NAFLD: A Practical Approach to Treatment
NAFLD: A Practical Approach to Treatment
Lifestyle modification aimed at weight loss and increased physical activity is vital in managing all patients with NAFLD irrespective of their underlying liver histology. Patients should be encouraged to avoid a sedentary lifestyle by increasing daily activities, undertaking regular exercise and eating healthily. Overall, lifestyle interventions including behavioural, dietary and exercise changes can be very effective in reducing body weight. In one study, patients who received dietary advice and undertook 200 min moderate physical activity per week for 48 weeks had an overall 9.3% reduction in body weight (versus 0.2% in the control arm) and had improvement in hepatic steatosis and inflammation on liver biopsy.
The optimum diet to treat NAFLD is not known. Until further evidence is available, a calorie restricted diet (600 Kcal less than a person needs to remain at the same weight) should be recommended aiming to lose 0.5–1 kg per week until the target weight is achieved. Patients with NAFLD should be advised to avoid saturated fats, simple carbohydrates and sweetened drinks. A 'fast food diet' (high in cholesterol, saturated fats and fructose) is associated with progressive fibrosis in mice models.
A Mediterranean diet (high in monounsaturated fatty acids), as compared with a diet low in fat and high in carbohydrates, has been shown to reduce hepatic steatosis and improve insulin sensitivity in non-diabetic subjects with NAFLD. Dietary supplementation with ω-3 polyunsaturated fatty acids (n-3 PUFAs) has also been shown to decrease liver fat, so fish oil supplementation could be a simple therapeutic option but further studies are needed.
Intensive 12-month dietician-led lifestyle interventions are more effective than standard care for patients with NAFLD in terms of weight loss (5.6 vs 0.6 kg) and achieving remission of NAFLD (64% vs 20%). Previous studies have shown that >7% and ≥9% loss of body weight was associated with reduced steatosis, hepatocellular injury and hepatic inflammation. The optimum amount of weight loss to reduce fibrosis is not known, but studies in subjects undergoing bariatric surgery where larger weight losses are seen (average reduction 30% of Body Mass Index (BMI) at 5 years) indicate that fibrosis regression occurs in the majority (65%), although minor increases in fibrosis were seen 5 years post-bariatric surgery in 20% (>90% of these were worsening from stage 0 to 1). Ideally, patients should be encouraged to lose >10% (but more is probably better) of body weight and maintain the weight loss or bring their waist circumference or BMI into their ethnicity specific 'normal' range (eg, for Caucasians: waist circumference <94 cm for men and <80 cm for women or BMI <25 m/kg).
People with NAFLD engage in less physical activity than their healthy counterparts and higher levels of habitual physical activity are associated with lower levels of steatosis. Aerobic exercise increases skeletal muscle insulin sensitivity and as a result reverses one of the key pathophysiological mechanisms that causes NAFLD (insulin resistance). Although the optimum exercise to treat NAFLD is not known, studies examining moderate intensity training, high intensity training and resistance exercise have shown improvement in liver enzymes and reduction in liver fat, independent of weight loss, but the effects on histology remain unknown. Therefore, all patients with NAFLD should be advised to increase physical activity and undertake regular exercise. Until further evidence is available, one approach is to recommend 30 min of moderate exercise five times weekly. In reality though, a significant proportion of patients with NAFLD do not comply with these recommendations. In such patients, the use of pedometers can be quite helpful. We recommend that patients increase their daily step count to >10 000 steps/day.
Orlistat is an enteric lipase inhibitor that leads to malabsorption of dietary fat and can aid weight loss in subjects with obesity in conjunction with lifestyle modification. One study demonstrated that orlistat treatment for NAFLD improved alanine transaminase (ALT) and steatosis, but a subsequent RCT conducted by Harrison et al showed that orlistat in combination with calorie restriction and vitamin E (800 IU/day) did not enhance weight loss, improve liver enzymes or improve histopathology compared with calorie restriction and vitamin E. In that study, they found that ≥9% weight loss resulted in improved histology irrespective of whether they received orlistat or placebo. National Institute of Health and Care Excellence (NICE) guidelines for obesity recommend that orlistat can be considered as an aid to weight loss in subjects who have not achieved their target weight by lifestyle intervention and have a BMI>30 kg/m, so it seems reasonable to consider this treatment in patients with obesity and NAFLD. If orlistat is initiated, only patients who achieve >5% loss of body weight in 3 months should continue the medication. Treatment duration should not be greater than 1 year as there is potential for fat soluble vitamin deficiency if continued for longer.
Bariatric surgery has an increasing role in the management of patients with obesity and the metabolic syndrome. Restrictive procedures such as the gastric band, gastric balloon and sleeve gastrectomy decrease stomach size leading to early satiety. Malabsorptive procedures such as gastric bypass limit the absorption of food. Weight loss after bariatric surgery has beneficial effects on the components of the metabolic syndrome including improving insulin sensitivity, lipid profile as well as reducing long-term mortality. It also has specific effects on liver histology including reduced steatosis, steatohepatitis and fibrosis. The majority of the histological benefits occur within the first year post-surgery. The optimum type of bariatric surgery for the treatment of NASH is not known. Although gastric bypass surgery produces the largest sustained weight loss compared with other bariatric procedures, Mathurin et al found no significant differences among the gastric band, bilio-intestinal and gastric bypass groups in terms of global NAFLD activity score (NAS), steatosis, inflammation or ballooning. As there is a lack of long-term outcome data about bariatric surgery as a specific treatment for NAFLD, bariatric surgery cannot be considered as a primary treatment for NASH. However, NICE guidance suggests that surgery should be considered as a treatment for obesity for patients with BMI >40 kg/m or between 35 and 40 kg/m with other significant disease that could be improved with weight loss. All appropriate non-surgical measures must be tried first and patients must receive intensive specialist management and be prepared to commit to long-term follow-up. Surgery can be considered as a first-line option for the treatment of obesity in adults with a BMI greater than 50 kg/m.
Bariatric surgery should be avoided in subjects with advanced cirrhosis with portal hypertension as there is a risk of hepatic decompensation with the rapid weight loss. Patients with decompensated cirrhosis have particularly high mortality rates post-bariatric surgery compared with compensated cirrhotics and non-cirrhotic patients (16.3% vs 0.9% and 0.3%, respectively, p=0.0002). In carefully selected patients with Child–Pugh A cirrhosis, gastric bypass and sleeve gastrectomy have been shown to achieve weight loss and improve obesity-related comorbidities. However, patients with cirrhosis should undergo bariatric surgery at centres that perform large numbers of these procedures.
For patients with biopsy-proven NASH, where lifestyle intervention has failed, liver-directed pharmacotherapy with pioglitazone or vitamin E can be considered.
Pioglitazone. Several studies have demonstrated benefit from the thiazolidinediones in patients with NASH both with and without diabetes. Aithal et al showed that 12 months of treatment with pioglitazone 30 mg/day reduced hepatocellular injury and fibrosis compared with placebo. More recently, the PIVENS study showed significantly more patients receiving pioglitazone had resolution of steatohepatitis (a secondary endpoint) than with placebo (47% vs 21% p=0.001), although the treatment arm narrowly failed to meet the very strict primary endpoint (improvement in NAS ≥2 with at least 1-point improvement in hepatocyte ballooning without increase in fibrosis score). A recent meta-analysis has demonstrated that pioglitazone treatment in NASH significantly improves steatosis, inflammation and to a lesser degree, fibrosis. While pioglitazone appears to be an effective treatment for NASH, there are also some concerns about its long-term safety. Treatment with pioglitazone is associated with weight gain (4.7% in the PIVENS study) and there have been reports of increased risk of congestive cardiac failure, bladder cancer and reduced bone density. However, a meta-analysis of 16 390 patients with type 2 diabetes mellitus (T2DM) treated with pioglitazone demonstrated an 18% reduction in death, myocardial infarction and stroke. Therefore, after assessing risk and benefit, treatment with pioglitazone can be recommended for patients with more aggressive NASH who have failed lifestyle interventions. Caution should clearly be exercised in patients with cardiac disease (a common comorbidity in patients with NAFLD) and echocardiography performed prior to considering treatment with pioglitazone. The optimum dose and duration of treatment are not known.
Vitamin E. Vitamin E is an antioxidant that has recently been shown to have beneficial effects on histology in non-diabetic patients with NASH. In the large PIVENS trial, significantly more patients had improvement in steatohepatitis following 96 weeks of vitamin E 800 IU/day compared with placebo (42% vs 19% p<0.001). This was confirmed in a study of childhood NASH, where vitamin E was shown to reduce steatohepatitis in a subgroup who had follow-up liver biopsies. Although vitamin E looks like a promising treatment for NASH, there are concerns about the long-term effects of vitamin E with a meta-analysis showing a small overall increase in all-cause mortality at doses >400 IU/day. It has also been reported that there might be an increased risk of haemorrhagic stroke and prostate cancer with high dose treatment. Vitamin E has not been evaluated in patients with cirrhosis or diabetes and NASH. Therefore, it should currently be reserved for selected patients with more advanced pre-cirrhotic NASH who have failed lifestyle interventions. The optimum dose and duration of treatment are not known.
Lifestyle Modification
Lifestyle modification aimed at weight loss and increased physical activity is vital in managing all patients with NAFLD irrespective of their underlying liver histology. Patients should be encouraged to avoid a sedentary lifestyle by increasing daily activities, undertaking regular exercise and eating healthily. Overall, lifestyle interventions including behavioural, dietary and exercise changes can be very effective in reducing body weight. In one study, patients who received dietary advice and undertook 200 min moderate physical activity per week for 48 weeks had an overall 9.3% reduction in body weight (versus 0.2% in the control arm) and had improvement in hepatic steatosis and inflammation on liver biopsy.
Diet
The optimum diet to treat NAFLD is not known. Until further evidence is available, a calorie restricted diet (600 Kcal less than a person needs to remain at the same weight) should be recommended aiming to lose 0.5–1 kg per week until the target weight is achieved. Patients with NAFLD should be advised to avoid saturated fats, simple carbohydrates and sweetened drinks. A 'fast food diet' (high in cholesterol, saturated fats and fructose) is associated with progressive fibrosis in mice models.
A Mediterranean diet (high in monounsaturated fatty acids), as compared with a diet low in fat and high in carbohydrates, has been shown to reduce hepatic steatosis and improve insulin sensitivity in non-diabetic subjects with NAFLD. Dietary supplementation with ω-3 polyunsaturated fatty acids (n-3 PUFAs) has also been shown to decrease liver fat, so fish oil supplementation could be a simple therapeutic option but further studies are needed.
Intensive 12-month dietician-led lifestyle interventions are more effective than standard care for patients with NAFLD in terms of weight loss (5.6 vs 0.6 kg) and achieving remission of NAFLD (64% vs 20%). Previous studies have shown that >7% and ≥9% loss of body weight was associated with reduced steatosis, hepatocellular injury and hepatic inflammation. The optimum amount of weight loss to reduce fibrosis is not known, but studies in subjects undergoing bariatric surgery where larger weight losses are seen (average reduction 30% of Body Mass Index (BMI) at 5 years) indicate that fibrosis regression occurs in the majority (65%), although minor increases in fibrosis were seen 5 years post-bariatric surgery in 20% (>90% of these were worsening from stage 0 to 1). Ideally, patients should be encouraged to lose >10% (but more is probably better) of body weight and maintain the weight loss or bring their waist circumference or BMI into their ethnicity specific 'normal' range (eg, for Caucasians: waist circumference <94 cm for men and <80 cm for women or BMI <25 m/kg).
Exercise
People with NAFLD engage in less physical activity than their healthy counterparts and higher levels of habitual physical activity are associated with lower levels of steatosis. Aerobic exercise increases skeletal muscle insulin sensitivity and as a result reverses one of the key pathophysiological mechanisms that causes NAFLD (insulin resistance). Although the optimum exercise to treat NAFLD is not known, studies examining moderate intensity training, high intensity training and resistance exercise have shown improvement in liver enzymes and reduction in liver fat, independent of weight loss, but the effects on histology remain unknown. Therefore, all patients with NAFLD should be advised to increase physical activity and undertake regular exercise. Until further evidence is available, one approach is to recommend 30 min of moderate exercise five times weekly. In reality though, a significant proportion of patients with NAFLD do not comply with these recommendations. In such patients, the use of pedometers can be quite helpful. We recommend that patients increase their daily step count to >10 000 steps/day.
Orlistat as an Aid to Weight Loss
Orlistat is an enteric lipase inhibitor that leads to malabsorption of dietary fat and can aid weight loss in subjects with obesity in conjunction with lifestyle modification. One study demonstrated that orlistat treatment for NAFLD improved alanine transaminase (ALT) and steatosis, but a subsequent RCT conducted by Harrison et al showed that orlistat in combination with calorie restriction and vitamin E (800 IU/day) did not enhance weight loss, improve liver enzymes or improve histopathology compared with calorie restriction and vitamin E. In that study, they found that ≥9% weight loss resulted in improved histology irrespective of whether they received orlistat or placebo. National Institute of Health and Care Excellence (NICE) guidelines for obesity recommend that orlistat can be considered as an aid to weight loss in subjects who have not achieved their target weight by lifestyle intervention and have a BMI>30 kg/m, so it seems reasonable to consider this treatment in patients with obesity and NAFLD. If orlistat is initiated, only patients who achieve >5% loss of body weight in 3 months should continue the medication. Treatment duration should not be greater than 1 year as there is potential for fat soluble vitamin deficiency if continued for longer.
Bariatric Surgery
Bariatric surgery has an increasing role in the management of patients with obesity and the metabolic syndrome. Restrictive procedures such as the gastric band, gastric balloon and sleeve gastrectomy decrease stomach size leading to early satiety. Malabsorptive procedures such as gastric bypass limit the absorption of food. Weight loss after bariatric surgery has beneficial effects on the components of the metabolic syndrome including improving insulin sensitivity, lipid profile as well as reducing long-term mortality. It also has specific effects on liver histology including reduced steatosis, steatohepatitis and fibrosis. The majority of the histological benefits occur within the first year post-surgery. The optimum type of bariatric surgery for the treatment of NASH is not known. Although gastric bypass surgery produces the largest sustained weight loss compared with other bariatric procedures, Mathurin et al found no significant differences among the gastric band, bilio-intestinal and gastric bypass groups in terms of global NAFLD activity score (NAS), steatosis, inflammation or ballooning. As there is a lack of long-term outcome data about bariatric surgery as a specific treatment for NAFLD, bariatric surgery cannot be considered as a primary treatment for NASH. However, NICE guidance suggests that surgery should be considered as a treatment for obesity for patients with BMI >40 kg/m or between 35 and 40 kg/m with other significant disease that could be improved with weight loss. All appropriate non-surgical measures must be tried first and patients must receive intensive specialist management and be prepared to commit to long-term follow-up. Surgery can be considered as a first-line option for the treatment of obesity in adults with a BMI greater than 50 kg/m.
Bariatric surgery should be avoided in subjects with advanced cirrhosis with portal hypertension as there is a risk of hepatic decompensation with the rapid weight loss. Patients with decompensated cirrhosis have particularly high mortality rates post-bariatric surgery compared with compensated cirrhotics and non-cirrhotic patients (16.3% vs 0.9% and 0.3%, respectively, p=0.0002). In carefully selected patients with Child–Pugh A cirrhosis, gastric bypass and sleeve gastrectomy have been shown to achieve weight loss and improve obesity-related comorbidities. However, patients with cirrhosis should undergo bariatric surgery at centres that perform large numbers of these procedures.
Liver-directed Pharmacotherapy
For patients with biopsy-proven NASH, where lifestyle intervention has failed, liver-directed pharmacotherapy with pioglitazone or vitamin E can be considered.
Pioglitazone. Several studies have demonstrated benefit from the thiazolidinediones in patients with NASH both with and without diabetes. Aithal et al showed that 12 months of treatment with pioglitazone 30 mg/day reduced hepatocellular injury and fibrosis compared with placebo. More recently, the PIVENS study showed significantly more patients receiving pioglitazone had resolution of steatohepatitis (a secondary endpoint) than with placebo (47% vs 21% p=0.001), although the treatment arm narrowly failed to meet the very strict primary endpoint (improvement in NAS ≥2 with at least 1-point improvement in hepatocyte ballooning without increase in fibrosis score). A recent meta-analysis has demonstrated that pioglitazone treatment in NASH significantly improves steatosis, inflammation and to a lesser degree, fibrosis. While pioglitazone appears to be an effective treatment for NASH, there are also some concerns about its long-term safety. Treatment with pioglitazone is associated with weight gain (4.7% in the PIVENS study) and there have been reports of increased risk of congestive cardiac failure, bladder cancer and reduced bone density. However, a meta-analysis of 16 390 patients with type 2 diabetes mellitus (T2DM) treated with pioglitazone demonstrated an 18% reduction in death, myocardial infarction and stroke. Therefore, after assessing risk and benefit, treatment with pioglitazone can be recommended for patients with more aggressive NASH who have failed lifestyle interventions. Caution should clearly be exercised in patients with cardiac disease (a common comorbidity in patients with NAFLD) and echocardiography performed prior to considering treatment with pioglitazone. The optimum dose and duration of treatment are not known.
Vitamin E. Vitamin E is an antioxidant that has recently been shown to have beneficial effects on histology in non-diabetic patients with NASH. In the large PIVENS trial, significantly more patients had improvement in steatohepatitis following 96 weeks of vitamin E 800 IU/day compared with placebo (42% vs 19% p<0.001). This was confirmed in a study of childhood NASH, where vitamin E was shown to reduce steatohepatitis in a subgroup who had follow-up liver biopsies. Although vitamin E looks like a promising treatment for NASH, there are concerns about the long-term effects of vitamin E with a meta-analysis showing a small overall increase in all-cause mortality at doses >400 IU/day. It has also been reported that there might be an increased risk of haemorrhagic stroke and prostate cancer with high dose treatment. Vitamin E has not been evaluated in patients with cirrhosis or diabetes and NASH. Therefore, it should currently be reserved for selected patients with more advanced pre-cirrhotic NASH who have failed lifestyle interventions. The optimum dose and duration of treatment are not known.