Vi Nguyen, Jiawei Li, and Dr Jude Oben (pictured) discuss the causes and diagnosis of NAFLD, and the need for a holistic, multidisciplinary, and individualised approach for optimal disease management

oben jude

Independent content logo

Read this article to learn more about:

  • the importance of treating NAFLD in preventing cirrhosis, end-stage liver disease, and early mortality
  • how lifestyle interventions remain the mainstay of treatment, with pharmacotherapy and surgery available as alternative options
  • the key role of primary care in screening and identification of those at risk, as well as providing education and preventive advice.

Key points

GP commissioning messages

The term non-alcoholic fatty liver disease (NAFLD) covers a range of conditions from liver fat (steatosis) through to hepatic inflammation (non-alcoholic steatohepatitis; NASH) and cirrhosis, which may result in end-stage liver disease and primary liver cancer. Non-alcoholic fatty liver disease is:

  • a diagnosis made in the absence of excess alcohol consumption (≥140 g/week for men, and ≥70 g/week for women)
  • invariably linked with being overweight or obese (although NAFLD is evident in 25% of individuals of normal weight1)
  • closely associated with other complications of the metabolic syndrome (impaired glucose tolerance, hypertension, and dyslipidaemia).2,3

Non-alcoholic fatty liver disease is now the leading cause of chronic liver disease in affluent countries and some emerging economies4 and is expected to become the main indication for liver transplantation in the United States between 2020 and 2025.5 The estimated prevalence of NAFLD largely parallels the obesity epidemic, and although it varies across different regions of the world, the unifying trend is the rapidly increasing rate being observed worldwide.5

According to the statistical report published by the Health and Social Care Information Centre (HSCIC) in March 2015, obesity rates among adults in England almost doubled between 1993 and 2013 (from 13.2% to 26% in men, and 16.4% to 23.8% in women).6 It is projected that more than 50% of the adult UK population will be obese by the year 2050. Of greatest concern, however, is the rising prevalence of obesity among the young, with approximately 20% of UK children now classified as overweight or obese according to the Organisation for Economic Co-operation and Development (OECD) in 2013.6

What causes fatty liver disease?

The pathogenesis of fatty liver disease remains incompletely understood. It is probably part of a more complex systemic disease process that is associated with increased calorie intake and reduced energy expenditure.

At the cellular level, a dysregulated response between adipose tissue and liver cells appears to be the principal biological change underlying NAFLD development. It is thought that fat from excessive nutrition initially accumulates in the liver, along with enhanced de novo lipid synthesis driven by insulin resistance—the 'first hit'. This subsequently stimulates a cascade of pro-inflammatory hormones and cytokines, and sensitises the liver to a 'second hit' of insults resulting in liver cell injury, as well as the promotion of a chronic state of low-grade systemic inflammation.7

There is a particularly strong association between NAFLD and insulin resistance; in fact virtually all patients with NASH are insulin resistant.8 The strength of this association is greatest in those with central (visceral) obesity and other features of the metabolic syndrome, particularly type 2 diabetes.9 The hyperinsulinaemia found in patients with NAFLD and metabolic syndrome is the result of greater insulin secretion by the body in an attempt to maintain normal glucose and lipid homeostasis.

Risk factors that have been associated with a greater incidence of NAFLD therefore include: obesity and visceral adiposity, impaired glucose tolerance, type 2 diabetes, hypertension, and dyslipidaemia. There also appears to be a higher risk among men, as well as certain ethnic and familial predispositions.9,10 Additionally, maternal obesity during pregnancy has been shown potentially to predispose offspring to the development of NAFLD and related complications later in life.11

Why is it important to recognise and treat NAFLD?

The consequences of untreated disease include liver inflammation, liver fibrosis, liver cirrhosis, end-stage liver disease, and primary liver cancer. Although the individual natural history of NAFLD is somewhat unclear, collective evidence demonstrates that approximately 20–30% of patients can progress to NASH. Long-term studies estimate that approximately 5% of these individuals will then progress to cirrhosis and end-stage liver disease, and develop other complications such as liver cancer over time, even in the absence of advanced liver damage.9,12

In addition to these liver-specific outcomes, it is important to remember that the presence of NAFLD is associated with a broader range of complications, including a higher risk of cardiovascular disease (CVD) and early mortality, as well as a greater risk of extra-hepatic malignancies.13,14 In fact, the leading cause of morbidity and death among patients with NAFLD/NASH remains adverse cardiovascular events.15

Again, comorbid conditions such as diabetes, greater central adiposity, and more advanced liver disease (such as higher grades of liver inflammation and fibrosis) predict worse long-term outcomes.

There are currently no definitive diagnostic tests for NAFLD. When suspected, other important causes of chronic liver disease should first be excluded, including viral hepatitis (HBV and HCV), significant alcohol intake, medications, autoimmune hepatitis, Wilson's disease, and haemochromatosis. A personal or family history of obesity, diabetes, hypertension, and dyslipidaemia are also further clues to the presence of NAFLD/NASH.

While liver function tests can be helpful if elevated, they can be normal in a substantial number of patients and, paradoxically, especially in those with more advanced liver disease, such as cirrhosis. A liver ultrasound can only detect hepatosteatosis when the extent is greater than approximately 30%.16 Absence on ultrasonography, therefore, does not necessarily exclude a diagnosis of NAFLD. Hepatic magnetic resonance imaging (MRI), and magnetic resonance spectroscopy (MRS) can better quantitate whole liver fat; however, these modalities are not currently widely available for this purpose outside of clinical trials.16

Controlled attenuation parameter (CAP) is a technique that measures the attenuation of an ultrasound wave propagated through the liver using a transient elastography probe. Transient elastography was designed to measure liver stiffness, which in turn correlates with fibrosis. Controlled attenuation parameter has now demonstrated good accuracy in the detection and grading of steatosis when compared with liver biopsy.17 Unfortunately, it can often be technically difficult to obtain accurate information using these tools in overweight and obese patients.

Apart from radiological options, several non-invasive serological tools have also been developed to help assess the degree of liver injury in the setting of NAFLD. Some of these validated tools include the NAFLD Fibrosis Score, Enhanced Liver Fibrosis (ELF) panel, and Fibrosis-4 (Fib-4) score. These tools calculate a risk score based on a number of clinical and biochemical markers. All have demonstrated high accuracy rates (>85%) in the prediction of advanced fibrosis in patients with NAFLD, and provide options to help assess disease stage and risk stratification.18,19,20

The current gold standard for the diagnosis and staging of NAFLD remains a liver biopsy. This is not ideal given its invasiveness and the risk of serious complications (1–3%),21 along with the fact that only a small segment of liver is of course taken at biopsy, making it subject to sampling errors.

New biomarkers are currently being developed to assist with the differentiation between steatosis and the more severe stage of NAFLD/NASH. Currently this can also only be accurately determined through a liver biopsy, but the development of a new promising marker, cytokeratin-18 (CK-18), may provide a reliable non-invasive measure for the detection of NASH in the near future.22

Current recommendations for management

There is no single treatment for NAFLD/NASH. While several potential therapeutic options are under development, lifestyle interventions remain the most effective treatment modality, especially given the maladaptive behaviours that often underlie the development of the metabolic syndrome and NAFLD (see Figure 1, below).

 

Figure 1: Distribution of ratings by key question for CQC general practice inspections (1 October 2014–11 June 2015)
current recommendations for management

NAFLD=non-alcoholic fatty liver disease; NASH=non-alcoholic steatohepatitis; LFT=liver function test; Fib-4=Fibrosis-4; BMI=body mass index; HCC=hepatocellular carcinoma

Lifestyle interventions

Lifestyle interventions typically involve dietary modifications and physical activity changes, and should also incorporate cognitive behavioural therapy wherever possible. It is important to remember that while weight loss in the overweight and obese is ideal, there is growing recognition of the many far-reaching benefits of lifestyle changes that can be achieved, independent of weight change.

Dietary recommendations

There are currently no widely recognised dietary recommendations for NAFLD. Some guidelines have recommended diets similar to those recommended for the management of diabetes.23 This generally involves a hypocaloric diet (1200–1500 kcal/day) ideally aiming for weight loss of at least 5–7% of baseline body weight. This has been shown to correlate with the greatest improvements in insulin resistance, anthropometrics, and histological changes on liver biopsies.24,25

The macronutrient composition of the diet may also be important. Findings from available studies to date suggest there are benefits from a diet that is low in saturated fatty acids and carbohydrates, and high in monounsaturated fatty acids and dietary fibre.26,27 A Mediterranean style diet, which incorporates many of these factors, would appear to confer the most benefit, especially given its association with reduced rates of CVD and malignancy, and improved overall mortality.28,29 In NAFLD, such a diet was found to significantly reduce insulin resistance and serum lipids—including liver function tests after just 6 weeks—independent of any weight change.30 However, as evidence in this area is still continuing to evolve, no definitive recommendations can be made at this time.

There is also increasing evidence on the importance of several micronutrients in the treatment of NAFLD. Vitamin D has been shown to have many more potential uses in addition to the optimisation of bone health. In liver disease, vitamin D supplementation has been found to reduce hepatic inflammation, improve glucose control, arrest liver fibrosis, and even correlate with improved outcomes with liver cancer. Similarly, coffee appears to have a number of hepatoprotective effects. It is therefore not unreasonable to ensure adequate vitamin D replacement, and recommend a moderate amount of coffee consumption in NAFLD.26,31

Finally, the intestinal microbiota (the 'microbiome') also appears to play a potential role in the pathogenesis and disease modification of NAFLD. To date, the results from several small studies have demonstrated improvements in transaminases, steatosis, and even liver fibrosis, when probiotics supplemented lifestyle interventions in the treatment of NAFLD.32

Physical activity recommendations

Regular physical activity has been associated with the prevention of diabetes, improved cardiovascular health, and even reduced cancer risk. The benefits are similar in NAFLD, with studies demonstrating improved insulin resistance, metabolic risk factors, and liver enzymes, independent of weight loss.33

Both aerobic and resistance training are of benefit. More moderate to vigorous levels of physical activity (versus lesser degrees of activity), and combined aerobic and resistance training may provide the best outcomes. Resistance training may be preferred by some patients with limited ability to undertake vigorous cardiovascular exercises, and/or those with musculoskeletal ailments. Furthermore, with an ageing population, there is also an increasingly recognised risk of 'sarcopaenic obesity'.34 This refers to the presence of low muscle mass in overweight individuals—thought to be the effect of declining muscle mass concurrent with increasing body weight/fat due to decreasing basal metabolic rates with age. It has been reported in up to 12% of older individuals,35 and highlights the need for caution when making physical activity recommendations, especially as aerobic training alone, when combined with calorie restriction, may cause further loss of muscle mass and functional decline among elderly patients.

While there are no broadly accepted physical activity guidelines for the management of NAFLD, the European Association for the Study of the Liver (EASL) recommends at least 150 minutes per week of moderate-intensity physical activity (such as brisk walking), and at least 75 minutes per week of vigorous-intensity physical activity (such as jogging), in addition to muscle strengthening activities at least twice a week.25 Ideally, any exercise prescription should be individualised, and delivered by a trained exercise physiologist.

Pharmacological therapies

Current drug therapies

The only insulin-sensitising agents with proven efficacy in the management of NAFLD are the thiazolidinediones (pioglitazone or rosiglitazone36). The landmark PIVENS trial compared pioglitazone (30 mg) and vitamin E (800 IU/day) with placebo in a large group of non-diabetic patients with biopsy-proven NASH.37 After 96 weeks of treatment, significant histological improvements in hepatic steatosis and inflammation were seen in those on both pioglitazone and vitamin E, although the effects were greatest with vitamin E. [NB At time of publication, pioglitazone is not licensed for treatment of NAFLD; the prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information.]

Vitamin E is a micronutrient with potent anti-oxidant properties. It is now recommended as first-line drug therapy for those with proven NASH,38 while pioglitazone can also be considered. Given the limited evidence with these agents among patients with diabetes and cirrhosis, however, these treatments cannot currently be recommended among these individuals. Also, further caution has been recommended with the longterm use of vitamin E in view of some reports suggesting a possible link with increased mortality.

There is no evidence supporting the use of metformin or ursodeoxycholic acid for the primary purpose of NAFLD/NASH management.

Upcoming drug therapies

Several new pharmacological agents are now being examined as potential therapies for NAFLD:

  • obeticholic acid is an agonist of the farnesoid-X receptor, the stimulation of which has been found to reduce hepatic fatty acid synthesis and improve insulin sensitivity. A recently published multicentre trial has demonstrated improvements in steatosis, inflammation, and fibrosis among a large group of patients with NASH, including those with diabetes, some of whom had previously failed on vitamin E therapy.39 However, a significant number of patients developed pruritus as a side effect (>20%), and the long-term safety of this agent remains uncertain
  • glucagon-like peptide-1 (GLP-1) analogues—such as exenatide and liraglutide—are already widely used in the management of type 2 diabetes. These analogues mimic the incretin hormone, which stimulates pancreatic release of insulin, and also reduces the appetite (at the level of the hypothalamus), as well as slowing gastric emptying from the stomach.40 In preliminary NAFLD studies, its use has been associated with improved lipid metabolism and reduced hepatic steatosis and inflammation41
  • finally, the use of angiotensin receptor blockers (telmisartan and losartan) has also shown promise in treating inflammatory changes in NASH in preclinical studies; these may provide future options for slowing progression of fibrosis in disease management as well.42,43

Other therapies

Bariatric surgery

Weight loss surgeries (i.e. gastric bypass, sleeve gastrectomy, and gastric banding) have been shown to improve hepatosteatosis, inflammatory changes, and fibrosis in NASH patients, and are currently the only treatments that offer significant, durable weight loss over the longer term. Not all patients, however, are suitable or eligible for bariatric surgery, especially given the higher risk of anaesthesia and impaired wound healing in obese patients. Furthermore, the feasibility of surgery for all obese patients will be hampered by a limited degree of access in several centres.

Bariatric endoscopy

Interim or definitive endoscopic procedures such as the intra-gastric balloon (IGB) or the duodenal-jejunal bypass sleeve (EndoBarrier®) may offer less invasive, reversible alternatives to effect weight loss in instances where lifestyle interventions have failed, and/or the patient is not a candidate for bariatric surgery. Several prospective studies have demonstrated the efficacy of IGBs in achieving significant weight loss, associated with improvements in the metabolic profile and liver transaminases in patients with NAFLD over the short to medium term.44

The EndoBarrier® is an intestinal 'bypass sleeve' made from an impermeable polymer that is endoscopically inserted into the first part of the duodenum. The sleeve promotes weight loss by partially impairing nutrient absorption, but more interesting is its ability to improve diabetes control prior to weight loss. This suggests that its crucial beneficial effect is through the modification of key gastrointestinal hormones involved with insulin sensitivity, satiety, and weight control (namely GLP-1). Further studies are currently underway to better define its efficacy and potential role in the management of obesity, and NAFLD.

At their centre, the authors offer the insertion of IGBs for weight loss in obese patients, particularly those who have failed lifestyle and drug interventions, and who are invariably at higher risk of adverse outcomes from untreated disease over the long term. This service is provided in conjunction with holistic dietetics support, with the intention of providing each patient with the tools to continue lifestyle change, and hopefully maintain weight loss following IGB removal.

Future projections: a central role for primary care

Although disease recognition has improved over the past few years, further work is required. Given the magnitude of the problem, a holistic, multidisciplinary, and individualised approach to disease management will be the key to achieving any realistic change. This will undoubtedly involve greater recognition of the problem at parliamentary level to enable broader education, and nationwide strategies aimed at the promotion of more widespread preventative measures.

There is an important role for primary care physicians, not only in the opportunistic screening and identification of people who are at risk, but also in the provision of essential education and preventive advice where possible. Although referral for specialist care is important, overly-stretched, limited hospital resources mean that reliable preliminary staging needs to be undertaken in the primary care setting. We advise the use of the algorithm shown in Figure 1 (above) for triaging patients with suspected NAFLD/NASH.

Where patients manifest any risk factors for more advanced disease, such as persistently abnormal liver function tests, an elevation or progression of fibrosis score (using a validated fibrosis scoring system), or concerning changes on liver imaging, it is suggested that referral to a specialist unit be made. Low-risk patients without risk for disease progression or complications, should be managed through supervised dietary and physical activity programmes, with regular monitoring of anthropometric and biochemical indices, and management of associated features of the metabolic syndrome (e.g. screening for diabetes, hypertension, dyslipidaemia), with further referral for specialist care as appropriate.

In the secondary care setting, further staging is usually undertaken (e.g. with transient elastography or liver biopsy), and ideally a multidisciplinary approach to disease management is provided (including the regular involvement of dietitians, exercise physiologists, and psychologists). Referral for centre-specific treatments—such as bariatric endoscopic devices and bariatric surgery—should also be considered whenever available, including access to novel therapies in a clinical research setting.

Conclusion

It is projected that NAFLD will become the principal cause of liver transplantation among affluent and emerging economies. Non-alcoholic fatty liver disease encompasses a spectrum of liver disease that is inextricably part of a more complex, systemic disease process, often linked with deeply entrenched maladaptive behaviours. Lifestyle interventions remain the mainstay of treatment, but several new pharmacological agents and endoscopic devices may provide additional therapeutic options. A holistic, multidisciplinary, and individualised approach will be the key to effective disease management, with a pivotal role for primary care in opportunistic screening and triage, provision of preliminary management and monitoring, and ensuring ongoing education and preventive measures.

Key points

  • Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disease that ranges from the accumulation of liver fat (steatosis) to hepatic inflammation and liver injury (non-alcoholic steatohepatitis [NASH])
  • Although NAFLD is a diagnosis made by exclusion of excessive alcohol consumption, it can often co-exist with many other causes of chronic liver disease, including alcoholic liver disease
  • NAFLD often accompanies other features of the metabolic syndrome (e.g. obesity, type 2 diabetes, hypertension, dyslipidaemia), and its prevalence closely parallels the rising incidence of obesity worldwide
  • The underlying cause is probably multifactorial, often associated with excess calorie consumption and reduced energy expenditure, and driven by maladaptive lifestyle behaviours
  • There are currently no definite diagnostic tests for NAFLD, and the gold standard for disease staging remains a liver biopsy. Standard ultrasonography cannot detect low levels of steatosis, and transient elastography can be technically difficult in people who are overweight and obese. There are several new tools being developed to provide more reliable diagnosis, and non-invasive staging in the future
  • Consequences of untreated disease include: liver inflammation, liver fibrosis, end-stage liver disease, and hepatocellular cancer. There is also a higher associated risk of cardiovascular disease, early mortality, and non-hepatic malignancies
  • There are no specific treatments for NAFLD/NASH. The mainstay of management remains lifestyle interventions incorporating dietary modifications, physical activity changes, and formal psychological support where available
  • Vitamin E and pioglitazone can be considered for treatment of active steatohepatitis in non-diabetic patients without advanced liver disease. Several new drug therapies, including angiotensin receptor antagonists, obeticholic acid, and GLP-1 agonists, are currently in development to provide further treatment options
  • Obese patients should be referred for consideration of bariatric surgery for durable weight control where lifestyle interventions have failed. Bariatric endoscopic devices may offer an alternative means for weight loss where surgery is not a feasible option
  • Primary care physicians have an important role in screening and triaging for suspected cases of NAFLD/NASH. Uncomplicated cases should continue to be managed and monitored in the community, while people with more advanced disease, or those whose disease is at risk of progressing, should be referred for secondary evaluation and specialised treatment where appropriate.

Back to top

GP commissioning messages

written by Dr David Jenner, NHS Alliance GMS contract/PBC Lead

  • NAFLD is a leading cause of chronic liver disease, with the majority of cases occurring in individuals who are overweight, and is increasing in incidence alongside rising rates of obesity
  • A small number of patients with NAFLD can progress to long-term liver failure or cancer, so accurate recognition, diagnosis, and monitoring is important to identify those who are at most risk
  • Commissioners and secondary care specialists should:
    • help define local algorithms (e.g. see Figure 1, above) and share these with primary care physicians. These algorithms will need to define key thresholds for referral to specialist care, and also which blood tests should be performed to exclude other causes of chronic liver disease (e.g. hepatitis C or haemochromatosis)
    • develop an educational programme in the use of tools such as Fib-4 or NAFLD, which currently are not often used in primary care
  • Lifestyle modification remains the key intervention for treating NAFLD, and can be implemented in primary care; however, pharmacotherapy (using drugs that are often outside their marketing authorisation) is probably best reserved for specialist care, or under shared-care agreements.

NAFLD=non-alcoholic fatty liver disease; Fib-4=Fibrosis-4

Back to top

References

  1. Caldwell S, Argo C. Non-alcoholic fatty liver disease and nutrition. In: Dooley J et al, editors.Sherlock's diseases of the liver and biliary system 12th edition. Wiley-Blackwell 2011; 546–564.
  2. International Diabetes Federation. Consensus worldwide definition of the metabolic syndrome. IDF, 2006. Available at: www.idf.org/webdata/ docs/IDF_Meta_def_final.pdf
  3. World Health Organization. Definition, diagnosis, and classification of diabetes mellitus and its complications. Geneva: Department of Noncommunicable Disease Surveillance. WHO 1999. Available at: apps.who.int/iris/ handle/10665/66040
  4. Argo C, Caldwell S. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin Liver Dis 2009; 13 (4): 511–531.
  5. Charlton M, Burns J, Pedersen R et al. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 2011;141 (4): 1249–1253.
  6. Health & Social Care Information Centre. Statistics on obesity, physical activity, and diet. HSCIC, 2015. Available at: www.hscic.gov. uk/catalogue/PUB16988/obes-phys-acti-dieteng-2015.pdf
  7. Day C, James O. Steatohepatitis: a tale of two 'hits'? Gastroenterology 1998; 114 (4): 842–845.
  8. Chitturi S, Abeygunasekera S, Farrell G et al. NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002;35 (2): 373–379.
  9. Ekstedt M, Franzen L, Mathiesen U et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2000;44 (4): 865–873.
  10. Kallwitz E, Kumar M, Aggarwal R et al. Ethnicity and nonalcoholic fatty liver disease in an obesity clinic: the impact of triglycerides.Dig Dis Sci 2008. 53 (5): 1358–1363.
  11. Oben J, Mouralidarane A, Samuelsson A et al. Maternal obesity during pregnancy and lactation programs the development of offspring non-alcoholic fatty liver disease in mice. J Hepatol 2010; 52 (6): 913–920.
  12. White D, Kanwal F, El-Serag H. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 2012; 10 (12): 1342–1359 e2.
  13. Adams L, Lymp J, Sauver J et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study.Gastroenterology 2005; 129 (1): 113–121.
  14. Calle E, Rodriguez C, Walker-Thurmond K et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003; 348 (17): 1625–1638.
  15. Lazo M, Hernaez R, Bonekamp S et al. Nonalcoholic fatty liver disease and mortality among US adults: prospective cohort study. BMJ 2011; 343 doi:10.1136/bmj.d6891.
  16. Charatcharoenwitthaya P, Lindor K. Role of radiologic modalities in the management of non-alcoholic steatohepatitis. Clin Liver Dis 2007; 11 (1): 37–54.
  17. Ledinghen V, Vergniol J, Foucher J et al. Non-invasive diagnosis of liver steatosis using controlled attenuation parameter (CAP) and transient elastography.Liver Int 2012; 32 (6): 911–918.
  18. Musso G, Gambino R, Cassader M et al. Metaanalysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011; 43 (8): 617–649.
  19. McPherson S, Stewart S, Henderson E et al. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut 2010;59 (9): 1265–1269.
  20. Angulo P, Hui J, Marchesini G et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007; 45 (4): 846–854.
  21. Bravo A, Sheth S, Chopra S. Liver biopsy. N Engl J Med 2001; 344 (7): 495–500.
  22. Feldstein A, Wieckowska A, Lopez A et al. Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 2009;50 (4): 1072–1078.
  23. Evert A, Boucher J, Cypress M et al. Nutrition therapy recommendations for the management of adults with diabetes. Diabetes Care 2013; 36 (11): 3821–3842.
  24. Promrat, K, Kleiner D, H.M. Niemeier H et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 2010; 51 (1): 121–129.
  25. Ratziu V, Bellentani S, Cortez-Pinto H et al. A position statement on NAFLD/NASH based on the EASL 2009 special conference.Hepatology 2010; 53 (2): 372–384.
  26. McCarthy E, Rinella M, The role of diet and nutrient composition in nonalcoholic fatty liver disease. J Acad Nutr Diet 2012; 112 (3): 401–409.
  27. Zivkovic A, German J, Sanyal A. Comparative review of diets for the metabolic syndrome: implications for nonalcoholic fatty liver disease. Am J Clin Nutr 2007; 86 (2): 285–300.
  28. Estruch R, Ros E, Salas-Salvado J et al. Primary prevention of cardiovascular disease with a Mediterranean diet.N Engl J Med 2013; 368 (14): 1279–1290.
  29. Sofi F, Cesari F, Abbate R et al. Adherence to Mediterranean diet and health status: metaanalysis. BMJ 2008; 337: a1344.
  30. Ryan M, Itsiopoulos C, Thodis T et al. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with nonalcoholic fatty liver disease. Hepatology 2013;59 (1): 138–143.
  31. Chen S, Teoh N, Chitturi, S et al. Coffee and non-alcoholic fatty liver disease: Brewing evidence for hepatoprotection? JGH 2014; 29: 435–441.
  32. Eslamparast T, Poustchi H, Zamani F et al. Synbiotic supplementation in nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled pilot study.Am J Clin Nutr 2014; 99: 535–542.
  33. Keating S, Hackett D, Parker H et al. Effect of aerobic exercise training dose on liver fat and visceral adiposity. Hepatology 2015; 63 (1): 174–182.
  34. Baumgartner R. Body composition in healthy aging. Ann N Y Acad Sci 2000; 904: 437–448.
  35. Davison K, Ford E, Cogswell M et al. Percentage of body fat and body mass index are associated with mobility limitations in people aged 70 and older from NHANES III. J Am Geriatr Soc 2002; 50 (11): 1802–1809.
  36. Neuschwander-Tetri B, Brunt E, Wehmeier K et al. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPARgamma ligand rosiglitazone. Hepatology 2003; 38 (4): 1008–1017.
  37. Sanyal A, Chalasani N, Kowdley K et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362 (18): 1675–1685.
  38. Chalasani N, Younossi Z, Lavine J 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. Hepatology 2012; 55 (6): 2005–2023.
  39. Neuschwander-Tetri B, Loomba R, Sanyal A et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, nonalcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385: 956–965.
  40. Reid T. Practical use of glucagon-like peptide-1 receptor agonist therapy in primary care. Clinical Diabetes 2013; 31 (4): 148–157.
  41. Wang X, Gusdon A, Liu H, Qu S. Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation. World J Gastroenterol 2014; 20 (40): 14821–14830.
  42. Kudo H, Yata Y, Takahara T et al. Telmisartan attenuates progression of steatohepatitis in mice: role of hepaticmacrophage infiltration and effects on adipose tissue. Liver International 2009; 29 (7): 988–996.
  43. Yang Y, Lee P, Huang Y. Involvement of the HIF-1α and Wnt/β-catenin pathways in the protective effects of losartan on fatty liver graft with ischaemia/reperfusion injury. Clin Sci (Lond) 2014; 126 (2): 163–174.
  44. Forlano R, Ippolito A, Iacobellis A et al. Effect of the BioEnterics intragastric balloon on weight, insulin resistance, and liver steatosis in obese patients. Gastrointest Endosc, 2010; 71 (6): 927–933.