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Nonalcoholic fatty liver disease: An agenda for clinical research
PERSPECTIVES IN CLINICAL HEPATOLOGY Nonalcoholic Fatty Liver Disease: An Agenda for Clinical Research Zobair M. Younossi,1 Anna Mae Diehl,2 and Janus P. Ong1 onalcoholic steatohepatitis (NASH) is a clinicopathologic condition often seen in obese, diabetic women in the absence of significant alcohol use (⬍20 g/d for women and ⬍30 g/d for men) and hepatic histology consistent with alcoholic hepatitis.1-5 NASH is part of a larger spectrum of conditions comprising nonalcoholic fatty liver (NAFL) that also includes hepatic steatosis alone and hepatic steatosis with nonspecific inflammation. This distinction is important because NASH can result in progressive liver disease while the other forms of NAFL may not.6 The histopathologic criteria for NASH are currently being defined, but generally include the presence of hepatic steatosis and lobular inflammation with any one of the following histopathologic features in zone 3 hepatocytes: (1) ballooning degeneration, (2) sinusoidal fibrosis, or (3) Mallory hyaline.6-9 This review summarizes the epidemiologic impact of NAFL, risk factors and determinants of severity of NAFL, the theories of pathogenesis of NASH, and treatment options.
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Disease Burden of NAFL and NASH The epidemiologic impact of NAFL and NASH is related to their prevalence and natural history. It is estimated that in the general population, the prevalence of NAFL is 20% (range 15% to 39%) and the prevalence of NASH is 2% to 3% (range 1.2% to 4.8%), making NAFL potentially the most common form of liver disease in the United States.10-14 The prevalence of NAFL is higher in patients with chroni-
Abbreviations: NASH, nonalcoholic steatohepatitis; NAFL, nonalcoholic fatty liver; AST, aspartate transaminase; ALT, alanine transaminase; ROS, reactive oxygen species; UDCA, ursodeoxycholic acid. From the 1Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA; and 2Division of Gastroenterology, Johns Hopkins University, Baltimore, MD. Received October 15, 2001; accepted January 12, 2002. Address reprint requests to: Zobair M. Younossi, M.D., M.P.H., Center for Liver Diseases, Inova Fairfax Hospital, 3300 Gallows Rd., Falls Church, VA 22042. E-mail: [email protected]; fax: 703-698-3481. Copyright © 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3504-0003$35.00/0 doi:10.1053/jhep.2002.32483 746
cally elevated serum aminotransferase levels with an estimated range between 21% to 63%.13 In patients with morbid obesity undergoing gastric bypass surgery, the prevalence of NAFL is 95%, whereas the prevalence of NASH is 25%.15 Additionally, the reported prevalence of NASH in patients with type II diabetes mellitus is very high, estimated at around 63%.16 The prevalence of NAFL and NASH is expected to increase as the rate of obesity in the United States continues to increase, yet accurate data on the incidence of NASH and NAFL are unavailable. The current literature on the natural history of these diseases supports the notion that NASH may be progressive, but hepatic steatosis alone or with nonspecific inflammation may not.3,6,17,18 Data from 3 studies reporting the histologic changes seen on the sequential biopsies of 26 patients with NASH who were followed for up to 9 years, suggest that 27% of these patients had progression in fibrosis with another 19% progressing to cirrhosis. Fifty percent showed no histologic progression on follow-up biopsy (Fig. 1).3,5,17,19 These data are consistent with another study evaluating a cohort of 132 patients with NAFL and at least 10 years of follow-up.6 In this study, 25% of patients whose hepatic steatosis was accompanied by histologic evidence of liver cell injury (NASH) progressed to cirrhosis, and 12% died of liverrelated causes.6 Further support for the progressive nature of NASH includes recent reports suggesting that cryptogenic cirrhosis may represent “burned-out NASH.”20,21 In these studies, patients with cryptogenic cirrhosis closely resembled those with NASH.20,21 Furthermore, high posttransplantation recurrence of NASH was reported in a cohort of patients who underwent liver transplantation for cryptogenic cirrhosis.22 Recurrence was associated with risk factors typically seen in patients with NASH (obesity and type II diabetes mellitus).22 These data, as well as additional case reports, suggest that NASH may be an important cause of cryptogenic cirrhosis and that NASH may recur after transplantation. Although interesting and provocative, it is important to remember that
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Fig. 1. Changes in histology on sequential biopsies in 26 patients with NASH. Data obtained from 3 studies.5,17,19
the evidence supporting the notion that cryptogenic cirrhosis may represent “burned out NASH” is indirect.
Conditions Associated With NAFL Several studies have shown a consistent relationship between NAFL, obesity, and type II diabetes mellitus.15,23-26 These conditions are a part of the insulin-resistance syndrome and potentially have similar underlying pathogenesis. Additionally, NAFL can be associated with medications (e.g., corticosteroids, synthetic estrogens, amiodarone, perhexiline, or nifedipine), surgical procedures (e.g., jejunoileal bypass or gastroplasty), and other factors (e.g., abetalipoproteinemia, total parenteral nutrition, or environmental toxins).3 Although some overlap is possible, the pathogenesis of NAFL in these conditions and the factors associated with their progression may be different. For example in patients with obesity-related fatty liver, leptin resistance and increased leptin levels may be the critical factor responsible for progression of steatosis alone to NASH and for worsening hepatic fibrosis. On the other hand in patients with jejunoileal bypass, intermittent endotoxemia may be the most important factor. These distinctions are important not only for the understanding of the liver disease associated with the spectrum of NAFL, but also in designing appropriate efficacy trials of agents being tested for treatment of these conditions.
Determinants of Disease Severity and Progression of NAFL Because NASH carries a risk of progression (about 20% over a decade or two), it would be helpful to identify clinical and histologic determinants of disease severity and disease progression. End points in natural history studies of chronic liver diseases usually include death, death from liver disease, need for liver transplantation, and the development of hepatocellular carcinoma. However, it is important to remember that these end points are unlikely to develop with appreciable frequency within short- and me-
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dium-term follow-up (3 to 6 years) in patients with NAFL, making epidemiologic studies difficult to design. Most studies of NASH and NAFL are cross-sectional and lack significant follow-up. In one cross-sectional study of 143 patients with NASH, Angulo et al. found that advanced age (⬎45), serum aspartate transaminase (AST)/ alanine transaminase (ALT) levels greater than 1.0, obesity, and type II diabetes mellitus were independently predictive of advanced fibrosis.27 The only study of NAFL patients with long-term follow-up shows that serum albumin and grade of fibrosis at the index biopsy, in addition to type II diabetes mellitus, may be independent predictors of cirrhosis and death on follow-up.28 These two studies suggest that a number of clinicopathologic features might predict disease severity in patients with NAFL and NASH, but they require validation in future prospective natural history studies of NAFL with sequential liver biopsies and longitudinal clinical data collection.
Liver Biopsy and NAFL Available natural history data suggest that liver biopsy may have important prognostic implications and is the gold standard in establishing grade of fibrosis and the stage of liver disease. Additionally, pathologic features that are important in distinguishing different categories of NAFL (steatosis alone vs. nonalcoholic steatohepatitis) such as ballooning degeneration, Mallory’s hyaline etc., can be only determined by a liver biopsy. Although, there is increasing consensus that liver biopsy provides crucial end points for the clinical trials and epidemiologic studies of NAFL, the role of liver biopsy in clinical practice remains controversial. To assess the current approach of hepatologists regarding the role of liver biopsy in NAFL, a survey of hepatologists practicing in the United States was recently carried out. Of 31 hepatologists responding to the survey, 87% considered NAFL a potentially progressive disease. Ninety-four percent considered a liver biopsy important for prognosis and 84% considered it important for establishing the diagnosis. However, only 10% of respondents considered liver biopsy for all patients suspected of having fatty liver and only 10% thought that a liver biopsy should be performed in patients with radiologic evidence of fatty liver but normal serum transaminase levels. Furthermore, only 10% of respondents would recommend a liver biopsy based on patient age greater than 45 years, 23% would recommend biopsy based on a history of hyperlipidemia or diabetes mellitus, and 48% would recommend biopsy for those with persistently elevated aminotransferases. Finally, 45% of respondents recommended liver biopsy if patients with NAFL did not respond biochemically to the reversal of their associated conditions, such as gradual weight loss for obesity
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Fig. 2. Suggested algorithm for evaluation and follow-up of patients with NAFL.
(Younossi, 2001, unpublished data). In addition to this information, a number of algorithms for the role of liver biopsy in NAFL have been proposed.27 One such algorithm recommends a liver biopsy for patients with persistently abnormal liver enzymes despite attempts to reverse known potential risk factors. This is especially important in patients with clinical conditions associated with the insulin resistance syndrome such as type II diabetes mellitus, hyperlipidemia, and obesity. These data can be used to develop a suggested algorithm on the role of liver biopsy in NAFL (Fig. 2).
Theories of Pathogenesis of NAFL and NASH Little is known about the pathogenesis of NASH and much less of the factors involved in its progression from steatosis to steatohepatitis to fibrosis and cirrhosis. Recent evidence suggests that the pathogenesis of NASH is multifactorial.29 Potential steps involved in the pathogenesis of NAFL and NASH include abnormalities of lipid metabolism, production of reactive oxygen species, increased hepatic lipid peroxidation, activated Stellate cells, and abnormal patterns of cytokine production, all of which lead
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to liver cell injury and fibrosis.4,29 Oxidative stress appears to be a key factor in the pathogenesis of NASH.29 The “multi-hit” theory suggests that the first “hit” involves accumulation of excess fat in the hepatic parenchyma.30 This step has been linked to insulin resistance, which is consistently observed in patients with NASH and NAFL. The second “hit” involves oxidative stress resulting from an imbalance between pro-oxidant and antioxidant processes in the liver,4,30 which may result from the induction of microsomal CYP2E1, mitochondrial release of reactive oxygen species (ROS), H2O2 release from peroxisomal -oxidation of fatty acids, and cytokines released from activated inflammatory cells.29,31,32 Oxidative stress can lead to peroxidation of membrane lipids causing the production of malondialdehyde and 4-hydroxynonenol, which in turn induces the production of proinflammatory cytokines, stellate cell activation, and fibrogenesis, as well as direct hepatocyte damage.29 These hypotheses are also supported by data suggesting that the saturation of the mitochondrial -oxidation pathway by increased free fatty acids can contribute to peroxisomal -oxidation, which leads to generation of H2O2 and oxidative stress. Mitochondrial ROS release may also be increased with the expression of uncoupling protein 2 leading to adenosine triphosphate depletion. Finally, elevation of serum tumor necrosis factor ␣ can also contribute to oxidative stress and apoptosis. In addition, recent data suggest a potential role for leptin in the pathogenesis of NASH and NAFL.29 Unlike the animal models of fatty liver, leptin levels are increased in obese humans, and resistance at the receptor site has been documented. In addition to mediating insulin sensitivity, leptin may play a crucial role in the fibrogenesis of NASH. It is important to emphasize that a number of pathways described here probably operate simultaneously, leading to an imbalance between pro-oxidant and antioxidant states prompting hepatocyte necrosis and fibrosis. Although attractive, these theories remain preliminary.
Treatment of NASH There is no universally effective treatment for NASH, and therapeutic strategies have been largely empirical because the pathogenesis remains unknown.33,34 Experimental trials of potential treatments have mostly been conducted in uncontrolled settings with small sample sizes, and have used serum aminotransferase levels as the end point so they are difficult to evaluate. Such treatments include modification of the clinical conditions associated with NASH including type II diabetes mellitus, hyperlipidemia, and obesity. Specific therapeutic interventions tested so far include weight reduction, the use of
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ursodeoxycholic acid (UDCA), clofibrate, betaine, N-acetylcysteine, gemfibrozil, atorvastatin, troglitazone, and vitamin E. Discontinuing Medications Known to Cause NASH. A number of medications are known to cause NASH. These include corticosteroids, synthetic estrogens, amiodarone, perhexiline, nifedipine, and salicylates.3,33 Discontinuation of most of these medications may lead to resolution of the liver disease.33 Although an important first step, discontinuation of certain medications (tamoxifen, lipid lowering agents, amiodarone, etc.) needs to be balanced against their clinical necessity and the alternative agents available. Modifying Clinical Conditions Associated With NASH. Data from epidemiologic studies point to associations between NASH and clinical conditions such as diabetes mellitus, hyperlipidemia, and obesity.1,2,5,6,17,27 The prevalence of obesity in patients with NAFL ranges from 39% to 95%. Weight reduction can improve liver enzyme abnormalities, and may improve liver histology in patients with NASH.33 An early case series that reported 3 overweight patients with histologically proven NASH who lost 7 to 20 kg showed improvement or normalization of liver enzymes in all 3 patients. Two of the 3 patients had a follow-up liver biopsy, which showed significant histologic improvement.35 In a different study, patients assigned to dietary restriction and exercise lost weight and achieved a significant improvement in their serum transaminase levels compared with those who maintained or gained weight.36 Serial liver biopsy results of these patients showed a significant improvement in hepatic steatosis only in patients who successfully lost weight.36 Palmer et al. have also reported that a weight loss of greater than 10% resulted in greater improvements in the overweight patients with abnormal serum transaminases or hepatomegaly than those patients with a weight loss of less than 10% or weight gain.37 Additionally, Franzese et al. reported a trial of 33 obese children who underwent a weight reduction of 500 g per week by adhering to a strict diet and exercise program over a period of approximately 6 months.38 As with the study by Palmer et al., liver enzymes and steatosis (as assessed by an ultrasound) improved in patients who achieved at least a 10% weight loss. Finally, Andersen et al. studied 41 morbidly obese patients who adhered to a very low caloric diet (288 kcal/d) and achieved a median weight loss of about 34 kg. Biochemical improvement was noted in most of these patients and sequential biopsies showed some improvement in the degree of steatosis.39 However, 20% of these patients, especially those with more rapid weight loss, showed an increase in portal inflammation and fibrosis.39 Thus, although gradual weight loss may be benefi-
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cial, very rapid weight loss may have a negative impact on the course of NASH. This is similar to weight loss in the setting of small bowel bypass surgery, which may cause more severe hepatic injury.39,40 It is difficult to glean from these studies the optimal amount and rate of weight loss needed to achieve clinical benefit in patients with NASH. However, a gradual weight loss program of 10% of initial weight over 6 months seems a reasonable approach and is recommended by some experts. In addition to obesity, hyperlipidemia is seen in 20% to 81% of patients with NASH.1,2,5,6,17,27 Studies of treatment strategies aimed at improving hyperlipidemia in patients with NASH have had conflicting results.41-43 In one study, 16 patients with hypertriglyceridemia and NASH were treated with clofibrate for 12 months.43 There were no significant changes in biochemical or histologic parameters. On the other hand, in a recent unpublished study, atorvastatin produced significant improvements in ballooning degeneration and inflammatory scores after at least 12 months of therapy when given to 7 patients with NASH.42 Interestingly, the pretreatment and posttreatment serum ALT levels were not significantly different in this small group of patients. The only randomized controlled trial of lipid lowering agents in the treatment of NASH examined 46 patients who were randomized to receive either gemfibrozil or no therapy regardless of serum triglyceride levels.41 There was a significant decrease in serum transaminases but histologic data were unavailable.41 As noted previously, these conditions are part of the spectrum of clinical manifestations of the insulin resistance syndrome. Therefore, agents that improve insulin sensitivity may be of particular value in the treatment of NASH. Experiments performed in insulin-resistant ob/ob mice showed that the administration of metformin resolves their hepatic steatosis and improves serum aminotransferase levels.44 Additionally, Marchesini et al. have recently reported a pilot study of 14 patients with NAFL who were given metformin 500 mg 3 times a day for 4 months.45 Although no sequential biopsies were available, significant improvement in the aminotransferase levels were noted.45 Furthermore, an open-label study of troglitazone, a peroxisome-proliferator activated receptor ␥ (PPAR-␥) agonist that improves insulin sensitivity, showed a significant decrease in liver volume as measured on magnetic resonance imaging in patients with lipoatrophic diabetes, severe insulin resistance, and NAFL.46 Caldwell et al. treated 10 patients with biopsy-proven NASH with troglitazone for 6 months.47 At the end of the treatment period, serum aminotransferase levels were normalized in 7 of the 10 patients; however, this biochemical
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improvement was accompanied by only a minimal improvement in histology on serial liver biopsies.47 Vitamin E and Other Therapies for NASH. Vitamin E refers to a group of naturally occurring compounds with antioxidant properties.48 They can potentially protect cellular structures against damage from oxygen-free radicals and reactive products of lipid peroxidation.48 Vitamin E has been used in several clinical conditions in which oxidative stress is thought to play a pathogenetic role, such as chronic hemolytic anemia, intermittent claudication, retrolental fibroplasia of premature infants, and cardiovascular disease, although the strength of the evidence for its use in these conditions is variable.48,49 Vitamin E appears to reverse or ameliorate liver injury in experimental models of liver injury and patients with chronic hepatitis by reducing oxidative stress and lipid peroxidation. As previously noted, oxidative stress is suspected to be responsible for the “second hit” in the pathogenesis of NASH and the use of an antioxidant such as vitamin E may therefore be therapeutic for NASH.33 To date, only one published study has assessed the effect of vitamin E in NASH. Lavine et al. treated 11 obese pediatric patients with abnormal liver enzymes and no other identifiable evidence of other liver diseases.50 Vitamin E was given at 400 IU/d and increased by 400 IU/d until liver enzymes normalized. Five patients required 400 IU/d, 4 more required a dose of 800 IU/d, and 2 patients required the maximum dose allowed in this study (1200 IU/d). All patients achieved normalization of liver enzymes. Furthermore, two patients who discontinued treatment had a rebound elevation in liver enzymes. The improvement in liver enzymes occurred despite the absence of any changes in the body mass index of these patients. One of the drawbacks of this study was the lack of histologic confirmation of the diagnosis of NASH. However, based on the evaluation performed on these patients and the fact that they all had fatty liver on ultrasound and fairly high serum aminotransferase levels (ALT 176 ⫾ 106 IU/L and AST 104 ⫾ 61 IU/L), many of those patients could have had NASH.50 Other therapies that have been evaluated in the treatment of NASH include the use of UDCA, betaine, and N-acetylcysteine. In a small study of 10 patients with NASH, the use of betaine, a metabolite of choline that increases S-adenosylmethionine levels, resulted in improved serum aminotransferases.51 Biochemical improvement of patients with NASH was reported in another small study investigating treatment with N-acetylcysteine.52 Finally, UDCA has also been used to treat NASH. UDCA is thought to have a membrane stabilizing or cytoprotective effect, which may be beneficial to patients
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with NASH.53 In an open-label study, 24 patients with histologically proven NASH were treated with UDCA for 12 months.43 Serum ALT, ␥-glutamyl transpeptidase, and hepatic steatosis all improved. There was, however, no significant change in the histologic grade of inflammation or fibrosis. These results were similar to another study in which UDCA was used in addition to a low-fat diet in patients with NASH. This combination resulted in greater and more rapid improvement in the serum aminotransferase levels than diet alone.54,55 In contrast, a third study of UDCA in obese pediatric patients showed no additional benefit over a lowfat diet.56 The efficacy of UDCA is currently being evaluated in a larger multicenter study.
Conclusions It is now clear that NAFL and its subgroup NASH are common causes of chronic liver disease. Current evidence supports the notion that NASH has the potential to progress to cirrhosis and liver-related mortality and morbidity. Despite recent gains in understanding this entity, a number of unresolved issues related to the natural history and the pathogenesis of NAFL/NASH remain. Studies evaluating therapeutic options for NASH and NAFL are largely preliminary and plagued with design flaws such as small sample size, open-labeled design, and lack of histologic end points. Only after a better understanding of the issues related to the epidemiology and pathogenesis of NASH and NAFL are achieved will we be able to design therapeutic interventions for NASH that can be tested in randomized clinical trials assessing their efficacy.
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Disease Burden of NAFL and NASH The epidemiologic impact of NAFL and NASH is related to their prevalence and natural history. It is estimated that in the general population, the prevalence of NAFL is 20% (range 15% to 39%) and the prevalence of NASH is 2% to 3% (range 1.2% to 4.8%), making NAFL potentially the most common form of liver disease in the United States.10-14 The prevalence of NAFL is higher in patients with chroni-
Abbreviations: NASH, nonalcoholic steatohepatitis; NAFL, nonalcoholic fatty liver; AST, aspartate transaminase; ALT, alanine transaminase; ROS, reactive oxygen species; UDCA, ursodeoxycholic acid. From the 1Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA; and 2Division of Gastroenterology, Johns Hopkins University, Baltimore, MD. Received October 15, 2001; accepted January 12, 2002. Address reprint requests to: Zobair M. Younossi, M.D., M.P.H., Center for Liver Diseases, Inova Fairfax Hospital, 3300 Gallows Rd., Falls Church, VA 22042. E-mail: [email protected]; fax: 703-698-3481. Copyright © 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3504-0003$35.00/0 doi:10.1053/jhep.2002.32483 746
cally elevated serum aminotransferase levels with an estimated range between 21% to 63%.13 In patients with morbid obesity undergoing gastric bypass surgery, the prevalence of NAFL is 95%, whereas the prevalence of NASH is 25%.15 Additionally, the reported prevalence of NASH in patients with type II diabetes mellitus is very high, estimated at around 63%.16 The prevalence of NAFL and NASH is expected to increase as the rate of obesity in the United States continues to increase, yet accurate data on the incidence of NASH and NAFL are unavailable. The current literature on the natural history of these diseases supports the notion that NASH may be progressive, but hepatic steatosis alone or with nonspecific inflammation may not.3,6,17,18 Data from 3 studies reporting the histologic changes seen on the sequential biopsies of 26 patients with NASH who were followed for up to 9 years, suggest that 27% of these patients had progression in fibrosis with another 19% progressing to cirrhosis. Fifty percent showed no histologic progression on follow-up biopsy (Fig. 1).3,5,17,19 These data are consistent with another study evaluating a cohort of 132 patients with NAFL and at least 10 years of follow-up.6 In this study, 25% of patients whose hepatic steatosis was accompanied by histologic evidence of liver cell injury (NASH) progressed to cirrhosis, and 12% died of liverrelated causes.6 Further support for the progressive nature of NASH includes recent reports suggesting that cryptogenic cirrhosis may represent “burned-out NASH.”20,21 In these studies, patients with cryptogenic cirrhosis closely resembled those with NASH.20,21 Furthermore, high posttransplantation recurrence of NASH was reported in a cohort of patients who underwent liver transplantation for cryptogenic cirrhosis.22 Recurrence was associated with risk factors typically seen in patients with NASH (obesity and type II diabetes mellitus).22 These data, as well as additional case reports, suggest that NASH may be an important cause of cryptogenic cirrhosis and that NASH may recur after transplantation. Although interesting and provocative, it is important to remember that
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Fig. 1. Changes in histology on sequential biopsies in 26 patients with NASH. Data obtained from 3 studies.5,17,19
the evidence supporting the notion that cryptogenic cirrhosis may represent “burned out NASH” is indirect.
Conditions Associated With NAFL Several studies have shown a consistent relationship between NAFL, obesity, and type II diabetes mellitus.15,23-26 These conditions are a part of the insulin-resistance syndrome and potentially have similar underlying pathogenesis. Additionally, NAFL can be associated with medications (e.g., corticosteroids, synthetic estrogens, amiodarone, perhexiline, or nifedipine), surgical procedures (e.g., jejunoileal bypass or gastroplasty), and other factors (e.g., abetalipoproteinemia, total parenteral nutrition, or environmental toxins).3 Although some overlap is possible, the pathogenesis of NAFL in these conditions and the factors associated with their progression may be different. For example in patients with obesity-related fatty liver, leptin resistance and increased leptin levels may be the critical factor responsible for progression of steatosis alone to NASH and for worsening hepatic fibrosis. On the other hand in patients with jejunoileal bypass, intermittent endotoxemia may be the most important factor. These distinctions are important not only for the understanding of the liver disease associated with the spectrum of NAFL, but also in designing appropriate efficacy trials of agents being tested for treatment of these conditions.
Determinants of Disease Severity and Progression of NAFL Because NASH carries a risk of progression (about 20% over a decade or two), it would be helpful to identify clinical and histologic determinants of disease severity and disease progression. End points in natural history studies of chronic liver diseases usually include death, death from liver disease, need for liver transplantation, and the development of hepatocellular carcinoma. However, it is important to remember that these end points are unlikely to develop with appreciable frequency within short- and me-
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dium-term follow-up (3 to 6 years) in patients with NAFL, making epidemiologic studies difficult to design. Most studies of NASH and NAFL are cross-sectional and lack significant follow-up. In one cross-sectional study of 143 patients with NASH, Angulo et al. found that advanced age (⬎45), serum aspartate transaminase (AST)/ alanine transaminase (ALT) levels greater than 1.0, obesity, and type II diabetes mellitus were independently predictive of advanced fibrosis.27 The only study of NAFL patients with long-term follow-up shows that serum albumin and grade of fibrosis at the index biopsy, in addition to type II diabetes mellitus, may be independent predictors of cirrhosis and death on follow-up.28 These two studies suggest that a number of clinicopathologic features might predict disease severity in patients with NAFL and NASH, but they require validation in future prospective natural history studies of NAFL with sequential liver biopsies and longitudinal clinical data collection.
Liver Biopsy and NAFL Available natural history data suggest that liver biopsy may have important prognostic implications and is the gold standard in establishing grade of fibrosis and the stage of liver disease. Additionally, pathologic features that are important in distinguishing different categories of NAFL (steatosis alone vs. nonalcoholic steatohepatitis) such as ballooning degeneration, Mallory’s hyaline etc., can be only determined by a liver biopsy. Although, there is increasing consensus that liver biopsy provides crucial end points for the clinical trials and epidemiologic studies of NAFL, the role of liver biopsy in clinical practice remains controversial. To assess the current approach of hepatologists regarding the role of liver biopsy in NAFL, a survey of hepatologists practicing in the United States was recently carried out. Of 31 hepatologists responding to the survey, 87% considered NAFL a potentially progressive disease. Ninety-four percent considered a liver biopsy important for prognosis and 84% considered it important for establishing the diagnosis. However, only 10% of respondents considered liver biopsy for all patients suspected of having fatty liver and only 10% thought that a liver biopsy should be performed in patients with radiologic evidence of fatty liver but normal serum transaminase levels. Furthermore, only 10% of respondents would recommend a liver biopsy based on patient age greater than 45 years, 23% would recommend biopsy based on a history of hyperlipidemia or diabetes mellitus, and 48% would recommend biopsy for those with persistently elevated aminotransferases. Finally, 45% of respondents recommended liver biopsy if patients with NAFL did not respond biochemically to the reversal of their associated conditions, such as gradual weight loss for obesity
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Fig. 2. Suggested algorithm for evaluation and follow-up of patients with NAFL.
(Younossi, 2001, unpublished data). In addition to this information, a number of algorithms for the role of liver biopsy in NAFL have been proposed.27 One such algorithm recommends a liver biopsy for patients with persistently abnormal liver enzymes despite attempts to reverse known potential risk factors. This is especially important in patients with clinical conditions associated with the insulin resistance syndrome such as type II diabetes mellitus, hyperlipidemia, and obesity. These data can be used to develop a suggested algorithm on the role of liver biopsy in NAFL (Fig. 2).
Theories of Pathogenesis of NAFL and NASH Little is known about the pathogenesis of NASH and much less of the factors involved in its progression from steatosis to steatohepatitis to fibrosis and cirrhosis. Recent evidence suggests that the pathogenesis of NASH is multifactorial.29 Potential steps involved in the pathogenesis of NAFL and NASH include abnormalities of lipid metabolism, production of reactive oxygen species, increased hepatic lipid peroxidation, activated Stellate cells, and abnormal patterns of cytokine production, all of which lead
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to liver cell injury and fibrosis.4,29 Oxidative stress appears to be a key factor in the pathogenesis of NASH.29 The “multi-hit” theory suggests that the first “hit” involves accumulation of excess fat in the hepatic parenchyma.30 This step has been linked to insulin resistance, which is consistently observed in patients with NASH and NAFL. The second “hit” involves oxidative stress resulting from an imbalance between pro-oxidant and antioxidant processes in the liver,4,30 which may result from the induction of microsomal CYP2E1, mitochondrial release of reactive oxygen species (ROS), H2O2 release from peroxisomal -oxidation of fatty acids, and cytokines released from activated inflammatory cells.29,31,32 Oxidative stress can lead to peroxidation of membrane lipids causing the production of malondialdehyde and 4-hydroxynonenol, which in turn induces the production of proinflammatory cytokines, stellate cell activation, and fibrogenesis, as well as direct hepatocyte damage.29 These hypotheses are also supported by data suggesting that the saturation of the mitochondrial -oxidation pathway by increased free fatty acids can contribute to peroxisomal -oxidation, which leads to generation of H2O2 and oxidative stress. Mitochondrial ROS release may also be increased with the expression of uncoupling protein 2 leading to adenosine triphosphate depletion. Finally, elevation of serum tumor necrosis factor ␣ can also contribute to oxidative stress and apoptosis. In addition, recent data suggest a potential role for leptin in the pathogenesis of NASH and NAFL.29 Unlike the animal models of fatty liver, leptin levels are increased in obese humans, and resistance at the receptor site has been documented. In addition to mediating insulin sensitivity, leptin may play a crucial role in the fibrogenesis of NASH. It is important to emphasize that a number of pathways described here probably operate simultaneously, leading to an imbalance between pro-oxidant and antioxidant states prompting hepatocyte necrosis and fibrosis. Although attractive, these theories remain preliminary.
Treatment of NASH There is no universally effective treatment for NASH, and therapeutic strategies have been largely empirical because the pathogenesis remains unknown.33,34 Experimental trials of potential treatments have mostly been conducted in uncontrolled settings with small sample sizes, and have used serum aminotransferase levels as the end point so they are difficult to evaluate. Such treatments include modification of the clinical conditions associated with NASH including type II diabetes mellitus, hyperlipidemia, and obesity. Specific therapeutic interventions tested so far include weight reduction, the use of
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ursodeoxycholic acid (UDCA), clofibrate, betaine, N-acetylcysteine, gemfibrozil, atorvastatin, troglitazone, and vitamin E. Discontinuing Medications Known to Cause NASH. A number of medications are known to cause NASH. These include corticosteroids, synthetic estrogens, amiodarone, perhexiline, nifedipine, and salicylates.3,33 Discontinuation of most of these medications may lead to resolution of the liver disease.33 Although an important first step, discontinuation of certain medications (tamoxifen, lipid lowering agents, amiodarone, etc.) needs to be balanced against their clinical necessity and the alternative agents available. Modifying Clinical Conditions Associated With NASH. Data from epidemiologic studies point to associations between NASH and clinical conditions such as diabetes mellitus, hyperlipidemia, and obesity.1,2,5,6,17,27 The prevalence of obesity in patients with NAFL ranges from 39% to 95%. Weight reduction can improve liver enzyme abnormalities, and may improve liver histology in patients with NASH.33 An early case series that reported 3 overweight patients with histologically proven NASH who lost 7 to 20 kg showed improvement or normalization of liver enzymes in all 3 patients. Two of the 3 patients had a follow-up liver biopsy, which showed significant histologic improvement.35 In a different study, patients assigned to dietary restriction and exercise lost weight and achieved a significant improvement in their serum transaminase levels compared with those who maintained or gained weight.36 Serial liver biopsy results of these patients showed a significant improvement in hepatic steatosis only in patients who successfully lost weight.36 Palmer et al. have also reported that a weight loss of greater than 10% resulted in greater improvements in the overweight patients with abnormal serum transaminases or hepatomegaly than those patients with a weight loss of less than 10% or weight gain.37 Additionally, Franzese et al. reported a trial of 33 obese children who underwent a weight reduction of 500 g per week by adhering to a strict diet and exercise program over a period of approximately 6 months.38 As with the study by Palmer et al., liver enzymes and steatosis (as assessed by an ultrasound) improved in patients who achieved at least a 10% weight loss. Finally, Andersen et al. studied 41 morbidly obese patients who adhered to a very low caloric diet (288 kcal/d) and achieved a median weight loss of about 34 kg. Biochemical improvement was noted in most of these patients and sequential biopsies showed some improvement in the degree of steatosis.39 However, 20% of these patients, especially those with more rapid weight loss, showed an increase in portal inflammation and fibrosis.39 Thus, although gradual weight loss may be benefi-
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cial, very rapid weight loss may have a negative impact on the course of NASH. This is similar to weight loss in the setting of small bowel bypass surgery, which may cause more severe hepatic injury.39,40 It is difficult to glean from these studies the optimal amount and rate of weight loss needed to achieve clinical benefit in patients with NASH. However, a gradual weight loss program of 10% of initial weight over 6 months seems a reasonable approach and is recommended by some experts. In addition to obesity, hyperlipidemia is seen in 20% to 81% of patients with NASH.1,2,5,6,17,27 Studies of treatment strategies aimed at improving hyperlipidemia in patients with NASH have had conflicting results.41-43 In one study, 16 patients with hypertriglyceridemia and NASH were treated with clofibrate for 12 months.43 There were no significant changes in biochemical or histologic parameters. On the other hand, in a recent unpublished study, atorvastatin produced significant improvements in ballooning degeneration and inflammatory scores after at least 12 months of therapy when given to 7 patients with NASH.42 Interestingly, the pretreatment and posttreatment serum ALT levels were not significantly different in this small group of patients. The only randomized controlled trial of lipid lowering agents in the treatment of NASH examined 46 patients who were randomized to receive either gemfibrozil or no therapy regardless of serum triglyceride levels.41 There was a significant decrease in serum transaminases but histologic data were unavailable.41 As noted previously, these conditions are part of the spectrum of clinical manifestations of the insulin resistance syndrome. Therefore, agents that improve insulin sensitivity may be of particular value in the treatment of NASH. Experiments performed in insulin-resistant ob/ob mice showed that the administration of metformin resolves their hepatic steatosis and improves serum aminotransferase levels.44 Additionally, Marchesini et al. have recently reported a pilot study of 14 patients with NAFL who were given metformin 500 mg 3 times a day for 4 months.45 Although no sequential biopsies were available, significant improvement in the aminotransferase levels were noted.45 Furthermore, an open-label study of troglitazone, a peroxisome-proliferator activated receptor ␥ (PPAR-␥) agonist that improves insulin sensitivity, showed a significant decrease in liver volume as measured on magnetic resonance imaging in patients with lipoatrophic diabetes, severe insulin resistance, and NAFL.46 Caldwell et al. treated 10 patients with biopsy-proven NASH with troglitazone for 6 months.47 At the end of the treatment period, serum aminotransferase levels were normalized in 7 of the 10 patients; however, this biochemical
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improvement was accompanied by only a minimal improvement in histology on serial liver biopsies.47 Vitamin E and Other Therapies for NASH. Vitamin E refers to a group of naturally occurring compounds with antioxidant properties.48 They can potentially protect cellular structures against damage from oxygen-free radicals and reactive products of lipid peroxidation.48 Vitamin E has been used in several clinical conditions in which oxidative stress is thought to play a pathogenetic role, such as chronic hemolytic anemia, intermittent claudication, retrolental fibroplasia of premature infants, and cardiovascular disease, although the strength of the evidence for its use in these conditions is variable.48,49 Vitamin E appears to reverse or ameliorate liver injury in experimental models of liver injury and patients with chronic hepatitis by reducing oxidative stress and lipid peroxidation. As previously noted, oxidative stress is suspected to be responsible for the “second hit” in the pathogenesis of NASH and the use of an antioxidant such as vitamin E may therefore be therapeutic for NASH.33 To date, only one published study has assessed the effect of vitamin E in NASH. Lavine et al. treated 11 obese pediatric patients with abnormal liver enzymes and no other identifiable evidence of other liver diseases.50 Vitamin E was given at 400 IU/d and increased by 400 IU/d until liver enzymes normalized. Five patients required 400 IU/d, 4 more required a dose of 800 IU/d, and 2 patients required the maximum dose allowed in this study (1200 IU/d). All patients achieved normalization of liver enzymes. Furthermore, two patients who discontinued treatment had a rebound elevation in liver enzymes. The improvement in liver enzymes occurred despite the absence of any changes in the body mass index of these patients. One of the drawbacks of this study was the lack of histologic confirmation of the diagnosis of NASH. However, based on the evaluation performed on these patients and the fact that they all had fatty liver on ultrasound and fairly high serum aminotransferase levels (ALT 176 ⫾ 106 IU/L and AST 104 ⫾ 61 IU/L), many of those patients could have had NASH.50 Other therapies that have been evaluated in the treatment of NASH include the use of UDCA, betaine, and N-acetylcysteine. In a small study of 10 patients with NASH, the use of betaine, a metabolite of choline that increases S-adenosylmethionine levels, resulted in improved serum aminotransferases.51 Biochemical improvement of patients with NASH was reported in another small study investigating treatment with N-acetylcysteine.52 Finally, UDCA has also been used to treat NASH. UDCA is thought to have a membrane stabilizing or cytoprotective effect, which may be beneficial to patients
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with NASH.53 In an open-label study, 24 patients with histologically proven NASH were treated with UDCA for 12 months.43 Serum ALT, ␥-glutamyl transpeptidase, and hepatic steatosis all improved. There was, however, no significant change in the histologic grade of inflammation or fibrosis. These results were similar to another study in which UDCA was used in addition to a low-fat diet in patients with NASH. This combination resulted in greater and more rapid improvement in the serum aminotransferase levels than diet alone.54,55 In contrast, a third study of UDCA in obese pediatric patients showed no additional benefit over a lowfat diet.56 The efficacy of UDCA is currently being evaluated in a larger multicenter study.
Conclusions It is now clear that NAFL and its subgroup NASH are common causes of chronic liver disease. Current evidence supports the notion that NASH has the potential to progress to cirrhosis and liver-related mortality and morbidity. Despite recent gains in understanding this entity, a number of unresolved issues related to the natural history and the pathogenesis of NAFL/NASH remain. Studies evaluating therapeutic options for NASH and NAFL are largely preliminary and plagued with design flaws such as small sample size, open-labeled design, and lack of histologic end points. Only after a better understanding of the issues related to the epidemiology and pathogenesis of NASH and NAFL are achieved will we be able to design therapeutic interventions for NASH that can be tested in randomized clinical trials assessing their efficacy.
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