Obesity-Associated Nonalcoholic Fatty Liver Disease Yusuf Yilmaz,
MD
a,b
, Zobair M. Younossi,
MD, MPH, AGAF
c,
*
KEYWORDS Obesity Nonalcoholic fatty liver disease Epidemiology Pathophysiology KEY POINTS Obesity is strongly associated with the prevalence of nonalcoholic fatty liver disease (NAFLD) in both adult and pediatric populations. NAFLD is not invariably associated with obesity; in particular, there is evidence suggesting that NAFLD associated with the carriage of the high-risk rs738409 C>G single-nucleotide polymorphism in PNPLA3 is characterized by an increase in liver fat but no insulin resistance or adipose tissue inflammation. Nutrition, physical activity, and behavioral modifications are a critical component of the treatment regimen for all obese patients with NAFLD. Bariatric surgeries that affect or restrict the flow or absorption of food through the gastrointestinal tract may improve liver histology in morbidly obese patients with nonalcoholic steatohepatitis (NASH), although randomized clinical trials and quasi-randomized clinical studies are lacking. Although primary prevention is the long-term goal for diminishing obesity, early detection of both NASH and hepatic fibrosis using noninvasive biochemical and imaging markers that may replace liver biopsy is the current challenge.
INTRODUCTION
In past decades, the prevalence of obesity and overweight has been largely on the rise and this condition is on the brink of replacing smoking as the leading cause of preventable death.1,2 Because of its association with an increased risk of suffering from multiple diseases, obesity takes enormous health and personal tolls on modern societies
Conflicts of Interest: The authors have nothing to disclose. a Department of Gastroenterology, School of Medicine, Marmara University, Fevzi Cakmak Mah, Mimar Sinan Cad. No. 41 Ust Kaynarca, Pendik, Istanbul 34899, Turkey; b Institute of Gastroenterology, Marmara University, Karaciger Arastirmalari Birimi, Basibuyuk, Maltepe, Istanbul 34840, Turkey; c Department of Medicine, Betty and Guy Beatty Center for Integrated Research, Center for Liver Diseases, Inova Health System, Inova Fairfax Hospital, Claude Moore Health Education and Research Building, 3rd Floor, 3300 Gallows Road, Falls Church, VA 22042, USA * Corresponding author. Betty and Guy Beatty Center for Integrated Research, Claude Moore Health Education and Research Building, 3rd Floor, 3300 Gallows Road, Falls Church, VA. E-mail address: [email protected] Clin Liver Dis 18 (2014) 19–31 http://dx.doi.org/10.1016/j.cld.2013.09.018 1089-3261/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
liver.theclinics.com
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(Box 1).3–17 In fact, recently, the American Medical Association classified obesity as a disease. The obesity pandemic is likely the result of dramatic changes in the health, financial, and cultural environment over the past century.18,19 Historically, in the years before the development of medical advancements that prevented debilitating diseases that caused their victims to become dreadfully feeble as they slowly died, being heavy was considered a sign of strength.20 Indeed, at times when food was scarce, having a rotund physique was regarded as a status symbol and an indicator of prosperity and good health. But as times changed, the detrimental effects that overweight and obesity had on health were discovered and the conditions became so prevalent that they are currently recognized as leading risk factors for morbidity and mortality worldwide.20 Although the fundamental cause of obesity is a positive imbalance between energy intake and energy expenditure, the etiology of obesity is multifactorial and involves a complex interaction among genetic, environmental, psychosocial, and behavioral factors.21,22 From a pathophysiological standpoint, the development of obesity is associated with adipose tissue remodeling,23 which leads to adipocyte dysfunction, abnormal cytokine secretion, and chronic low-grade inflammation.24 Obesity also contributes to fat deposition in nonadipose tissues as ectopic fat, and it is a major risk factor for nonalcoholic fatty liver disease (NAFLD).8 NAFLD is a clinicopathological condition characterized by lipid accumulation in the liver causing liver damage similar to alcohol, but occurring in individuals without a history of chronic alcohol consumption.25–30 NAFLD represents a wide spectrum of liver diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and fibrosis to irreversible cirrhosis. Simple steatosis is defined histologically as greater than 5% hepatic lipid accumulation that rarely progresses to advanced liver diseases, whereas NASH constitutes an inflammation and hepatocellular damage having a strong potential to progress into cirrhosis, end-stage liver failure, and hepatocellular
Box 1 Main obesity-associated diseases Disease Type 2 diabetes Malignancies Ischemic heart disease and heart failure Venous thrombosis Gastroesophageal reflux disease Nonalcoholic fatty liver disease Erectile dysfunction Stroke Hypertension Osteoarthritis Gout Gallbladder disease Obstructive sleep apnea Asthma Depression
Obesity and NAFLD
carcinoma (HCC).31,32 Although NAFLD is an independent risk for cardiovascular disease and mortality, only NASH is associated with advanced liver disease. Therefore, treatment strategies to address NAFLD will be important, primarily, from a cardiovascular disease standpoint. On the other hand, clinical trials focused on liver disease must focus on patients with established diagnosis of NASH. Concomitant with obesity, NAFLD is an increasingly recognized condition; up to 30% of adults in Western countries have NAFLD.33 Insulin resistance is the key pathogenic abnormality associated with obesity-associated NAFLD.34 A fatty liver is insulin resistant and overproduces glucose and very low density lipoprotein, and also other proinflammatory molecules, such as C-reactive protein and interleukin-6, which lead to hyperglycemia, hyperinsulinemia, and lipid disorders.34 Due to those metabolic consequences, NAFLD is closely linked to the metabolic syndrome and is considered its hepatic expression.25,35 However, not all obese persons deposit fat in the liver35 and liver fat content is recognized to be independent of age, sex, and body mass index.36 The deviation in liver fat accumulation between individuals is thought to explain, at least in part, why some obese and even lean individuals develop metabolic syndrome and insulin resistance, whereas others equally obese do not.37 Similarly, not all patients with NAFLD have a diagnosis of metabolic syndrome.38 Over the past several years, epidemiologic studies have informed the public health impact of obesity-associated NAFLD. The aim of the present review is to give an overview of the epidemiology and the possible mechanisms underlying the observed association between obesity and NAFLD.
PREVALENCE AND INCIDENCE OF OBESITY-ASSOCIATED NAFLD
The prevalence of obesity has increased dramatically worldwide (Fig. 1), and the rate of obesity has more than doubled since 1980.39 At least 1.46 billion adults were overweight or obese and 170 million of the world’s children were overweight or obese in 2008.40 In future prospects this number will only increase further.41 In Europe, obesity
Prevalence of NAFLD: 6-33% (Median 20%) Prevalence of NASH 3-5%
23.4% 4.7% to 38.5% 30-46%
12.9-28.9% 23.4% 2 23 4% 9 4 9.3% to 29% 15.8% 17.1%
Obese: 75% NAFLD and 19% NASH Morbidly Obese: 93% NAFLD and 26-49% NASH Diabetes: 49.5-87% NAFLD
Fig. 1. Worldwide prevalence of NAFLD.
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has increased 10% to 40% in the past 10 years, and 10% to 25% of men and 10% to 30% of women are obese depending on the European country.42 In the United States, 64% and 50% of the population are currently estimated to be overweight or obese, respectively.43 The trend of the obesity epidemics is not only true for adults, but has also trickled down to affect children of all ages.44 For children between the ages of 2 and 5, the prevalence of overweight and obesity increased from 5.0% to almost 14.0%, from 6.5% to almost 19.0% for children aged 6 to 11 years, and from 5.0% to 17.5% for adolescents between the ages of 12 and 19.45 Owing largely to the obesity epidemic, NAFLD is now the most common chronic liver condition worldwide. Based on the available data, NAFLD is estimated to occur in one-third of the general population in the United States.46 In adults, women are most frequently diagnosed with NAFLD,47 but this likely to represent a bias because men traditionally drink more alcohol than women and therefore may get excluded from a diagnosis based on alcohol intake. Concerning ethnicity, the lowest rates of NAFLD are seen in African American individuals and the highest in Asian and Hispanic individuals, with White in between.48,49 Differently from NAFLD that can be screened by ultrasound and liver enzymes, determining the true prevalence of NASH is complicated.28,29 Liver biopsy provides the only definitive diagnosis of NASH,32 but its invasiveness and cost complicate its use as a diagnostic tool in the general population.33 However, NASH seems to occur in approximately 3% of the lean population, 19% of the obese population, and the almost half of morbidly obese persons.50,51 Importantly, the increasing burden of obesity-associated NAFLD will be transposed in the future to an increased need for hepatic transplantation for NASH. In fact, currently, NASH ranks as the third most common indication for liver transplantation (2001: 1.2%; 2009: 9.7%).52 Another important future consequence of the epidemic of obesity-associated NAFLD will likely be a higher incidence of HCC. In a recent study conducted in 6 European countries, a total of 160 cases of HCC were detected during a 22-month follow-up; of note, 43% of the cases occurred in the absence of any other risk factor, such as alcohol abuse, cirrhosis, or infection with hepatitis B or C.53 Therefore, the high prevalence of obesity-associated NAFLD will lead to a higher incidence of HCC in the general population with a concomitant burden on treatment availability, including liver transplantation. Data on the incidence, predictive factors, and remission rates of NAFLD remain scanty. In particular, it is still difficult to draw firm conclusions regarding people from the general population who do not drink alcohol. A recent study conducted in a sample of the 147 patients who did not have NAFLD at baseline showed that 28 (19%) developed NAFLD at a 7-year follow-up.54 Baseline body mass index, homeostasis model assessment of insulin resistance (HOMA-IR) score, blood cholesterol, triglycerides, leptin levels, and weight gain were significantly higher and adiponectin was lower among those who developed NAFLD at 7-year follow-up, compared with those who remained NAFLD-free. However, only weight gain and baseline HOMA-IR were independent predictors for the development of NAFLD.54 Collectively, these longitudinal results suggest that obesity (and associated insulin resistance) is an important driving force behind the development of NAFLD. Conversely, one-third of patients with NAFLD showed improvement of their disease within the 7-year follow-up; such cases were chiefly dependent on modest weight reduction. Taken together, these data indicate that weight gain is an independent predictor of incident NAFLD in initially healthy subjects. Therefore, weight loss interventions represent the optimal (and probably the only effective) population-based strategy to reduce the future burden of NAFLD.
Obesity and NAFLD
WORLDWIDE DIFFERENCES IN OBESITY-ASSOCIATED NAFLD
Although obesity and NAFLD are major health concerns worldwide, there are significant geographic differences in the prevalence of these conditions. In the United States, obesity is particularly associated with a heavy reliance on high-fat, high-calorie meals (“junk food”), which is more common among people of low socioeconomic position.55 However, the opposite phenomenon can be found in developing countries, where it is the better-educated population that has the highest prevalence of obesity.56 In general, robust comparisons of obesity prevalence between countries are difficult because of different methodological approaches in data collection.57 The most important of these differences is probably that between measured and self-reported measures, with self-reported data more likely to underestimate the presence of obesity compared with actual measurements.58–60 The worldwide prevalence of obesity is monitored by the World Health Organization through the Global Database on body mass index.61,62 Although methodological caveats limit the reliability of comparisons between countries, Asia has the lowest and the Pacific Islands have the highest estimates of obesity prevalence.62 Overall, most countries have rising trends of obesity. However, decreasing trends in the prevalence of obesity have been noted in men from Denmark and Saudi Arabia, as well as among women living in Denmark, Ireland, Saudi Arabia, Finland, and Spain.62 In parallel with the obesity epidemics, NAFLD has become the most common form of liver disease in the United States and most countries worldwide. Importantly, estimates in the US general population suggest that approximately 6 million individuals have progressed to NASH and about 600,000 to NASH-related cirrhosis.63 NAFLD is also considered a major health issue in Japan, Australia, Europe, and the Middle East.64–68 Studies conducted in the United States have suggested the presence of racial and ethnic variations in NAFLD, which result in a nonuniform distribution, with the disorder being most common among Latino individuals and least prevalent among African American individuals.48,69–72 In general, Hispanic individuals have the highest prevalence of NAFLD, followed by non-Hispanic white individuals, whereas African American individuals have the lowest rates.73 Such differences do not seem to be entirely explained by variations in the prevalence of the stereotypical metabolic risk factors and the effect of HOMA-IR on the risk of NASH is modified by ethnicity.74 In particular, HOMA-IR does not seem to be a significant risk factor for NASH among Latinos, but it is significant among non-Latino whites.75 Therefore, ethnicity may act as an important modifier of the association between obesity and NAFLD. It is also possible that these ethnic variations may reflect differences in genetic susceptibility to visceral adiposity, including hepatic involvement.70 In general, the ongoing search for relevant genetic variants should result in a better understanding of energy metabolism and hopefully clarify the molecular mechanisms underlying the association between obesity and NAFLD. For example, Lallukka and colleagues75 recently showed that NAFLD associated with the carriage of the high-risk rs738409 C>G singlenucleotide polymorphism in PNPLA3 is characterized by an increase in liver fat but no insulin resistance or adipose tissue inflammation, whereas obesity-associated NAFLD has all 3 of these features. Moreover, the Genetics of Obesity-Related Liver Disease (GOLD) Consortium has shown that NAFLD is about 26% to 27% heritable with 5 single-nucleotide polymorphisms in the PNPLA3, NCAN, GCKR, LYPLAL1, and PPP1R3B genes found to be associated with hepatic steatosis as measured using computed tomography in individuals of European ancestry.76 In the future, it will be necessary to understand how specific combinations of environmental and genetic factors can give rise to ethnic differences in obesity-associated NAFLD. In this context,
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eliminating ethnic disparities in health should be an international priority, and obesity and NAFLD are prime targets. CLINICAL CORRELATIONS
As discussed previously, NAFLD is a complex phenotype that arises from numerous genetic, environmental, behavioral, and even social origins.34,63 The lifestyle factors contributing to the rising epidemic of obesity, and hence obesity-related NAFLD, are embedded in changes in society worldwide, mainly increased sedentary or inactive lifestyles77 and consumption of calorie-rich foods in the form of soft drinks,78 fast foods,79 and sugar-enriched products.80 Importantly, the clustering of unhealthy behaviors in obese children, such as poor nutritional habits, low levels of physical activity, and “junk-food” consumption dictate the need for multifaceted global programs to tackle global NAFLD risk at an early stage.81,82 However, further research is needed to identify culturally sensitive strategies for obesity prevention and their impact not only on body weight, but also on NAFLD morbidity and mortality. The importance of lifestyle management in the treatment of patients with obesityrelated NAFLD cannot be overemphasized.82 Adoption of a healthy lifestyle facilitates weight loss and decreases insulin resistance, and produces independent beneficial effects on the liver.83–86 It is noteworthy that obesity-related metabolic abnormalities and fatty infiltration of the liver may be present even at a young age, and progress asymptomatically for decades before clinical manifestations set in.87,88 In this scenario, nutrition, physical activity, and behavioral modifications aimed at weight loss are a critical component of the treatment regimen for all obese patients with NAFLD, even at a young age. Besides exercise and dieting, many therapeutic targets have been recently identified, on both the intake and the expenditure side of the energy balance equation, thereby providing hope that new agents may become available in the future.89 For obese patients with NAFLD who do not respond to a trial of diet, exercise, and behavioral therapy, pharmacotherapy can be tried.90 The use of drugs should be individualized, taking into account the severity of liver disease, comorbidities, and practical considerations related to cost, side effects, and frequency of dosing. Randomized trials and carefully constructed observational studies are needed to optimize effectiveness of nonsurgical weight loss interventions in obese patients and determine if the small weight losses they produce can have an impact on NAFLD incidence and clinical course. Moreover, intensive counseling and behavioral treatments need to be implemented to support long-term weight loss maintenance. Among weight loss interventions, bariatric surgery results in the most dramatic weight loss, and, thus, studies of obese patients are the most likely to show reduced risk of NAFLD. Restrictive surgical procedures are indeed capable of inducing earlier satiety by decreasing the volume of the stomach (laparoscopic-adjustable gastric banding) or restricting the stomach and bypassing the small bowel (Roux-en-Y gastric bypass). Bariatric surgeries that affect or restrict the flow of food through the gastrointestinal tract have been shown to be an important therapeutic option that may result in a histologic improvement of NASH in morbidly obese patients (body mass index 35 kg/m2).91 Although long-term weight loss and resolution of obesity-associated NAFLD have been reported in most patients,92 the lack of randomized clinical trials and quasi-randomized clinical studies still does not allow assessment of the benefits and harms of bariatric surgery as a therapeutic approach for patients with NASH.93 Taken together, these data indicate that preventing and managing obesity-related NAFLD requires multiple, parallel efforts.
Obesity and NAFLD
Table 1 Example of therapeutic interventions for NASH Therapy
Histologic Improvement
Liver Enzymes
Impact on Use Hepatic Fibrosis Recommended
Metformin
Not consistently Not consistently improved
Unknown
Not recommended
Rosiglitazone
Not consistently Improvement noted
Unknown
Not recommended
Pioglitazone
Not consistently Not consistently
No
Considered to treat diabetes but not solely for NASH
Vitamin E
Improvement
Improvement
No
Recommended for nondiabetic individuals with biopsy-proven NASH
Statins
Unknown
Unknown
Unknown
Not recommended for treatment of NASH but can be used to treat hyperlipidemia in patients with NAFLD
Orlistat
No
Possible Unknown improvement with weight loss
Not recommended solely for NASH
Not consistently
Not recommended
Ursodeoxycholic No acid improvement
No
In addition to weight reduction strategies to address obesity-related NAFLD, there have been a number of medical therapies designed to treat histologic NASH. These include antioxidants, such as vitamin E, insulin sensitizers, such as pioglitazone and metformin, lipid-lowering agents, such as statins, and cytoprotective agents, such as ursodeoxycholic acid (Table 1).94,95 Despite decades of clinical trials, current evidence suggests that only vitamin E may be beneficial for treatment of nondiabetic patients with NASH, but no single treatment can be recommended to all patients with NASH.94,95 SUMMARY
The main conclusions from this review are the following: (1) obesity is strongly associated with the prevalence of NAFLD in both adult and pediatric populations95,96; (2) obesity is an independent predictor of incident NAFLD in initially healthy subjects; (3) NAFLD is not invariably associated with obesity, in particular there is evidence suggesting that NAFLD associated with high-risk rs738409 C>G single-nucleotide polymorphism in PNPLA3 is characterized by an increase in liver fat but no insulin resistance or adipose tissue inflammation; (4) there are significant ethnic variations in the prevalence of obesity-related NAFLD, which may be explained by both environmental and genetic factors; (5) nutrition, physical activity, and behavior modifications aimed at weight loss are a critical component of the treatment regimen for all obese patients with NAFLD; (6) bariatric surgeries that affect or restrict the flow of food
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through the gastrointestinal tract may improve liver histology in morbidly obese patients with NASH, although randomized clinical trials and quasi-randomized clinical studies are lacking; (7) because only patients with histologically proven NASH are shown to have progressive liver disease, clinical trials must focus on this subtype of NAFLD; and (8) although vitamin E is recommended for nondiabetic individuals with NASH, no single treatment could be recommended to all patients with NASH. In general, obesity-associated NAFLD should be considered an important and often underrecognized public health problem. As the prevalence of obesity increases, the prevalence of NAFLD with its associated morbidity and mortality will increase as well. Although primary prevention is the long-term goal for diminishing the prevalence of obesity, early detection of both NASH and hepatic fibrosis using noninvasive biochemical and imaging markers that may replace liver biopsy is the overriding current challenge.97–102 From a clinical standpoint, treating NAFLD in the obese requires addressing obesity as part of the therapeutic plan. Lifestyle management is required in every case, with a focus on weight loss and risk reduction. In most patients, additional therapies, including medications, aggressive diet counseling, behavioral techniques, and sometimes bariatric surgery in morbidly obese subjects, will be required. Data showing improved liver histology among individuals who lose weight and maintain the loss strengthen confidence in the obesity-NAFLD link, and also provide a note of hope that weight loss in obese individuals may help them prevent end-stage liver disease. Research on the biologic mechanisms underlying the obesity-NAFLD link is still in early stages, but may lead to potential treatments and preventive agents. REFERENCES
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36. Jakobsen MU, Berentzen T, Sørensen TI, et al. Abdominal obesity and fatty liver. Epidemiol Rev 2007;29:77–87. 37. Kotronen A, Yki-Ja¨rvinen H. Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol 2008;28:27–38. 38. Yilmaz Y. NAFLD in the absence of metabolic syndrome: different epidemiology, pathogenetic mechanisms, risk factors for disease progression? Semin Liver Dis 2012;32:14–21. 39. Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in obesity among US adults, 1999–2008. JAMA 2010;303:235–41. 40. Swinburn BA, Sacks G, Hall KD, et al. The global obesity pandemic: shaped by global drivers and local environments. Lancet 2011;378:804–14. 41. Shamseddeen H, Getty JZ, Hamdallah IN, et al. Epidemiology and economic impact of obesity and type 2 diabetes. Surg Clin North Am 2011;91: 1163–72. 42. Tsigos C, Hainer V, Basdevant A, et al. Management of obesity in adults: European clinical practice guidelines. Obes Facts 2008;1:106–16. 43. Ogden CL, Carroll MD. Prevalence of overweight, obesity, and extreme obesity among adults: United States, trends 1960–1962 through 2007–2008. Hyattsville, MD: National Center for Health Statistics; 2010. 44. Skelton JA, Irby MB, Grzywacz JG, et al. Etiologies of obesity in children: nature and nurture. Pediatr Clin North Am 2011;58:1333–54. 45. Ben-Sefer E, Ben-Natan M, Ehrenfeld M. Childhood obesity: current literature, policy and implications for practice. Int Nurs Rev 2009;56:166–73. 46. Sanyal AJ. NASH: a global health problem. Hepatol Res 2011;41:670–4. 47. Sheth SG, Gordan FD, Chopra S. Nonalcoholic steatohepatitis. Ann Intern Med 1997;126:137–45. 48. Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40:1387–95. 49. Petersen KF, Dufour S, Feng J, et al. Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men. Proc Natl Acad Sci U S A 2006;103:18273–7. 50. Silverman JF, O’Brien KF, Long S, et al. Liver pathology in morbidly obese patients with and without diabetes. Am J Gastroenterol 1990;85:1349–55. 51. Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 1990;12:1106–10. 52. Charlton MR, Burns JM, Pedersen RA, et al. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 2011;141:1249–53. 53. Reeves H, Villa E, Bellentani S, et al. The emerging impact of hepatocellular carcinoma arising on a background of NAFLD. J Hepatol 2012;56(Suppl 2):S3. 54. Zelber-Sagi S, Lotan R, Shlomai A, et al. Predictors for incidence and remission of NAFLD in the general population during a seven-year prospective follow-up. J Hepatol 2012;56:1145–51. 55. Jeffery RW, French SA. Epidemic obesity in the United States: are fast foods and television viewing contributing? Am J Public Health 1998;88:277–80. 56. Drewnowski A, Specter SE. Poverty and obesity: the role of energy density and energy costs. Am J Clin Nutr 2004;79:6–16. 57. Ford ES, Mokdad AH, Giles WH, et al. Geographic variation in the prevalence of obesity, diabetes, and obesity-related behaviors. Obes Res 2005;13: 118–22.
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58. Shields M, Connor Gorber S, Janssen I, et al. Bias in self-reported estimates of obesity in Canadian health surveys: an update on correction equations for adults. Health Rep 2011;22:35–45. 59. Dauphinot V, Wolff H, Naudin F, et al. New obesity body mass index threshold for self-reported data. J Epidemiol Community Health 2009;63:128–32. 60. Bolton-Smith C, Woodward M, Tunstall-Pedoe H, et al. Accuracy of the estimated prevalence of obesity from self reported height and weight in an adult Scottish population. J Epidemiol Community Health 2000;54:143–8. 61. Nguyen DM, El-Serag HB. The epidemiology of obesity. Gastroenterol Clin North Am 2010;39:1–7. 62. Nishida C, Mucavele P. Monitoring the rapidly emerging public health problem of overweight and obesity: the WHO global database on body mass index. SCN News 2005;29:5–12. 63. Erickson SK. Nonalcoholic fatty liver disease. J Lipid Res 2009;50(Suppl): S412–6. 64. Bacon BR, Farahvash MJ, Janney CG, et al. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994;107:1103–9. 65. Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999;116: 1413–9. 66. Powell EE, Cooksley WG, Hanson R, et al. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990;11:74–80. 67. Nonomura A, Mizukami Y, Unoura M, et al. Clinicopathologic study of alcohollike liver disease in non-alcoholics; non-alcoholic steatohepatitis and fibrosis. Gastroenterol Jpn 1992;27:521–8. 68. el Hassan AY, Ibrahim EM, al Mulhim FA, et al. Fatty infiltration of the liver: analysis of prevalence, radiological and clinical features and influence on patient management. Br J Radiol 1992;65:774–8. 69. Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003;98: 960–7. 70. Weston SR, Leyden W, Murphy R, et al. Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. Hepatology 2005;41:372–9. 71. Caldwell SH, Harris DM, Patrie JT, et al. Is NASH underdiagnosed among African Americans? Am J Gastroenterol 2002;97:1496–500. 72. Mohanty SR, Troy TN, Huo D, et al. Influence of ethnicity on histological differences in non-alcoholic fatty liver disease. J Hepatol 2009;50:797–804. 73. Attar BM, Van Thiel DH. Current concepts and management approaches in nonalcoholic fatty liver disease. ScientificWorldJournal 2013;2013:481893. 74. Bambha K, Belt P, Abraham M, et al. Ethnicity and nonalcoholic fatty liver disease. Hepatology 2012;55:769–80. 75. Lallukka S, Sevastianova K, Perttila¨ J, et al. Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3. Diabetologia 2013;56:886–92. 76. Speliotes EK, Yerges-Armstrong LM, Wu J, et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 2011;7:e1001324. 77. Rector RS, Thyfault JP. Does physical inactivity cause nonalcoholic fatty liver disease? J Appl Physiol 2011;111:1828–35.
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78. Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R, et al. Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population based study. J Hepatol 2007;47:711–7. 79. Zelber-Sagi S, Ratziu V, Oren R. Nutrition and physical activity in NAFLD: an overview of the epidemiological evidence. World J Gastroenterol 2011;17: 3377–89. 80. Yilmaz Y. Review article: fructose in non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2012;35:1135–44. 81. Caporaso N, Morisco F, Camera S, et al. Dietary approach in the prevention and treatment of NAFLD. Front Biosci 2012;17:2259–68. 82. Centis E, Marzocchi R, Suppini A, et al. The role of lifestyle change in the prevention and treatment of NAFLD. Curr Pharm Des 2013;19(29):5270–9. 83. Rodriguez B, Torres DM, Harrison SA. Physical activity: an essential component of lifestyle modification in NAFLD. Nat Rev Gastroenterol Hepatol 2012;9: 726–31. 84. Thoma C, Day CP, Trenell MI. Lifestyle interventions for the treatment of nonalcoholic fatty liver disease in adults: a systematic review. J Hepatol 2012;56: 255–66. 85. Patel AA, Torres DM, Harrison SA. Effect of weight loss on nonalcoholic fatty liver disease. J Clin Gastroenterol 2009;43:970–4. 86. Harrison SA, Day CP. Benefits of lifestyle modification in NAFLD. Gut 2007;56: 1760–9. 87. Pacifico L, Anania C, Martino F, et al. Management of metabolic syndrome in children and adolescents. Nutr Metab Cardiovasc Dis 2011;21:455–66. 88. Nobili V, Svegliati-Baroni G, Alisi A, et al. A 360-degree overview of paediatric NAFLD: recent insights. J Hepatol 2013;58:1218–29. 89. Malinowski SS, Byrd JS, Bell AM, et al. Pharmacologic therapy for nonalcoholic fatty liver disease in adults. Pharmacotherapy 2013;33:223–42. 90. Nakajima K. Multidisciplinary pharmacotherapeutic options for nonalcoholic fatty liver disease. Int J Hepatol 2012;2012:950693. 91. Rabl C, Campos GM. The impact of bariatric surgery on nonalcoholic steatohepatitis. Semin Liver Dis 2012;32:80–91. 92. Pillai AA, Rinella ME. Non-alcoholic fatty liver disease: is bariatric surgery the answer? Clin Liver Dis 2009;13:689–710. 93. Chavez-Tapia NC, Tellez-Avila FI, Barrientos-Gutierrez T, et al. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database Syst Rev 2010;(1):CD007340. 94. Sanyal AJ, Chalasani N, Kowdley KV, et al, NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362(18): 1675–85. 95. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012;143(2): 503. 96. Younossi ZM, Stepanova M, Afendy M, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 2011;9(6):524–30. 97. Yilmaz Y, Ulukaya E. Toward a biochemical diagnosis of NASH: insights from pathophysiology for distinguishing simple steatosis from steatohepatitis. Curr Med Chem 2011;18:725–32.
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98. Wieckowska A, Feldstein AE. Diagnosis of nonalcoholic fatty liver disease: invasive versus noninvasive. Semin Liver Dis 2008;28:386–95. 99. Wieckowska A, McCullough AJ, Feldstein AE. Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future. Hepatology 2007;46: 582–9. 100. Miele L, Forgione A, Gasbarrini G, et al. Noninvasive assessment of fibrosis in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Transl Res 2007;149:114–25. 101. Younossi ZM, Page S, Rafiq N, et al. A biomarker panel for non-alcoholic steatohepatitis (NASH) and NASH-related fibrosis. Obes Surg 2011;21:431–9. 102. Younossi ZM, Jarrar M, Nugent C, et al. A novel diagnostic biomarker panel for obesity-related nonalcoholic steatohepatitis (NASH). Obes Surg 2008;18: 1430–7.
31
MD
a,b
, Zobair M. Younossi,
MD, MPH, AGAF
c,
*
KEYWORDS Obesity Nonalcoholic fatty liver disease Epidemiology Pathophysiology KEY POINTS Obesity is strongly associated with the prevalence of nonalcoholic fatty liver disease (NAFLD) in both adult and pediatric populations. NAFLD is not invariably associated with obesity; in particular, there is evidence suggesting that NAFLD associated with the carriage of the high-risk rs738409 C>G single-nucleotide polymorphism in PNPLA3 is characterized by an increase in liver fat but no insulin resistance or adipose tissue inflammation. Nutrition, physical activity, and behavioral modifications are a critical component of the treatment regimen for all obese patients with NAFLD. Bariatric surgeries that affect or restrict the flow or absorption of food through the gastrointestinal tract may improve liver histology in morbidly obese patients with nonalcoholic steatohepatitis (NASH), although randomized clinical trials and quasi-randomized clinical studies are lacking. Although primary prevention is the long-term goal for diminishing obesity, early detection of both NASH and hepatic fibrosis using noninvasive biochemical and imaging markers that may replace liver biopsy is the current challenge.
INTRODUCTION
In past decades, the prevalence of obesity and overweight has been largely on the rise and this condition is on the brink of replacing smoking as the leading cause of preventable death.1,2 Because of its association with an increased risk of suffering from multiple diseases, obesity takes enormous health and personal tolls on modern societies
Conflicts of Interest: The authors have nothing to disclose. a Department of Gastroenterology, School of Medicine, Marmara University, Fevzi Cakmak Mah, Mimar Sinan Cad. No. 41 Ust Kaynarca, Pendik, Istanbul 34899, Turkey; b Institute of Gastroenterology, Marmara University, Karaciger Arastirmalari Birimi, Basibuyuk, Maltepe, Istanbul 34840, Turkey; c Department of Medicine, Betty and Guy Beatty Center for Integrated Research, Center for Liver Diseases, Inova Health System, Inova Fairfax Hospital, Claude Moore Health Education and Research Building, 3rd Floor, 3300 Gallows Road, Falls Church, VA 22042, USA * Corresponding author. Betty and Guy Beatty Center for Integrated Research, Claude Moore Health Education and Research Building, 3rd Floor, 3300 Gallows Road, Falls Church, VA. E-mail address: [email protected] Clin Liver Dis 18 (2014) 19–31 http://dx.doi.org/10.1016/j.cld.2013.09.018 1089-3261/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
liver.theclinics.com
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(Box 1).3–17 In fact, recently, the American Medical Association classified obesity as a disease. The obesity pandemic is likely the result of dramatic changes in the health, financial, and cultural environment over the past century.18,19 Historically, in the years before the development of medical advancements that prevented debilitating diseases that caused their victims to become dreadfully feeble as they slowly died, being heavy was considered a sign of strength.20 Indeed, at times when food was scarce, having a rotund physique was regarded as a status symbol and an indicator of prosperity and good health. But as times changed, the detrimental effects that overweight and obesity had on health were discovered and the conditions became so prevalent that they are currently recognized as leading risk factors for morbidity and mortality worldwide.20 Although the fundamental cause of obesity is a positive imbalance between energy intake and energy expenditure, the etiology of obesity is multifactorial and involves a complex interaction among genetic, environmental, psychosocial, and behavioral factors.21,22 From a pathophysiological standpoint, the development of obesity is associated with adipose tissue remodeling,23 which leads to adipocyte dysfunction, abnormal cytokine secretion, and chronic low-grade inflammation.24 Obesity also contributes to fat deposition in nonadipose tissues as ectopic fat, and it is a major risk factor for nonalcoholic fatty liver disease (NAFLD).8 NAFLD is a clinicopathological condition characterized by lipid accumulation in the liver causing liver damage similar to alcohol, but occurring in individuals without a history of chronic alcohol consumption.25–30 NAFLD represents a wide spectrum of liver diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and fibrosis to irreversible cirrhosis. Simple steatosis is defined histologically as greater than 5% hepatic lipid accumulation that rarely progresses to advanced liver diseases, whereas NASH constitutes an inflammation and hepatocellular damage having a strong potential to progress into cirrhosis, end-stage liver failure, and hepatocellular
Box 1 Main obesity-associated diseases Disease Type 2 diabetes Malignancies Ischemic heart disease and heart failure Venous thrombosis Gastroesophageal reflux disease Nonalcoholic fatty liver disease Erectile dysfunction Stroke Hypertension Osteoarthritis Gout Gallbladder disease Obstructive sleep apnea Asthma Depression
Obesity and NAFLD
carcinoma (HCC).31,32 Although NAFLD is an independent risk for cardiovascular disease and mortality, only NASH is associated with advanced liver disease. Therefore, treatment strategies to address NAFLD will be important, primarily, from a cardiovascular disease standpoint. On the other hand, clinical trials focused on liver disease must focus on patients with established diagnosis of NASH. Concomitant with obesity, NAFLD is an increasingly recognized condition; up to 30% of adults in Western countries have NAFLD.33 Insulin resistance is the key pathogenic abnormality associated with obesity-associated NAFLD.34 A fatty liver is insulin resistant and overproduces glucose and very low density lipoprotein, and also other proinflammatory molecules, such as C-reactive protein and interleukin-6, which lead to hyperglycemia, hyperinsulinemia, and lipid disorders.34 Due to those metabolic consequences, NAFLD is closely linked to the metabolic syndrome and is considered its hepatic expression.25,35 However, not all obese persons deposit fat in the liver35 and liver fat content is recognized to be independent of age, sex, and body mass index.36 The deviation in liver fat accumulation between individuals is thought to explain, at least in part, why some obese and even lean individuals develop metabolic syndrome and insulin resistance, whereas others equally obese do not.37 Similarly, not all patients with NAFLD have a diagnosis of metabolic syndrome.38 Over the past several years, epidemiologic studies have informed the public health impact of obesity-associated NAFLD. The aim of the present review is to give an overview of the epidemiology and the possible mechanisms underlying the observed association between obesity and NAFLD.
PREVALENCE AND INCIDENCE OF OBESITY-ASSOCIATED NAFLD
The prevalence of obesity has increased dramatically worldwide (Fig. 1), and the rate of obesity has more than doubled since 1980.39 At least 1.46 billion adults were overweight or obese and 170 million of the world’s children were overweight or obese in 2008.40 In future prospects this number will only increase further.41 In Europe, obesity
Prevalence of NAFLD: 6-33% (Median 20%) Prevalence of NASH 3-5%
23.4% 4.7% to 38.5% 30-46%
12.9-28.9% 23.4% 2 23 4% 9 4 9.3% to 29% 15.8% 17.1%
Obese: 75% NAFLD and 19% NASH Morbidly Obese: 93% NAFLD and 26-49% NASH Diabetes: 49.5-87% NAFLD
Fig. 1. Worldwide prevalence of NAFLD.
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has increased 10% to 40% in the past 10 years, and 10% to 25% of men and 10% to 30% of women are obese depending on the European country.42 In the United States, 64% and 50% of the population are currently estimated to be overweight or obese, respectively.43 The trend of the obesity epidemics is not only true for adults, but has also trickled down to affect children of all ages.44 For children between the ages of 2 and 5, the prevalence of overweight and obesity increased from 5.0% to almost 14.0%, from 6.5% to almost 19.0% for children aged 6 to 11 years, and from 5.0% to 17.5% for adolescents between the ages of 12 and 19.45 Owing largely to the obesity epidemic, NAFLD is now the most common chronic liver condition worldwide. Based on the available data, NAFLD is estimated to occur in one-third of the general population in the United States.46 In adults, women are most frequently diagnosed with NAFLD,47 but this likely to represent a bias because men traditionally drink more alcohol than women and therefore may get excluded from a diagnosis based on alcohol intake. Concerning ethnicity, the lowest rates of NAFLD are seen in African American individuals and the highest in Asian and Hispanic individuals, with White in between.48,49 Differently from NAFLD that can be screened by ultrasound and liver enzymes, determining the true prevalence of NASH is complicated.28,29 Liver biopsy provides the only definitive diagnosis of NASH,32 but its invasiveness and cost complicate its use as a diagnostic tool in the general population.33 However, NASH seems to occur in approximately 3% of the lean population, 19% of the obese population, and the almost half of morbidly obese persons.50,51 Importantly, the increasing burden of obesity-associated NAFLD will be transposed in the future to an increased need for hepatic transplantation for NASH. In fact, currently, NASH ranks as the third most common indication for liver transplantation (2001: 1.2%; 2009: 9.7%).52 Another important future consequence of the epidemic of obesity-associated NAFLD will likely be a higher incidence of HCC. In a recent study conducted in 6 European countries, a total of 160 cases of HCC were detected during a 22-month follow-up; of note, 43% of the cases occurred in the absence of any other risk factor, such as alcohol abuse, cirrhosis, or infection with hepatitis B or C.53 Therefore, the high prevalence of obesity-associated NAFLD will lead to a higher incidence of HCC in the general population with a concomitant burden on treatment availability, including liver transplantation. Data on the incidence, predictive factors, and remission rates of NAFLD remain scanty. In particular, it is still difficult to draw firm conclusions regarding people from the general population who do not drink alcohol. A recent study conducted in a sample of the 147 patients who did not have NAFLD at baseline showed that 28 (19%) developed NAFLD at a 7-year follow-up.54 Baseline body mass index, homeostasis model assessment of insulin resistance (HOMA-IR) score, blood cholesterol, triglycerides, leptin levels, and weight gain were significantly higher and adiponectin was lower among those who developed NAFLD at 7-year follow-up, compared with those who remained NAFLD-free. However, only weight gain and baseline HOMA-IR were independent predictors for the development of NAFLD.54 Collectively, these longitudinal results suggest that obesity (and associated insulin resistance) is an important driving force behind the development of NAFLD. Conversely, one-third of patients with NAFLD showed improvement of their disease within the 7-year follow-up; such cases were chiefly dependent on modest weight reduction. Taken together, these data indicate that weight gain is an independent predictor of incident NAFLD in initially healthy subjects. Therefore, weight loss interventions represent the optimal (and probably the only effective) population-based strategy to reduce the future burden of NAFLD.
Obesity and NAFLD
WORLDWIDE DIFFERENCES IN OBESITY-ASSOCIATED NAFLD
Although obesity and NAFLD are major health concerns worldwide, there are significant geographic differences in the prevalence of these conditions. In the United States, obesity is particularly associated with a heavy reliance on high-fat, high-calorie meals (“junk food”), which is more common among people of low socioeconomic position.55 However, the opposite phenomenon can be found in developing countries, where it is the better-educated population that has the highest prevalence of obesity.56 In general, robust comparisons of obesity prevalence between countries are difficult because of different methodological approaches in data collection.57 The most important of these differences is probably that between measured and self-reported measures, with self-reported data more likely to underestimate the presence of obesity compared with actual measurements.58–60 The worldwide prevalence of obesity is monitored by the World Health Organization through the Global Database on body mass index.61,62 Although methodological caveats limit the reliability of comparisons between countries, Asia has the lowest and the Pacific Islands have the highest estimates of obesity prevalence.62 Overall, most countries have rising trends of obesity. However, decreasing trends in the prevalence of obesity have been noted in men from Denmark and Saudi Arabia, as well as among women living in Denmark, Ireland, Saudi Arabia, Finland, and Spain.62 In parallel with the obesity epidemics, NAFLD has become the most common form of liver disease in the United States and most countries worldwide. Importantly, estimates in the US general population suggest that approximately 6 million individuals have progressed to NASH and about 600,000 to NASH-related cirrhosis.63 NAFLD is also considered a major health issue in Japan, Australia, Europe, and the Middle East.64–68 Studies conducted in the United States have suggested the presence of racial and ethnic variations in NAFLD, which result in a nonuniform distribution, with the disorder being most common among Latino individuals and least prevalent among African American individuals.48,69–72 In general, Hispanic individuals have the highest prevalence of NAFLD, followed by non-Hispanic white individuals, whereas African American individuals have the lowest rates.73 Such differences do not seem to be entirely explained by variations in the prevalence of the stereotypical metabolic risk factors and the effect of HOMA-IR on the risk of NASH is modified by ethnicity.74 In particular, HOMA-IR does not seem to be a significant risk factor for NASH among Latinos, but it is significant among non-Latino whites.75 Therefore, ethnicity may act as an important modifier of the association between obesity and NAFLD. It is also possible that these ethnic variations may reflect differences in genetic susceptibility to visceral adiposity, including hepatic involvement.70 In general, the ongoing search for relevant genetic variants should result in a better understanding of energy metabolism and hopefully clarify the molecular mechanisms underlying the association between obesity and NAFLD. For example, Lallukka and colleagues75 recently showed that NAFLD associated with the carriage of the high-risk rs738409 C>G singlenucleotide polymorphism in PNPLA3 is characterized by an increase in liver fat but no insulin resistance or adipose tissue inflammation, whereas obesity-associated NAFLD has all 3 of these features. Moreover, the Genetics of Obesity-Related Liver Disease (GOLD) Consortium has shown that NAFLD is about 26% to 27% heritable with 5 single-nucleotide polymorphisms in the PNPLA3, NCAN, GCKR, LYPLAL1, and PPP1R3B genes found to be associated with hepatic steatosis as measured using computed tomography in individuals of European ancestry.76 In the future, it will be necessary to understand how specific combinations of environmental and genetic factors can give rise to ethnic differences in obesity-associated NAFLD. In this context,
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eliminating ethnic disparities in health should be an international priority, and obesity and NAFLD are prime targets. CLINICAL CORRELATIONS
As discussed previously, NAFLD is a complex phenotype that arises from numerous genetic, environmental, behavioral, and even social origins.34,63 The lifestyle factors contributing to the rising epidemic of obesity, and hence obesity-related NAFLD, are embedded in changes in society worldwide, mainly increased sedentary or inactive lifestyles77 and consumption of calorie-rich foods in the form of soft drinks,78 fast foods,79 and sugar-enriched products.80 Importantly, the clustering of unhealthy behaviors in obese children, such as poor nutritional habits, low levels of physical activity, and “junk-food” consumption dictate the need for multifaceted global programs to tackle global NAFLD risk at an early stage.81,82 However, further research is needed to identify culturally sensitive strategies for obesity prevention and their impact not only on body weight, but also on NAFLD morbidity and mortality. The importance of lifestyle management in the treatment of patients with obesityrelated NAFLD cannot be overemphasized.82 Adoption of a healthy lifestyle facilitates weight loss and decreases insulin resistance, and produces independent beneficial effects on the liver.83–86 It is noteworthy that obesity-related metabolic abnormalities and fatty infiltration of the liver may be present even at a young age, and progress asymptomatically for decades before clinical manifestations set in.87,88 In this scenario, nutrition, physical activity, and behavioral modifications aimed at weight loss are a critical component of the treatment regimen for all obese patients with NAFLD, even at a young age. Besides exercise and dieting, many therapeutic targets have been recently identified, on both the intake and the expenditure side of the energy balance equation, thereby providing hope that new agents may become available in the future.89 For obese patients with NAFLD who do not respond to a trial of diet, exercise, and behavioral therapy, pharmacotherapy can be tried.90 The use of drugs should be individualized, taking into account the severity of liver disease, comorbidities, and practical considerations related to cost, side effects, and frequency of dosing. Randomized trials and carefully constructed observational studies are needed to optimize effectiveness of nonsurgical weight loss interventions in obese patients and determine if the small weight losses they produce can have an impact on NAFLD incidence and clinical course. Moreover, intensive counseling and behavioral treatments need to be implemented to support long-term weight loss maintenance. Among weight loss interventions, bariatric surgery results in the most dramatic weight loss, and, thus, studies of obese patients are the most likely to show reduced risk of NAFLD. Restrictive surgical procedures are indeed capable of inducing earlier satiety by decreasing the volume of the stomach (laparoscopic-adjustable gastric banding) or restricting the stomach and bypassing the small bowel (Roux-en-Y gastric bypass). Bariatric surgeries that affect or restrict the flow of food through the gastrointestinal tract have been shown to be an important therapeutic option that may result in a histologic improvement of NASH in morbidly obese patients (body mass index 35 kg/m2).91 Although long-term weight loss and resolution of obesity-associated NAFLD have been reported in most patients,92 the lack of randomized clinical trials and quasi-randomized clinical studies still does not allow assessment of the benefits and harms of bariatric surgery as a therapeutic approach for patients with NASH.93 Taken together, these data indicate that preventing and managing obesity-related NAFLD requires multiple, parallel efforts.
Obesity and NAFLD
Table 1 Example of therapeutic interventions for NASH Therapy
Histologic Improvement
Liver Enzymes
Impact on Use Hepatic Fibrosis Recommended
Metformin
Not consistently Not consistently improved
Unknown
Not recommended
Rosiglitazone
Not consistently Improvement noted
Unknown
Not recommended
Pioglitazone
Not consistently Not consistently
No
Considered to treat diabetes but not solely for NASH
Vitamin E
Improvement
Improvement
No
Recommended for nondiabetic individuals with biopsy-proven NASH
Statins
Unknown
Unknown
Unknown
Not recommended for treatment of NASH but can be used to treat hyperlipidemia in patients with NAFLD
Orlistat
No
Possible Unknown improvement with weight loss
Not recommended solely for NASH
Not consistently
Not recommended
Ursodeoxycholic No acid improvement
No
In addition to weight reduction strategies to address obesity-related NAFLD, there have been a number of medical therapies designed to treat histologic NASH. These include antioxidants, such as vitamin E, insulin sensitizers, such as pioglitazone and metformin, lipid-lowering agents, such as statins, and cytoprotective agents, such as ursodeoxycholic acid (Table 1).94,95 Despite decades of clinical trials, current evidence suggests that only vitamin E may be beneficial for treatment of nondiabetic patients with NASH, but no single treatment can be recommended to all patients with NASH.94,95 SUMMARY
The main conclusions from this review are the following: (1) obesity is strongly associated with the prevalence of NAFLD in both adult and pediatric populations95,96; (2) obesity is an independent predictor of incident NAFLD in initially healthy subjects; (3) NAFLD is not invariably associated with obesity, in particular there is evidence suggesting that NAFLD associated with high-risk rs738409 C>G single-nucleotide polymorphism in PNPLA3 is characterized by an increase in liver fat but no insulin resistance or adipose tissue inflammation; (4) there are significant ethnic variations in the prevalence of obesity-related NAFLD, which may be explained by both environmental and genetic factors; (5) nutrition, physical activity, and behavior modifications aimed at weight loss are a critical component of the treatment regimen for all obese patients with NAFLD; (6) bariatric surgeries that affect or restrict the flow of food
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through the gastrointestinal tract may improve liver histology in morbidly obese patients with NASH, although randomized clinical trials and quasi-randomized clinical studies are lacking; (7) because only patients with histologically proven NASH are shown to have progressive liver disease, clinical trials must focus on this subtype of NAFLD; and (8) although vitamin E is recommended for nondiabetic individuals with NASH, no single treatment could be recommended to all patients with NASH. In general, obesity-associated NAFLD should be considered an important and often underrecognized public health problem. As the prevalence of obesity increases, the prevalence of NAFLD with its associated morbidity and mortality will increase as well. Although primary prevention is the long-term goal for diminishing the prevalence of obesity, early detection of both NASH and hepatic fibrosis using noninvasive biochemical and imaging markers that may replace liver biopsy is the overriding current challenge.97–102 From a clinical standpoint, treating NAFLD in the obese requires addressing obesity as part of the therapeutic plan. Lifestyle management is required in every case, with a focus on weight loss and risk reduction. In most patients, additional therapies, including medications, aggressive diet counseling, behavioral techniques, and sometimes bariatric surgery in morbidly obese subjects, will be required. Data showing improved liver histology among individuals who lose weight and maintain the loss strengthen confidence in the obesity-NAFLD link, and also provide a note of hope that weight loss in obese individuals may help them prevent end-stage liver disease. Research on the biologic mechanisms underlying the obesity-NAFLD link is still in early stages, but may lead to potential treatments and preventive agents. REFERENCES
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