Roux-en-Y gastric bypass (RYGB) with the patients in the control group who did not. Along with the sibutramine-associated loss of weight, the size of the left liver lobe decreased in the sibutramine-treated patients and increased in the control group, and the levels of glutamic pyruvic transaminase followed this trend. Finally, time in the operating room was shorter for patients with preoperative weight loss owing to sibutramine intake.[36] However, in a study that compared effects of a 6-month hypocaloric diet plus sibutramine with a hypocaloric diet showed no changes in hepatic enzyme levels in any study group despite significant weight reduction.[37] The side effects of sibutramine included increased heart rate and blood pressure.

There is evidence that weight loss induced by orlistat reverses fatty infiltration and improves hepatic fibrosis in obese patients with NAFLD.[38] However, another study with better design showed that orlistat did not enhance weight loss or improve liver enzymes, nor did it prove to show an additional benefit from the standpoints of insulin resistance and histopathology.[39] In both arms of the study, subjects who lost ≥5% of bodyweight over 9 months demonstrated improved insulin resistance and steatosis, and those subjects who lost ≥9% of bodyweight also achieved improved hepatic histological changes.[38] It is important to note that orlistat has predominant gastrointestinal side effects. Moreover, the postmarketing review by the US FDA identified 13 cases of severe liver injury associated with orlistat.[40] Therefore, orlistat interventions in patients with advanced liver disease should be performed with caution.

Despite indications that diet and exercise might improve NAFLD through the alleviation of insulin resistance, future studies evaluating the long-term efficacy of lifestyle modifications and weight loss-inducing drugs are warranted. Effects of experimental antiobesity medications on NAFLD remain to be evaluated.

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