Management of NAFLD and NASH
Until recently, no professional body had produced best practice guidelines for the care of people with nonalcoholic fatty liver disease (NAFLD). Although a number of guidelines have now been formulated, most are suggestive rather than prescriptive.
In the absence of approved pharmacotherapies, guidelines issued by the European Association for the Study of the Liver (EASL) state that for individuals with a diagnosis of nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH), the goal for management is to maintain stable disease or reduce steatosis and inflammation.
The main difference in management approaches is between people found to have simple steatosis, remaining under primary care, and those referred to specialists due to high risk of advanced fibrosis. Lifestyle intervention is recommended as the first-line treatment option for all people with NAFLD, however, those with advanced disease may require surgical intervention.
As discussed in the referral and diagnosis section, in cases of steatosis, where advanced fibrosis cannot be ruled out, referral to a liver specialist for further investigation is vital. If a diagnosis of advanced fibrosis due to NASH is confirmed, a shared management and follow-up programme should be agreed between primary and secondary care providers.
The optimal follow-up period for people with NAFLD is still undetermined. People with advanced fibrosis due to NASH should be referred to a liver specialist and monitored, while those at risk or with early stage disease may be monitored by their primary care provider (PCP).
NAFLD status may change over time, warranting transfer of care between PCPs and liver specialists and individuals may require more or less frequent follow-up as their NAFLD status changes.
EASL recommendations on follow-up1
Advanced fibrosis due to NASH
6 months – 1 year
NAFL without worsening of metabolic risk factors
2 – 3 years
Patients with metabolic risk factors
3 – 5 years
Lifestyle interventions are recommended for everyone with NAFLD regardless of severity. The focus should be on weight loss and regaining glycaemic control through diet and exercise, similar to interventions in people with obesity and/or type 2 diabetes mellitus (T2DM).2–4
Adherence to diet and exercise regimens in people with NAFLD can lead to improvements in overall liver histology, fibrosis severity and in some instances, complete reversal of steatosis, regardless of overall weight loss.3,4
Achieving a healthy weight should be the primary lifestyle goal for people with NAFLD who are overweight or obese. Even modest reductions in body weight have been shown to improve steatosis, with the effect on liver health linked to the percentage of weight lost.
In a study of 293 people with T2DM, weight loss due to lifestyle intervention was shown to correlate with a reduction in NAFLD and NASH. Of the participants that who achieved >5% weight loss, 58% experienced NASH resolution, and 82% experienced a 2-point reduction in NAFLD activity score (NAS). In those that achieved >10% weight loss, 90% had NASH resolution, 100% saw a 2-point reduction in NAD, and 45% had fibrosis regression.5 In another study, eight people with obesity, T2DM and NAFLD were placed on a moderately hypocaloric, very-low-fat diet (3% fat by weight). In some cases, hepatic steatosis was almost entirely reversed by moderate weight loss. A reduction in body weight of ~8% normalised fasting plasma glucose and led to an ~80% improvement in steatosis.2
Even modest reductions in body weight have been shown to improve steatosis, with the effect on liver health linked to the percentage of weight lost.
The most effective route to weight loss is through a calorie-restricted diet. While no particular type of diet is recommended for people with NAFLD, some dietary factors have been associated with positive outcomes.
The Mediterranean diet (high in monounsaturated fat) has been associated with additional steatosis reduction. This diet was investigated in a study of 12 people without diabetes, compared with a standard low-fat, high-carbohydrate diet.6 All participants undertook both diets in random order for 6 weeks each, with a 6-week wash-out period in between. The Mediterranean diet resulted in a greater reduction in steatosis vs the low-fat, high-carbohydrate diet over the same time period, despite the total weight loss remaining the same for each diet.
Restricting carbohydrate intake via a ketogenic diet, defined as <20 g carbohydrate/day, may provide an additional benefit to people with NAFLD. A pilot study in five people with NASH placed on a low-carbohydrate, ketogenic diet resulted in histological improvements by biopsy in four participants.7
Other studies evaluating low-calorie, low-carbohydrate and low-fructose diets have found similar benefits in reversing steatosis and NASH.8,9 Ultimately, the ability to adhere may be the most important factor when choosing a diet, as long as calorie restriction is incorporated
Alcohol consumption at moderate levels (20g, men; 30g, women), does not significantly impact steatosis and may even be protective against NAFLD. However, in people with NASH, total abstinence should be considered to reduce the risk of hepatocellular carcinoma (HCC).1,10 Drinking coffee has also been shown to be protective in NAFLD.1
Referral to a specialist dietician or other multi-disciplinary weight management service may be considered for those who have difficulty managing their diet.11
Exercise should supplement dietary changes where possible to assist weight loss and development of a healthy lifestyle. Regular exercise combined with dietary changes has been shown to significantly improve weight loss and reduce hepatic fat deposits.3
In a study of 50 people with NAFLD, attainment of high fitness levels was associated with significantly reduced (−31%) hepatic fat deposits. Baseline fitness was the strongest factor predicting change in liver steatosis, followed by exercise intensity.
Although new exercise regimens are usually coupled with dietary alterations, multiple studies have found that exercise in isolation has a positive effect on hepatic steatosis, independent of weight loss.3,4 In terms of exercise type, both aerobic and resistance training have been shown to benefit people with NAFLD. In a randomised, controlled trial comparing both exercise types in 40 participants, hepatic fat content decreased by 32.8% and 25.9% in aerobic and resistance exercise groups, respectively. Hepatic steatosis also disappeared in approximately one quarter of both groups.12
Referral to an exercise physiologist, or a physiotherapist if injuries are preventing exercise, may help people achieve these goals.
Regular exercise combined with dietary changes has been shown to significantly improve weight loss and reduce hepatic fat deposits.3
Surgical interventions may be considered for people with more severe weight issues. Bariatric surgery can help some people lose weight, with potential knock-on or independent effects on reducing NAFLD severity.13–15 Liver transplantation is generally considered to be a last resort for people with NASH who are experiencing liver failure with no chance of disease reversal and restoration of healthy liver functioning.
Randomised trials exploring the efficacy of bariatric surgery for the treatment of NAFLD or NASH have not been conducted,16,13 however, several retrospective and prospective studies have compared liver histology before and after surgery.13–15 In a prospective study of 381 adults followed over 5 years, there was a significant improvement in the prevalence and severity of steatosis and ballooning following either gastric band, biliointestinal bypass or gastric bypass procedures. In addition, people with probable or definite NASH experienced significant improvements in steatosis, ballooning, and resolution of NASH itself.14 Further meta-analyses appear to corroborate these findings,15 but the lack of randomised trials prevents endorsement of bariatric surgery to treat NASH or NAFLD in clinical guidelines.1
People with NASH who have progressed to liver failure, or have developed HCC, are candidates for liver transplantation. NASH is currently the second leading risk factor for liver disease and is on a trajectory to become the leading indication for liver transplantation following a four-fold increase in just 10 years.17,18
People with NASH-HCC have the most urgent requirement for liver transplantation. Among all causes of HCC, including alcoholic liver disease and hepatitis C virus (HCV), people with NASH-HCC have the largest 90-day waitlist mortality.17–19
Currently no pharmacological therapies are approved for the treatment of NAFL or NASH.
A number of insulin-sensitising agents have been investigated in people with NASH, however, results have been largely inconclusive. Studies into these compounds have shown either limited efficacy or concerning long-term safety profiles.20–25 As such, none of the compounds are endorsed by EASL for the treatment of NAFLD.1
The antioxidant properties of vitamin E have been shown to have beneficial effects on NASH histology in people without diabetes; a greater number of people showed improvement in steatohepatitis following 800 IU/day for 96 weeks compared with placebo.22 Despite this potential benefit, concerns also remain over long-term safety.1 For this reason, vitamin E supplementation is also not recommended by EASL guidelines for use in NAFLD patients.
Given the links between NASH and common morbidities, such as obesity, people with NAFLD may benefit from a multi-disciplinary team (MDT) approach.26 While the composition of MDTs will vary between units, a typical MDT will likely include hepatologists, diabetes consultants, dieticians and specialist nurses.27,28
In one study, the MDT approach led to new diagnoses of severe asymptomatic NAFLD in people with T2DM, and the involvement of dieticians resulted in weight loss and associated reductions in biomarkers of liver stress, indicating significant improvement of hepatic steatosis.26
Although potentially effective, the MDT approach to NAFLD investigation and management has not been extensively studied and use of such an approach is rare in clinical practice.29
NAFLD and NASH
A brief introduction to NAFLD and NASH and related content on site.
The Burden of NAFLD and NASH
Exploring the epidemiology, comorbidities and societal impact of NAFLD and NASH.
Identifying people with NAFLD
Information on primary care tests such as the NAFLD fibrosis score, ELF™ score and Fibrosis-4 index.
Referral and diagnosis
An overview of diagnostic testing which can help detect advanced fibrosis due to NASH.
Obesity and NASH
Exploring the links between obesity and advanced fibrosis due to NASH and obesity and NAFLD.
Diabetes and NASH
An overview of NAFLD and advanced fibrosis due to NASH in the context of type 2 diabetes mellitus.
- European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64:1388–402.
- Petersen KF, et al. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 2005;54:603–8.
- Promrat K, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 2010;51:121–9.
- Kantartzis K, et al. High cardiorespiratory fitness is an independent predictor of the reduction in liver fat during a lifestyle intervention in non-alcoholic fatty liver disease. Gut 2009;58:1281–8.
- Vilar-Gomez E, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterol 2015;149:367–78.
- Ryan MC, et al. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol 2013;59:138–43.
- Tendler D, et al. The effect of a low-carbohydrate, ketogenic diet on nonalcoholic fatty liver disease: A pilot study. Dig Dis Sci 2007;52:589–93.
- Barrera F and George J. The role of diet and nutritional intervention for the management of patients with NAFLD. Clin Liver Dis 2014;18:91–112.
- Huang MA, et al. One-year intense nutritional counseling results in histological improvement in patients with non-alcoholic steatohepatitis: a pilot study. Am J Gastroenterol 2005;100:1072–81.
- Dunn W, et al. Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with nonalcoholic fatty liver disease (NAFLD). J Hepatol
- Public Health England. Let’s talk about weight: A step-by-step guide to conversations about weight management with children and families for health and care professionals. Available at: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/620405/weight_management_toolkit_Let_s_talk_about_weight.pdf
(last accessed March 2019).
- Bacchi E, et al. Both resistance training and aerobic training reduce hepatic fat content in type 2 diabetic subjects with nonalcoholic fatty liver disease (the RAED2 Randomized Trial). Hepatology 2013;58:1287–95.
- Chavez-Tapia N, et al. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database Syst Rev 2010:CD007340.
- Mathurin P, et al. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterol 2009;137:532–40.
- Mummadi R, et al. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and metaanalysis. Clinical Gastro and Hepatol 2008;6:1396–402.
- Chalasani N, et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Gastroenterol 2012;142:1592–609.
- Wong RJ, et al. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the US. Hepatology
- Wong RJ, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterol 2015;148:547–55.
- Charrez B, et al. Hepatocellular carcinoma and non-alcoholic steatohepatitis: The state of play. World J Gastroenterol 2016;22:2494–502.
- Haukeland JW, et al. Metformin in patients with non-alcoholic fatty liver disease: A randomized, controlled trial. Scand J Gastroenterol 2009;44:853–60.
- Shields WW, et al. The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): A pilot trial. Therap Adv Gastroenterol 2009;2:157–63.
- Sanyal AJ, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675–85.
- Aithal GP, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 2008;135:1176–84.
- Boettcher E, et al. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2012;35:66–75.
- Lago RM, et al. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: A meta-analysis of randomised clinical trials. Lancet 2007;370:1129–36.
- Armstrong M, et al. Severe asymptomatic non-alcoholic fatty liver disease in routine diabetes care; a multi-disciplinary team approach to diagnosis and management. QJM 2014;107:33–41.
- Cobbold J, et al. Piloting a multidisciplinary clinic for the management of nonalcoholic fatty liver disease: initial 5-year experience. Frontline Gastroenterol 2013;4:263–269.
- Phillips A, et al. Service evaluation: A diabetes service in the nonalcoholic fatty liver disease and post-liver-transplant clinics. J Diabetes Nursing 2018;22:JDN039.
- Marchesini G, et al. Review article: The treatment of fatty liver disease associated with the metabolic syndrome. Aliment Pharmacol Ther 2005;22:37–9.
LID/IHQ/18-12//1048d(1) Date of preparation August 2019