Over the past couple of decades, it has become increasingly clear that nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are now the number 1 cause of liver disease in the western countries. The prevalence of NAFLD has doubled during last 20 years, whereas the prevalence of other chronic liver diseases has remained stable or even decreased. More recent data confirm that NAFLD and NASH play an equally important role in the Middle East, Far East, Africa, the Caribbean, and Latin America.
NAFLD is a condition defined by excessive fat accumulation in the form of triglycerides (steatosis) in the liver. A subgroup of NAFLD patients displays liver cell injury and inflammation in addition to excessive fat (steatohepatitis). The latter condition, designated NASH, is virtually indistinguishable histologically from alcoholic steatohepatitis. While the simple steatosis of NAFLD does not correlate with increased short-term morbidity or mortality, progression of this condition to that of NASH dramatically increases the risks of cirrhosis, liver failure, and hepatocellular carcinoma.
The exact cause of NASH has not been elucidated, and it is almost certainly not the same in every patient. Although it is most closely related to insulin resistance, obesity, and the metabolic syndrome, not all patients with these conditions have NAFLD/NASH, and not all patients with NAFLD/NASH suffer from one of these conditions. NASH is a potentially fatal condition, leading to cirrhosis, liver failure, and hepatocellular carcinoma.
Cascades: A Resource-sensitive Approach
A gold-standard approach is feasible for regions and countries in which the full scale of diagnostic tests and medical treatment options are available for the management of NASH. However, such resources are not available throughout much of the world. With their diagnostic and treatment cascades, the World Gastroenterology Organisation guidelines provide a resource-sensitive approach.
NASH is an increasingly common chronic liver disease with worldwide distribution that is closely associated with diabetes and obesity, which have both reached epidemic proportions. It is estimated that there are at least 1.46 billion obese adults worldwide. Approximately 6 million individuals in the USA are estimated to have progressed to NASH and some 600,000 to NASH-related cirrhosis. There are significant cultural and geographic differences in the prevalence of obesity.
Whereas in most western countries, the preferred body image, especially in women, is very thin with minimal body fat, which is not necessarily true globally. In many other cultures, obesity is considered desirable and also regarded as a distinct sign of prosperity. In the USA, obesity is particularly epidemic in those from lower socioeconomic groups who rely heavily on diets provided by high-fat, high-calorie fast food outlets (junk food). The opposite is true in many poorer countries, where it is the well-to-do, better-educated population that has the highest prevalence of obesity (Table 1).
Diagnostic Strategy for NASH
NASH represents the most severe histologic form of NAFLD, which is defined by fat accumulation in the liver exceeding 5% of its weight. Uniform criteria for diagnosing and staging NASH are still debated.
Insulin resistance is related to obesity and is central to the pathogenesis of NAFLD. In addition, oxidative stress and cytokines are important contributing factors, together resulting in steatosis and progressive liver damage in genetically susceptible individuals.
The disease can remain asymptomatic for years, or can progress to cirrhosis and hepatocellular carcinoma.
Triggers for considering a diagnosis of NASH and starting testing of liver enzymes are: hypertension, type 2 diabetes, sleep apnea, a positive family history, nonblack ethnicity, obesity, hyperlipidemia, and a sedentary lifestyle (Figs. 1–3).
Cascade: Options for Diagnosis in Patients With Suspected NAFLD/NASH
See Table 2.
Treatment Options for NASH
Treatment of Metabolic Conditions
Proper control of diabetes, hyperlipidemia, and cardiovascular risks is recommended. Studies with atorvastatin and pravastatin have shown improvement in histology in patients with NASH. NAFLD patients with dyslipidemia should be treated with statins. Patients with underlying liver disease do not seem to have any additional risk of statin toxicity. Serious hepatotoxicity from statins is rare.
Improving Insulin Sensitivity: Weight Reduction
* Diet: A weight loss of 5% to 10% should be aimed for, and a 25% decrease in calories from the normal diet (ca. 2500 calories/d) for the patient’s age and sex. A moderately calorie-restricted diet with modified macronutrient composition produces better results in comparison with a very low-caloric diet. Attention should be given to the role of a hypocaloric diet and counseling about the type of foods to be consumed—avoiding fructose and trans-fats present in soft drinks and fast foods, and increasing omega-3/omega-6 polyunsaturated fatty acids in diet. This may be difficult for the patient to adhere to, and many patients regain weight after an initial loss.
* Exercise: A moderate exercise program 3 to 4 times a week should be encouraged to achieve a heart rate of 60% to 75% of the age-based maximum.
* The efficacy of dietary and exercise measures should be assessed after a 6-month period; if they have been ineffective, additional therapeutic options such as pharmacologic therapy may then be considered.
* Weight loss (bariatric) surgery may be beneficial for patients with morbid obesity; again, this should be considered early, as most programs will decline such surgery for patients who are already cirrhotic. Limited studies have reported a dramatic improvement in liver disease, as well as other complications of metabolic syndrome/insulin resistance, following successful bariatric surgery.
* Drugs targeting insulin resistance, such as thiazolidinediones and metformin, are approved for diabetes therapy but not for NAFLD/NASH, and should be considered experimental (see the reference list below for more information and detailed discussion).
Antioxidants and Antifibrotic Agents
Antioxidants and antifibrotic agents, such as vitamin E and pentoxifylline, have not been approved for NASH/NAFLD treatment. For all of them, there are limited data and few if any data from double-blind controlled trials. They are all considered experimental (see the reference list below for more information and detailed discussion).
Cascades: Options for Therapy
See Table 3.
* NAFLD and NASH represent a major global public health problem, which is pandemic and affects rich and poor countries alike.
* There is insufficient evidence to justify screening for NASH/advanced liver disease in the general population.
* The diagnosis should be sought in all patients who present with risk factors for NASH. Not all patients with risk factors will have NAFLD or NASH, and not all patients with NASH will have standard risk factors.
* Not every person with fatty liver needs aggressive therapy.
* Diet and exercise should be instituted for all patients.
* Liver biopsy should be reserved for those patients who have risk factors for NASH and/or other liver diseases.
* Patients with NASH or risk factors for NASH should first be treated with diet and exercise. Vitamin E or pentoxifylline may be added in these patients. Experimental therapy should be considered only in appropriate hands and only in patients who fail to achieve a 5% to 10% weight reduction over 6 months to 1 year of successful lifestyle changes.
* Bariatric surgery should be considered in patients in whom the above approaches fail, and it should be performed before the patient becomes cirrhotic.
* Liver transplantation is successful in patients who meet the criteria for liver failure; however, NASH may recur after transplantation and is likely to be denied to patients with morbid obesity.
* NAFLD and NASH are also becoming an increasingly serious problem in pediatric patients, including those under the age of 10.
* Ultimately, NAFLD and NASH are diagnoses of exclusion and require careful consideration of other diagnoses. Just as the clinician cannot diagnose NASH on the basis of clinical data alone, the pathologist can document the histologic lesions of steatohepatitis, but cannot reliably distinguish those of nonalcoholic origin from those of alcoholic origin.
Position statements and reviews:
Insufficient randomized, controlled, double blind studies are available to provide evidence-based data for a formal guideline, as discussed in the Introduction above. The following is a listing of selected position statements, reviews, and expert opinion articles.
1. Angulo P.Nonalcoholic fatty liver disease.N Engl J Med.2002;346:1221–1231.
2. Angulo P.Diagnosing steatohepatitis and predicting liver-related mortality in patients with NAFLD: two distinct concepts.Hepatology.2011;53:1792–1794.
3. Brunt EM.Nonalcoholic steatohepatitis.Semin Liver Dis.2004;24:3–20.
4. Chalasani N, Younossi Z, Lavine JE, 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;55:2005–2023.
5. Cheung O, Sanyal AJ.Recent advances in nonalcoholic fatty liver disease.Curr Opin Gastroenterol.2010;26:202–208.
6. Clark JM, Brancati FL, Diehl AM.Nonalcoholic fatty liver disease.Gastroenterology.2002;122:1649–1657.
7. Dowman JK, Tomlinson JW, Newsome PN.Systematic review: the diagnosis and staging of non-alcoholic steatohepatitis.Aliment Pharmacol Ther.2011;33:525–540.
8. Fabbrini E, Sullivan S, Klein S.Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications.Hepatology.2010;51:679–689.
9. Lancet. 2011 Aug 27–Sept 2;378(9793): virtually this entire issue addresses the global obesity pandemic, with articles on world epidemiology, cultural and political costs, pathogenesis, therapy, and proposed approaches to the problem. A virtual primer on global obesity. Articles are detailed in the next section, under Epidemiology.
10. Rafiq N, Younossi ZM.Nonalcoholic fatty liver disease: a practical approach to evaluation and management.Clin Liver Dis.2009;13:249–266.
11. Ratziu V, Bellentani S, Cortez-Pinto H, et al..A position statement on NAFLD/NASH based on the EASL 2009 special conference.J Hepatol.2010;53:372–384.
12. Sanyal AJ, Brunt EM, Kleiner DE, et al..Endpoints and clinical trial design for nonalcoholic steatohepatitis.Hepatology.2011;54:344–353.
13. Torres DM, Harrison SA.Diagnosis and therapy of nonalcoholic steatohepatitis.Gastroenterology.2008;134:1682–1698.
14. Vernon G, Baranova A, Younossi ZM.Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.Aliment Pharmacol Ther.2011;24:274–285.
15. Vuppalachi R, Chalasani N.Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: selected practical issues in their evaluation and management.Hepatology.2009;49:306–317.
For those wishing additional information and documentation of the basis for the recommendations given in this guideline, further references are available in the expanded online version of it, listed under the headings of epidemiology, pediatric epidemiology, histologic diagnosis, noninvasive diagnosis, hepatitis C and NAFLD/NASH, pathophysiology, and treatment.