Preamble These recommendations are based on the following: (i) a formal review and analysis of the recently published world literature on the topic (Medline search up to June 2011); (ii) the American College of Physicians' Manual for Assessing Health Practices and Designing Practice Guidelines; (1) (iii) guideline policies of the three societies approving this document; and (iv) the experience of the authors and independent reviewers with regards to non-alcoholic fatty liver disease (NAFLD). Intended for use by physicians and allied health professionals, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible and adjustable for individual patients. Specific recommendations are evidence based wherever possible, and when such evidence is not available or inconsistent, recommendations are made based on the consensus opinion of the authors. To best characterize the evidence cited in support of the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) workgroup with minor modifications (Table 1) (2). The strength of recommendations in the GRADE system is classified as strong (1) or weak (2). The quality of evidence supporting strong or weak recommendations is designated by one of three levels: high (A), moderate (B), or low quality (C) (2). This is a practice guideline for clinicians rather than a review article and interested readers can refer to several comprehensive reviews published recently (3,4,5,6,7,8).Table 1: Grading of recommendations, assessment, development, and evaluation (GRADE)Definitions The definition of NAFLD requires that (i) there is evidence of hepatic steatosis, either by imaging or by histology and (ii) there are no causes for secondary hepatic fat accumulation such as significant alcohol consumption, use of steatogenic medication, or hereditary disorders (Table 2). In the majority of patients, NAFLD is associated with metabolic risk factors such as obesity, diabetes mellitus, and dyslipidemia. NAFLD is histologically further categorized into non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) (Table 3). NAFL is defined as the presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes. NASH is defined as the presence of hepatic steatosis and inflammation with hepatocyte injury (ballooning) with or without fibrosis.Table 2: Common causes of secondary hepatic steatosisTable 3: Nonalcoholic fatty liver disease and related definitionsIncidence and prevalence in the general population The incidence of NAFLD has been investigated in a limited number of studies. Two Japanese studies (9,10) reported an incidence rate of 31 and 86 cases of suspected NAFLD per 1,000 person-years, respectively, whereas another study from England showed a much lower incidence rate of 29 cases per 100,000 person-years (11). More studies are needed to better understand the incidence of NAFLD across different age, ethnic, and geographic groups. The reported prevalence of NAFLD varies widely depending on the population studied and the definition used. The prevalence of histologically defined NAFLD was 20 and 51% in two different studies comprised of potential living liver donors (12,13). The reported prevalence of NAFLD when defined by liver ultrasound (US) ranged between 17 and 46% depending on the population studied (4). In a study consisting of nearly 400 middle-aged individuals, the prevalence of NAFLD defined by ultrasonography was 46% and the prevalence of histologically confirmed NASH was 12.2% (14). In the Dallas Heart Study, when assessed by magnetic resonance (MR) spectroscopy, the prevalence of NAFLD in the general population was 31% (15). The prevalence of suspected NAFLD when estimated using aminotransferases alone without imaging or histology ranged between 7 and 11%, but aminotransferases can be normal in individuals with NAFLD (4). In summary, estimates of the worldwide prevalence of NAFLD ranges from 6.3 to 33%, with a median of 20% in the general population, based on a variety of assessment methods (4). On the other hand, the estimated prevalence of NASH is lower, ranging from 3 to 5% (4). The prevalence of NASH cirrhosis in the general population is not known. Prevalence of NAFLD in high-risk groups (Table 4) Obesity is a common and well-documented risk factor for NAFLD. Both excessive body mass index (BMI) and visceral obesity are recognized risk factors for NAFLD. In patients with severe obesity undergoing bariatric surgery, the prevalence of NAFLD can exceed 90% and up to 5% of patients may have unsuspected cirrhosis (4,16,17,18,19,20). There is a very high prevalence of NAFLD in individuals with type 2 diabetes mellitus (T2DM) (4). An ultrasonographic study of patients with T2DM showed a 69% prevalence of NAFLD (21). In another study, 127of 204 diabetic patients displayed fatty infiltration on US, and 87% of the patients with fatty infiltration who consented to biopsy had histologic confirmation of NAFLD (22). High serum triglyceride levels and low serum HDL levels are very common in patients with NAFLD. The prevalence of NAFLD in individuals with dyslipidemia attending lipid clinics was estimated to be 50% (23). Age, gender, and ethnicity are also associated with a differential prevalence for NAFLD (4). A number of studies have shown that the prevalence of NAFLD increases with age (24,25,26,27,28). The likelihood of disease progression to advanced fibrosis or mortality increases in older patients with NAFLD (29,30,31). Many recent studies have reported that male gender is a risk factor for fatty liver disease (4). For example, in a study of 26,527 subjects undergoing medical checkups, the prevalence of NAFLD was 31% in men and 16% in women (32). Compared with non-Hispanic whites, Hispanic individuals have significantly higher and non-Hispanic blacks have significantly lower prevalence of NAFLD (15,33,34,35). The prevalence of NAFLD in American-Indian and Alaskan-Native populations appears lower, ranging from 0.6 to 2.2%, although the lack of histologic definition makes it likely that is an underestimate (36,37). There are data to suggest that hypothyroidism, hypopituitarism, hypogonadism, sleep apnea, and polycystic ovary syndrome independent of obesity are important risk factors for the presence of NAFLD (Table 4) (3).Table 4: Risk factors associated with NAFLDNatural history The evolution of hepatic histologic changes in patients with NAFL and NASH has been investigated by several studies, but these generally included smaller number of patients and had relatively modest duration of follow-up (4,7). Nonetheless, it is generally agreed that patients with simple steatosis have very slow, if any, histological progression, while patients with NASH can exhibit histological progression to cirrhotic-stage disease (4,7). The long-term outcomes of patients with NAFLD and NASH have been reported in several studies (31,38,39,40,41,42,43,44,45). Their detailed discussion is beyond the scope of this guideline, but their findings can be summarized as follows: (i) patients with NAFLD have increased overall mortality compared with matched control populations; (ii) the most common cause of death in patients with NAFLD, NAFL, and NASH is cardiovascular disease; and (iii) patients with NASH (but not NAFL) have an increased liver-related mortality rate. Another piece of indirect evidence that supports the progressive nature of NASH is in the features of cryptogenic cirrhosis, which is closely related to NAFLD (46,47). Patients with cryptogenic cirrhosis have disproportionately high prevalence of metabolic risk factors (T2DM, obesity, metabolic syndrome) typical of patients with NAFLD, their liver biopsies frequently show one or more features of NASH, and studies have demonstrated the loss of histological features of NASH with the development of cirrhosis (4,7,46,47). Patients with NAFLD are at increased risk for HCC, but this risk is likely limited to those with advanced fibrosis and cirrhosis (48,49,50,51,52,53). Several studies investigated the natural history of NASH cirrhosis in comparison to patients with hepatitis C cirrhosis (54,55,56,57). One large prospective US-based study (55) observed a lower rate of decompensation and mortality in patients with NASH cirrhosis as compared with patients with hepatitis C cirrhosis. However, a more recent international study (56) of 247 NAFLD patients with advanced fibrosis and cirrhosis followed over a mean duration of 85.6±54.5 months showed an overall 10-year survival of 81.5% that was not different from matched patients with hepatitis C cirrhosis. Importantly, both studies have shown that patients with NASH cirrhosis are at significantly lower risk for HCC than patients with hepatitis C cirrhosis (55,56). Alcohol consumption and definition of NAFLD By definition, NAFLD indicates the lack of any evidence of ongoing or recent consumption of significant quantities of alcohol. However, the precise definition of significant alcohol consumption in patients with suspected NAFLD is uncertain. A recent consensus meeting (58) concluded that, for NASH clinical trials candidate eligibility purposes, significant alcohol consumption be defined as >21 drinks per week in men and >14 drinks per week in women over a 2-year period before baseline liver histology. Furthermore, this group recommended that validated questionnaires should be used to quantify the amount of alcohol consumption in the context of clinical trials. The definition of significant alcohol consumption in the published NAFLD literature has been inconsistent and ranged from >1 alcoholic drink (∼10 g of alcohol per one drink unit) per day to >40 g per day, and published studies have not always used gender-specific definitions (59). If self-reported alcohol consumption details are not consistent with clinical suspicion when evaluating a patient with suspected NAFLD, confirmation with a family member or a close friend should be considered.Figure: No Caption available.Evaluation of incidentally discovered hepatic steatosis Some patients undergoing thoracic and abdominal imaging for reasons other than liver symptoms, signs, or biochemistry may demonstrate unsuspected hepatic steatosis. While this phenomenon is not uncommon in clinical practice, studies have not systematically examined the characteristics or natural history of NAFLD in this patient population.Figure: No Caption available.Screening in primary care, diabetes, and obesity clinics It can be argued that there should be systematic screening for NAFLD, at least among higher-risk individuals attending diabetes and obesity clinics. However, at present there are significant gaps in our knowledge regarding the diagnosis, natural history, and treatment of NAFLD. As liver biochemistries can be within normal ranges in patients with NAFLD and NASH, they may not be sufficiently sensitive to serve as screening tests, whereas liver US is potentially more sensitive but it is expensive and cumbersome as a screening test.Figure: No Caption available.Screening of family members Anecdotal experience and some published studies suggest familial clustering and heritability of NAFLD (60,61,62,63), but conclusive studies are lacking. In a retrospective cohort study, Willner et al. (61) observed that 18% of patients with NASH have a similarly affected first-degree relative. A small familial aggregation study observed that patients with NAFLD have a significantly higher number of first-degree relatives with cirrhosis and a trend toward familial clustering of NAFLD or cryptogenic cirrhosis than matched healthy controls (62). In another familial aggregation study (63) of overweight children with and without NAFLD, after adjusting for age, gender, race, and BMI, the heritability of MR-measured liver fat fraction was 0.386, and fatty liver was present in 18% of family members of children with NAFLD despite normal alanine aminotransferase (ALT) and lack of obesity.Figure: No Caption available.Initial evaluation The diagnosis of NAFLD requires that (i) there is hepatic steatosis by imaging or histology, (ii) there is no significant alcohol consumption, (iii) there are no competing etiologies for hepatic steatosis, and (iv) there are no coexisting causes for chronic liver disease. Common alternative causes of hepatic steatosis are significant alcohol consumption, hepatitis C, medications, parenteral nutrition, Wilson's disease, and severe malnutrition (Table 2). When evaluating a patient with newly suspected NAFLD, it is important to exclude coexisting etiologies for chronic liver disease including hemochromatosis, autoimmune liver disease, chronic viral hepatitis, and Wilson's disease (3). Mildly elevated serum ferritin is common in patients with NAFLD and it does not necessarily indicate increased iron stores (3,64). Elevated serum ferritin and transferrin saturation in patients with suspected NAFLD should lead to testing for genetic hemochromatosis. Mutations in the HFE gene occur with variable frequency in patients with NAFLD and their clinical significance is unclear (64). One should consider a liver biopsy to assess hepatic iron concentration and to exclude significant hepatic injury and fibrosis in a patient with suspected NAFLD with elevated serum ferritin and a homozygote or compound heterozygote C282Y mutation in the HFE gene (65). Elevated serum autoantibodies are common in patients with NAFLD and are generally considered to be an epiphenomenona (3). In a recently published large study from the NASH Clinical Research Network, positive serum autoantibodies, defined as antinuclear antibody >1:160 or antismooth muscle antibody >1:40 were present in 21% of patients with well-phenotyped NAFLD and were not associated with more advanced histologic features (66).Figure: No Caption available.Non-invasive assessment of steatohepatitis and advanced fibrosis in NAFLD The natural history of NAFLD is fairly dichotomous—NAFL is generally benign whereas NASH can progress to cirrhosis, liver failure, and liver cancer. Existing dogma posits that liver biopsy is the most reliable approach for identifying the presence of steatohepatitis and fibrosis in patients with NAFLD, but it is generally acknowledged that biopsy is limited by cost, sampling error, and procedure-related morbidity and mortality. Serum aminotransferase levels and imaging tests such as US, computerized tomography, and MR do not reliably assess steatohepatitis and fibrosis in patients with NAFLD. Therefore, there has been significant interest in developing clinical prediction rules and non-invasive biomarkers for identifying steatohepatitis in patients with NAFLD (7), but their detailed discussion is beyond the scope of this practice guideline. The presence of metabolic syndrome is a strong predictor for the presence of steatohepatitis in patients with NAFLD (3,7,67,68,69) and may be used to best identify patients with persistently abnormal liver biochemistries who would benefit diagnostically and prognostically from a liver biopsy. There has been intense interest in non-invasive methods to identify advanced fibrosis in patients with NAFLD (7); these include the NAFLD Fibrosis Score (70), ELF (enhanced liver fibrosis) panel (70) and transient elastography. The NAFLD Fibrosis Score is based on six readily available variables (age, BMI, hyperglycemia, platelet count, albumin, AST (aspartate aminotransferase)/ALT ratio) and it is calculated using the published formula (http://nafldscore.com). In a meta-analysis of 13 studies consisting of 3,064 patients (7), NAFLD Fibrosis Score has an AUROC (area under the receiver operating curve) of 0.85 for predicting advanced fibrosis (i.e., bridging fibrosis or cirrhosis) and a score <−1.455 had 90% sensitivity and 60% specificity to exclude advanced fibrosis whereas a score >0.676 had 67% sensitivity and 97% specificity to identify the presence of advanced fibrosis. The ELF panel consists of plasma levels of three matrix turnover proteins (hyaluronic acid, TIMP-1, and PIIINP) had an AUROC of 0.90 with 80% sensitivity and 90% specificity for detecting advanced fibrosis (71). Circulating levels of cytokeratin-18 (CK18) fragments have been investigated extensively as novel biomarkers for the presence of steatohepatitis in patients with NAFLD (7,72). Wieckowska et al. (70) measured CK18 fragments in plasma that had been obtained from 44 consecutive patients with suspected NAFLD at the time of liver biopsy, and correlated the findings with hepatic immunohistochemistry data. Plasma CK18 fragments were markedly increased in patients with NASH compared with patients with simple steatosis or normal biopsies (median 765.7 U/l vs. 202.4 U/l or 215.5 U/l, respectively; P<0.001), and independently predicted NASH (odds ratio (OR): 1.95; 95% confidence interval (CI): 1.18–3.22 for every 50 U/l increase). This observation was reproduced in several subsequent studies and a recent meta-analysis estimated that plasma CK18 levels have a sensitivity of 78%, specificity of 87%, and an AUROC of 0.82 (95% CI: 0.78–0.88) for steatohepatitis in patients with NAFLD (7). Although these are very encouraging results, currently this assay is not commercially available. Furthermore, as each study utilized a study-specific cutoff value, there is not an established cutoff value for identifying steatohepatitis. Transient elastography, which measures liver stiffness non-invasively, has been successful in identifying advanced fibrosis in patients with hepatitis B and hepatitis C. Although a recent meta-analysis showed high sensitivity and specificity for identifying fibrosis in NAFLD (7), it has a high failure rate in individuals with a higher BMI. Furthermore, it is not commercially available in the United States. Other imaging tools such as MR elastography, although commercially available in the United States, is rarely used in clinical practice. A major limitation of these prediction models and biomarkers is that they have largely been investigated in cross-sectional studies and thus their utility in monitoring disease natural history, predicting outcomes, or response to therapeutic intervention is unknown.Figure: No Caption available.When to obtain a liver biopsy in patients with NAFLD? Liver biopsy remains the gold standard for characterizing liver histology in patients with NAFLD. However, it is expensive and carries some morbidity and very rare mortality risk. Thus, it should be performed in those who would benefit the most from diagnostic, therapeutic guidance, and prognostic perspectives.Figure: No Caption available.MANAGEMENT OF PATIENTS WITH NAFLD The management of patients with NAFLD consists of treating liver disease as well as the associated metabolic comorbidities such as obesity, hyperlipidemia, insulin resistance, and T2DM. As patients with NAFLD without steatohepatitis have excellent prognosis from a liver standpoint, treatments aimed at improving liver disease should be limited to those with NASH. Lifestyle intervention Many studies indicate that lifestyle modification may reduce aminotransferases and improve hepatic steatosis when measured by either US (73,74,75,76,77,78,79,80) or MR imaging and spectroscopy (81,82,83,84,85,86,87,88,89,90,91,92,93,94). In a meta-analysis of 15 early case series and clinical studies spanning between 1967 through 2000, most studies reported reductions in aminotransferases and hepatic steatosis by US across a broad spectrum of diets of different caloric restriction intensities and macronutrient composition (low vs. high carbohydrate, low vs. high fat, saturated vs. unsaturated fat diets) (95). However, these early studies were inconclusive as a result of being small, largely uncontrolled and few using histology as the primary end point. More recent uncontrolled studies also showed an improvement in aminotransferases and hepatic steatosis on histology with lifestyle modification (96,97,98). Orlistat (an enteric lipase inhibitor) in conjunction with lifestyle modification was investigated in two randomized controlled trials. In the study by Zelber-Sagi et al. (99), orlistat reportedly improved ALT and steatosis by US, but its effect on liver histology could not be evaluated because the majority of patients did not undergo a follow-up liver biopsy. However, in the study by Harrison et al. (100), orlistat did not improve body weight or liver histology. The best evidence for weight loss as a means to improve liver histology in NASH comes from a trial that randomized 31 obese persons with NASH to intensive lifestyle changes (diet, behavior modification, and 200 min a week of moderate physical activity for 48 weeks) vs. structured basic education alone (101). The intensive arm had 9.3% weight loss (vs. 0.2% in the dietary counseling alone arm) and led to an improvement in steatosis, necrosis, and inflammation, but not fibrosis. Importantly, participants with ≥ 7% weight loss had significant improvement in steatosis, lobular inflammation, ballooning, and NAFLD Activity Score (NAS) (101). There was a similar pattern in the study by Harrison et al. (100), where participants who lost >5% body weight improved steatosis, whereas individuals with ≥ 9% weight loss had significant improvement in steatosis, lobular inflammation, ballooning, and NAS. A number of recent studies used MR spectroscopy to assess changes in hepatic fat in response to lifestyle modification. The results from these studies using a variety of interventions, either by diet alone (81,83,84,89,92,93) or in combination with different exercise prescriptions (82,85,86,87,88,92,94), have consistently reported a significant reduction in liver fat by an average of ∼40% (ranging from 20 to 81%). The degree of hepatic fat reduction was proportional to the intensity of the lifestyle intervention and generally required a body weight loss between ∼5 and 10% (82,88,92). The effect of exercise without dietary modification on hepatic steatosis was investigated in four studies using MR spectroscopy (102,103,104,105). Exercise programs consisted of 2–3 sessions a week of 30–60 min over a period of 6–12 weeks. In all but one study (101), liver fat content diminished without a significant change in body weight.Figure: No Caption available.INSULIN SENSITIZING AGENTS Metformin Several studies investigated the effect of metformin on aminotransferases and liver histology in patients with NASH. Early small, open-label studies demonstrated a reduction in insulin resistance and aminotransferases (106,107,108) but no significant improvement in liver histology (107,108). An open-label trial consisting of110 patients with NASH received either metformin 2 g/day (55 patients), vitamin E 800 IU/day (28 patients), or dietary-induced weight loss (27 patients) for 12 months (109). Aminotransferases improved more with metformin than with vitamin E or diet alone. However, there was only a modest improvement in hepatic steatosis and inflammation in the subset of 17 patients undergoing paired liver biopsies with metformin treatment. In a 48-week open-label study in 26 patients, metformin improved NASH activity in only 30% of patients, although interpretation of the study was confounded by a significant weight loss in the responders (19% lost >10 kg) (110). Haukeland et al. (112) reported a similar lack of efficacy in a larger (n=48) randomized control trial (RCT) of metformin vs. placebo with a similar dietary and exercise intervention in both groups. Other studies also failed to show major benefit for metformin on hepatic insulin sensitivity, aminotransferases (111,112,113,114,115,116) or liver histology (112,113,116). A recent meta-analysis (4) concluded that 6–12 months of metformin plus lifestyle intervention did not improve aminotransferases or liver histology, compared with lifestyle intervention alone, independently of metformin dose or the presence of diabetes.Figure: No Caption available.Thiazolidinediones Several studies investigated the effect of pioglitazone and rosiglitazone on aminotransferases and liver histology in adults with NASH. In an early uncontrolled open-label study (117) in 22 subjects with biopsy-proven NASH, rosiglitazone improved aminotransferases and hepatic steatosis, ballooning and inflammation scores, but not fibrosis. But in a subsequent RCT, Ratziu et al. (118) observed that rosiglitazone improved aminotransferases and hepatic steatosis, but not necroinflammation or fibrosis and its 2-year open-label extension phase also showed similar results (119). Belfort et al. (120) conducted a RCT of pioglitazone (45 mg/day) in patients with NASH who had impaired glucose tolerance or T2DM. Although there was a significant weight gain (2.5±0.5 kg) with pioglitazone, it significantly improved aminotransferases, steatosis, ballooning, and inflammation. The NAS improved with pioglitazone in 73% compared with 24% of placebo-treated patients (P<0.001) and there was a trend toward improvement in fibrosis among patients randomized to pioglitazone (P=0.08). Aithal et al. (121) performed a RCT of lifestyle intervention with either pioglitazone 30 mg/day or placebo for 12 months in a total of 74 patients with NASH. While steatosis did not improve significantly compared with placebo, hepatocellular injury and fibrosis improved significantly (121). The PIVENS (pioglitazone vs. vitamin E vs. placebo for the treatment of non-diabetic patients with non-alcoholic steatohepatitis) (122) study is a large multicenter RCT that randomized 247 non-diabetic patients with NASH to pioglitazone (30 mg/day), vitamin E (800 IU/day), or placebo for 24 months. The primary end point was an improvement in NAS≥2 points with at least one-point improvement in hepatocellular ballooning and one-point improvement in either the lobular inflammation or steatosis score, and no increase in the fibrosis score (122). It was achieved in 19% in the placebo group compared with 34% in the pioglitazone group (P=0.04 vs. placebo) and 43% in the vitamin E group (P=0.001 vs. placebo) (122). Because this study consisted of two primary comparisons (pioglitazone vs. placebo and vitamin E vs. placebo), a P value of 0.025 was considered to be significant a priori. Therefore, although there were histological benefits associated with pioglitazone, this study concluded that pioglitazone did not meet the primary end point. However, resolution of NASH, a key secondary end point, was achieved in significantly higher number of patients receiving pioglitazone than receiving placebo (47 vs. 21%, P=0.001) (122). Of note, pioglitazone was associated with a 4.7-kg weight gain compared with placebo (P<0.001). Vitamin E and pioglitazone were well tolerated and there were no differences in other adverse events. A recent meta-analysis (4) that included five RCTs showed that pioglitazone significantly improved steatosis (OR: 4.05, 95% CI: 2.58–6.35) and inflammation (OR: 3.53, 95% CI: 2.21–5.64), but not fibrosis (OR: 1.40, 95% CI: 0.87–2.24). There has been considerable debate about the long-term safety of thiazolidinediones regarding cardiovascular disease, congestive heart failure, bladder cancer, and bone loss. In a recent meta-analysis (123) of 19 trials enrolling a total of 16,390 patients with T2DM, pioglitazone treatment was associated with a significant reduction (∼18%) in the primary outcome of death, myocardial infarction, or stroke (P=0.005). However, there was also a higher rate of congestive heart failure with pioglitazone (2.3 vs. 1.8% in the control group, P=0.002), so caution must be exercised when considering its use in patients with impaired myocardial function. Due to increased risk of coronary events, rosiglitazone is no longer marketed in Europe and its use is highly restricted in the United States.Figure: No Caption available.Vitamin E Oxidative stress is considered to be a key mechanism of hepatocellular injury and disease progression in subjects with NASH. Vitamin E is an antioxidant and has been investigated to treat NASH (124,125,126,127,128). Comparison between these trials is difficult due to varying criteria for entry into the study, different doses of vitamin E, and unclear formulations of vitamin E used, which could affect its bioavailability, the additional use of other antioxidants or other drugs, and limited histologic data to assess outcomes. Also, most studies were relatively underpowered and did not meet or publish CONSORT criteria for clinical trials. Despite these limitations, it can be summarized that (i) the use of vitamin E is associated with a decrease in aminotransferases in subjects with NASH; (ii) studies where histologic end points were evaluated indicate that vitamin E causes improvement in steatosis, inflammation, and ballooning and resolution of steatohepatitis in adults with NASH; and (iii) vitamin E has no effect on hepatic fibrosis. Although two meta-analyses (8,129) failed to observe significant histological benefits with vitamin E in patients with NASH, these analyses were conducted before PIVENS (122) and TONIC (treatment of non-alcoholic fatty liver disease in children) (130) trials were published. In the largest clinical trial (PIVENS) (122) reported to date, the pure form of rrrα-tocopherol was orally administered at a dose of 800 IU/day for 96 weeks. The primary end point as stated previously was achieved in a significantly greater number of participants receiving vitamin E compared with placebo (42 vs. 19%, P<0.001, number needed to treat=4.4). One concern with vitamin E is the controversial issue of whether it increases all-cause mortality. Some meta-analyses have reported an increase in all-cause mortality with high-dose vitamin E (131,132), but others failed to confirm such an a
