Current efforts and trends in the treatment of NASH

Of all the aspects of non-alcoholic fatty liver disease (NAFLD), the slowest advances have occurred in the therapeutic field. Thirty-five years after its formal description and after 15 years of intense scrutiny from researchers worldwide, there is still no approved drug for the treatment of non-alcoholic steatohepatits (NASH). In the meantime, progress in the understanding of pathophysiology, diagnosis – both invasive and non-invasive, epidemiology and even natural history have been substantial or, at times, spectacular. In contrast, hepatitis C virus (HCV) therapy underwent constant improvement and even before the great acceleration of the past few years, patients were already being offered approved therapies that were increasingly more efficient.What then explains such a slow pace of therapeutic advances in NASH, and will this change in the near future? Here we will review commonly-held myths that have diverted attention from therapy of NASH, obstacles that have slowed down industrial development of drugs for this indication, and recent achievements that will create better conditions for drug development programs. We will also briefly review current knowledge of non-pharmacological and pharmacological management in this early era of NASH therapies. Of all the aspects of non-alcoholic fatty liver disease (NAFLD), the slowest advances have occurred in the therapeutic field. Thirty-five years after its formal description and after 15 years of intense scrutiny from researchers worldwide, there is still no approved drug for the treatment of non-alcoholic steatohepatits (NASH). In the meantime, progress in the understanding of pathophysiology, diagnosis – both invasive and non-invasive, epidemiology and even natural history have been substantial or, at times, spectacular. In contrast, hepatitis C virus (HCV) therapy underwent constant improvement and even before the great acceleration of the past few years, patients were already being offered approved therapies that were increasingly more efficient. What then explains such a slow pace of therapeutic advances in NASH, and will this change in the near future? Here we will review commonly-held myths that have diverted attention from therapy of NASH, obstacles that have slowed down industrial development of drugs for this indication, and recent achievements that will create better conditions for drug development programs. We will also briefly review current knowledge of non-pharmacological and pharmacological management in this early era of NASH therapies. Several long-held myths have considerably slowed the development of drugs for non-alcoholic steatohepatits (NASH). Because non-alcoholic fatty liver disease (NAFLD) implies the presence of steatosis, and steatosis was historically considered a benign lesion, many physicians did not perceive NASH as a disease of concern. It was seen as a generally benign manifestation of obesity or at most a complication of diabetes with questionable clinical relevance. Most practicing diabetologists did not see and still do not see their diabetic patients when they develop cirrhosis or liver-related mortality. This generated a lack of attention for NASH as a disease worth diagnosing, investigating and treating. Consequently, most of the new and innovative drugs intended to correct insulin resistance were developed for a diabetic indication. Yet observational studies of large cohorts of diabetic patients became available and showed that diabetic patients can die of liver disease [1de Marco R. Locatelli F. Zoppini G. Verlato G. Bonora E. Muggeo M. Cause-specific mortality in type 2 diabetes. The Verona Diabetes Study.Diabetes Care. 1999; 22: 756-761Crossref PubMed Scopus (234) Google Scholar, 2Adams L.A. Harmsen S. St Sauver J.L. Charatcharoenwitthaya P. Enders F.B. Therneau T. et al.Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study.Am J Gastroenterol. 2010; 105: 1567-1573Crossref PubMed Scopus (94) Google Scholar]. Competing risk from other causes of death and the slowly evolving course of chronic liver disease explains why, in absolute values, liver-related mortality is considerably less frequent than death from cardiovascular or neoplastic causes. However, having diabetes still increases the risk of death from cirrhosis to the same or even a larger extent than that of death from the other associated diseases [[3]Zoppini G. Fedeli U. Gennaro N. Saugo M. Targher G. Bonora E. Mortality from chronic liver diseases in diabetes.Am J Gastroenterol. 2014; 109: 1020-1025Crossref PubMed Scopus (15) Google Scholar]. For instance, the standardized mortality ratio for liver cirrhosis (adjusted for multiple confounders) was 2.33 (CI 1.99–2.73) for men and 2.59 (2.15–3.12) for women, while that for ischemic heart disease was 2.11 (2.05–2.16) and 2.46 (2.39–2.53), respectively [[4]Campbell P.T. Newton C.C. Patel A.V. Jacobs E.J. Gapstur S.M. Diabetes and cause-specific mortality in a prospective cohort of one million U.S. adults.Diabetes Care. 2012; 35: 1835-1844Crossref PubMed Scopus (73) Google Scholar]. It may be anticipated that better prevention of cardiovascular death and improved screening programs for neoplasia will result in the emergence of increased liver-related mortality in a population of ageing diabetics. A precedent for this shift in the causes of death was witnessed during the AIDS epidemic when a better control of opportunistic infections allowed chronic viral hepatitis to emerge as a major threat. Even though patients with diabetes can have cirrhosis of different etiologies, non-alcoholic, non-viral cirrhosis accounts for most causes of cirrhosis-related death [[3]Zoppini G. Fedeli U. Gennaro N. Saugo M. Targher G. Bonora E. Mortality from chronic liver diseases in diabetes.Am J Gastroenterol. 2014; 109: 1020-1025Crossref PubMed Scopus (15) Google Scholar]. Equally relevant, death from primary liver cancer almost mirrors the rising risk and prevalence of cirrhosis in diabetics outlined above [[5]Seshasai S.R. Kaptoge S. Thompson A. Di Angelantonio E. Gao P. Sarwar N. et al.Diabetes mellitus, fasting glucose, and risk of cause-specific death.N Engl J Med. 2011; 364: 829-841Crossref PubMed Scopus (667) Google Scholar]. These findings are important as they demonstrate the existence of the unmet medical need for effective therapy in patients with NASH, a concept long overlooked by physicians other than hepatogastroenterologists from a tertiary care settings. Appreciation of this medical need is required before the considerable financial risk and human effort needed for successful NASH drug development programs will be undertaken. Another misconception that is consubstantial to the view of NASH simply as a complication of diabetes, is that antidiabetic drugs, if successful in controlling diabetes will suffice to curb the course of NASH, hence making NASH-specific therapy unnecessary. This argument ignores the fact that most NASH patients do not have uncontrolled diabetes, and that the three most commonly used drugs in type 2 diabetes, namely metformin, sulfamides and insulin are totally ineffective for NASH. Similarly, since most NAFLD patients are overweight, do not eat healthy diets and do not exercise enough [6Zelber-Sagi S. Nitzan-Kaluski D. Goldsmith R. Webb M. Blendis L. Halpern Z. et al.Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population based study.J Hepatol. 2007; 47: 711-717Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 7Zelber-Sagi S. Nitzan-Kaluski D. Goldsmith R. Webb M. Zvibel I. Goldiner I. et al.Role of leisure-time physical activity in nonalcoholic fatty liver disease: a population-based study.Hepatology. 2008; 48: 1791-1798Crossref PubMed Scopus (106) Google Scholar], many in the field believe that diet and lifestyle modifications but not sophisticated pharmacological approaches are a reasonable (and cheaper and safer) choice. By this reasoning, it would be better to spend the same effort but only a fraction of the resources necessary to bring drugs to the market in implementing these lifestyle changes in NASH patients. However, even in the context of a clinical trial, in which incentive and monitoring are maximized, patients are typically unable to sustain the assigned dietary goals and the initial weight loss [[8]Sacks F.M. Bray G.A. Carey V.J. Smith S.R. Ryan D.H. Anton S.D. et al.Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates.N Engl J Med. 2009; 360: 859-873Crossref PubMed Scopus (771) Google Scholar]. Exceptions to this observation are rare, although occasionally young patients naive to medical intervention do achieve the desired weight loss with ensuing hepatic improvement. By contrast, most patients who seek hepatological advice have a long history of unsuccessful attempts at dietary and lifestyle changes [[9]Dansinger M.L. Tatsioni A. Wong J.B. Chung M. Balk E.M. Meta-analysis: the effect of dietary counseling for weight loss.Ann Intern Med. 2007; 147: 41-50Crossref PubMed Google Scholar]. The considerable effort and resources necessary to increase patient compliance are beyond the means and expertise of most hepatological centers [[10]Bellentani S. Dalle Grave R. Suppini A. Marchesini G. Behavior therapy for nonalcoholic fatty liver disease: the need for a multidisciplinary approach.Hepatology. 2008; 47: 746-754Crossref PubMed Scopus (129) Google Scholar], and therefore there is little chance for a better outcome than that achieved by specialists with expertise in nutrition, diabetes or endocrinology. Finally, while these conceptual obstacles had started to subside, a different theoretical concern emerged as a potential deterrent to the development of specific drug therapy for NASH. Specifically, it was suggested that large clinical trials in NASH might be impractical because of the requirement of histological documentation, both for inclusion and for assessing of therapeutic efficacy. However, recent developments have again proved this wrong. Several phase 2b trials of reasonably large sample size have been initiated and recruited fully (Table 1), showing that the medical need and patient and caregiver expectations are high enough to overcome the hurdle of liver biopsy (Fig. 2).Table 1Recently completed and ongoing randomized controlled trails for NASH.∗www.clinicaltrials.gov accessed on February 9th 2015. Open table in a new tab Fig. 2Registered interventional trials for adult NASH. Open studies. Data downloaded from www.clinicaltrials.gov on Feb 9th 2015.View Large Image Figure ViewerDownload Hi-res image Download (PPT) ∗www.clinicaltrials.gov accessed on February 9th 2015. Even when the myths surrounding drug development in NASH will have largely disappeared, real obstacles will still stand in the way. One of these stems from our current level of understanding of the pathogenesis of NASH. A multitude of potential pathogenic pathways along with their regulators have been described (Fig. 3), all of them able to alter the histologic and metabolic phenotype of a diet-induced insulin resistant rodent. Each one of these could be an attractive target for therapy. In fact, disappointingly, most of these potential pharmacological targets fail to materialize into human drug candidates either because of insufficient potency to curb the progression of human disease or because of alternate or duplicate pathways that rescue the NASH phenotype. PDE4 inhibitors [[11]Ratziu V. Bedossa P. Francque S.M. Larrey D. Aithal G.P. Serfaty L. et al.Lack of efficacy of an inhibitor of PDE4 in phase 1 and 2 trials of patients with nonalcoholic steatohepatitis.Clin Gastroenterol Hepatol. 2014; 12: 1724-1730Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar], selective caspase inhibitors [[12]Ratziu V. Sheikh M.Y. Sanyal A.J. Lim J.K. Conjeevaram H. Chalasani N. et al.A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis.Hepatology. 2012; 55: 419-428Crossref PubMed Scopus (56) Google Scholar], resveratrol [13Yoshino J. Conte C. Fontana L. Mittendorfer B. Imai S. Schechtman Kenneth B. et al.Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance.Cell Metab. 2012; 16: 658-664Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 14Chachay V.S. Macdonald G.A. Martin J.H. Whitehead J.P. O’Moore-Sullivan T.M. Lee P. et al.Resveratrol does not benefit patients with nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol. 2014; 12: e2096Abstract Full Text Full Text PDF Scopus (14) Google Scholar], omega 3 fatty acid preparations [[15]Sanyal A.J. Abdelmalek M.F. Suzuki A. Cummings O.W. Chojkier M. No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial.Gastroenterology. 2014; 147: e371Abstract Full Text Full Text PDF Scopus (7) Google Scholar], anti-TNF alpha and probiotics, are examples of drugs that work well only in rodent models of NASH. Related to these failures is our inability to test the potency of these molecules in pre-clinical models that faithfully recapitulate in small animals both the spectrum of liver injury in humans (from steatosis to cirrhosis and hepatocellular carcinoma) and the associated metabolic conditions including insulin resistance. Some NASH models do not replicate insulin resistance and related comorbidities (the methionine/choline deficient model); others are genetic oddities that have no equivalent in regular human NASH and might be excessively pathway-dependent (MAT1, PTEN, NEMO deficient mice, ob/ob and db/db knockout mice lacking leptin and thus fibrogenesis); yet others do not fully progress to steatohepatitis and fibrosis (standard high fat diet or high sucrose diets). Although refinements of dietary models exist (Western diet, high fructose, trans fat, atherogenic diet models or a combination thereof) and allow steatohepatitis and early fibrosis to develop within an acceptable time frame of several months, their use for antifibrotic testing in the context of NASH is still not optimal. It follows that only limited predictions for human efficacy are achievable through pre-clinical models. Therefore this mandates early testing in humans, which is a risk multiplier in terms of financial and ethical commitments. To make things worse, most proof of concept trials in NASH need to rely on evidence of histological efficacy; the duration and size of such trials do not provide quick answers on whether a drug candidate for NASH should move forward. All this considerably complicates the drug development process. An important area of progress has been the identification and better understanding of the roles of the various morphological lesions in the natural history of NASH. Ludwig et al. [[16]Ludwig J. Viggiano T.R. McGill D.B. Ott B.J. Nonalcoholic steatohepatitis. Mayo Clinic experiences with a hitherto unnamed disease.Mayo Clin Proc. 1980; 55: 434-438PubMed Google Scholar], who coined the term “non-alcoholic steatohepatitis” defined it as a disease that mimics alcoholic hepatitis and may progress to cirrhosis. Subsequent publications with variable diagnostic criteria for NASH described a range of disease severity from inconsequential to rapidly progressive. This was clarified by Matteoni et al. [[17]Matteoni C.A. Younossi Z.M. Gramlich T. Boparai N. Liu Y.C. McCullough A.J. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.Gastroenterology. 1999; 116: 1413-1419Abstract Full Text Full Text PDF PubMed Scopus (1984) Google Scholar], who reintroduced the term “non-alcoholic fatty liver disease”, (used occasionally before this) to describe the spectrum of clinical and pathological severity in relation to progression to cirrhosis and mortality, which were limited to those whose liver biopsies had hepatocellular ballooning, Mallory-Denk bodies and/or fibrosis. Brunt et al. in 1999 [[18]Brunt E.M. Janney C.G. DiBisceglie A.M. Neuschwander-Tetri B.A. Bacon B.R. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions.Am J Gastroenterol. 1999; 94: 2467-2474Crossref PubMed Scopus (2012) Google Scholar] proposed a three-grade, four-stage system to characterize and stratify the histologic lesions. These advances were further refined in 2005 by the NASH CRN [[19]Kleiner D.E. Brunt E.M. Van Natta M. Behling C. Contos M.J. Cummings O.W. et al.Design and validation of a histological scoring system for nonalcoholic fatty liver disease.Hepatology. 2005; 41: 1313-1321Crossref PubMed Scopus (2843) Google Scholar], which provided operational histologic definitions of NAFLD and NASH and a morphologic tool to measure histological changes (i.e. the NAS score). Both are crucial in the context of clinical trials, as these rely on histology for inclusion and also for assessing treatment effects. Thus, the term steatohepatitis, defined histologically by the association of steatosis, lobular inflammation and hepatocyte ballooning with a predominant centrilobular pattern of distribution has come to be used for a morphological feature with clinical implications. It has been associated with a more severe clinical profile, more advanced insulin resistance and more advanced fibrotic disease than non-NASH NAFLD [[20]Neuschwander-Tetri B.A. Clark J.M. Bass N.M. Van Natta M.L. Unalp-Arida A. Tonascia J. et al.Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease.Hepatology. 2010; 52: 913-924Crossref PubMed Scopus (163) Google Scholar]. It has also been correlated with increased mortality and liver-related events [21Younossi Z.M. Stepanova M. Rafiq N. Makhlouf H. Younoszai Z. Agrawal R. et al.Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality.Hepatology. 2011; 53: 1874-1882Crossref PubMed Scopus (136) Google Scholar, 22Ekstedt M. Franzen L.E. Mathiesen U.L. Thorelius L. Holmqvist M. Bodemar G. et al.Long-term follow-up of patients with NAFLD and elevated liver enzymes.Hepatology. 2006; 44: 865-873Crossref PubMed Scopus (1019) Google Scholar, 23Angulo P. Kleiner D.E. dam-Larsen S. Adams L.A. Bjornsson E. Charatcharoenwitthaya P. et al.Long-term prognostic relevance of liver histology in non-alcoholic fatty liver disease: the PRELHIN study.Hepatology. 2014; 60: 226AGoogle Scholar], which provides justification for use as a selection criterion for participants in drug therapy trials. The NAS score may be used to characterize the lesions, but it must be remembered that as defined by the NASH CRN, [[24]Brunt E.M. Kleiner D.E. Wilson L.A. Belt P. Neuschwander-Tetri B.A. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings.Hepatology. 2011; 53: 810-820Crossref PubMed Scopus (215) Google Scholar] the diagnosis of steatohepatitis is a matter of pattern of injury and not of a score. Unfortunately, the NAS is not predictive of clinical outcomes [21Younossi Z.M. Stepanova M. Rafiq N. Makhlouf H. Younoszai Z. Agrawal R. et al.Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality.Hepatology. 2011; 53: 1874-1882Crossref PubMed Scopus (136) Google Scholar, 25Ekstedt M. Franzen L.E. Mathiesen U.L. Kechagias S. Low clinical relevance of the nonalcoholic fatty liver disease activity score (NAS) in predicting fibrosis progression.Scand J Gastroenterol. 2012; 47: 108-115Crossref PubMed Scopus (12) Google Scholar, 26Ekstedt M. Hagstrom H. Nasr P. Fredrikson M. Stal P. Kechagias S. et al.Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.Hepatology. 2015; ([in press])https://doi.org/10.1002/hep.27368Crossref PubMed Scopus (82) Google Scholar], and therefore changes in NAS on therapy are probably not an adequate outcome surrogate. This of course does not mean that it cannot be used to measure the histological impact of different therapies; it simply may not be sufficient as a predictor of clinical benefit, and therefore its use for registration purposes is uncertain. Recently a new histological classification was proposed by a panel of pathologists from the FLIP consortium. The FLIP algorithm and the SAF score were initially described and validated in a large population of morbidly obese patients undergoing bariatric surgery [[27]Bedossa P. Poitou C. Veyrie N. Bouillot J.L. Basdevant A. Paradis V. et al.Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients.Hepatology. 2012; 56: 1751-1759Crossref PubMed Scopus (66) Google Scholar] and later in a NASH hepatological population [[28]Bedossa P. Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease.Hepatology. 2014; 60: 565-575Crossref PubMed Scopus (29) Google Scholar]. Clinical correlates with the metabolic profile and disease severity have also been reported [[29]Nascimbeni F. Bedossa P. Fedchuck L. Pais R. Lebray P. Poynard T. et al.Clinical validation of the FLIP algorithm and SAF score in non-alcoholic fatty liver disease.J Hepatol. 2014; 60: S348Abstract Full Text PDF Google Scholar], although outcome studies are not yet available. This classification system uses a standardized definition of the elementary histological lesions and has been shown to increase agreement for the diagnosis of NASH between hepatopathologists with different levels of expertise [[28]Bedossa P. Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease.Hepatology. 2014; 60: 565-575Crossref PubMed Scopus (29) Google Scholar]. It remains to be seen how this will be applied in clinical trials. Another major advance is in the regulatory field (Table 2). Both the European and the American drug agencies now agree that NASH is a valid indication for therapy and as such, it can follow a regulatory path for drug approval. There is a need to develop therapeutics even in early stage NASH, especially in those patients at risk of progression [[30]Sanyal A.J. Friedman S.L. McCullough A.J. Dimick L. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an american association for the study of liver diseases (aasld) – food and drug administration (fda) joint workshop.Hepatology. 2015; ([in press])https://doi.org/10.1002/hep.27678Crossref Scopus (31) Google Scholar]. Trial outcomes with clinical and regulatory value have been defined and are currently being used in several large trials of new drugs in NASH [30Sanyal A.J. Friedman S.L. McCullough A.J. Dimick L. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an american association for the study of liver diseases (aasld) – food and drug administration (fda) joint workshop.Hepatology. 2015; ([in press])https://doi.org/10.1002/hep.27678Crossref Scopus (31) Google Scholar, 31Sanyal A.J. Brunt E.M. Kleiner D.E. Kowdley K.V. Chalasani N. Lavine J.E. et al.Endpoints and clinical trial design for nonalcoholic steatohepatitis.Hepatology. 2011; 54: 344-353Crossref PubMed Scopus (181) Google Scholar]. Given the high unmet medical need, the concept of accelerated approval followed by confirmation in outcome trials appears legitimate [[30]Sanyal A.J. Friedman S.L. McCullough A.J. Dimick L. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an american association for the study of liver diseases (aasld) – food and drug administration (fda) joint workshop.Hepatology. 2015; ([in press])https://doi.org/10.1002/hep.27678Crossref Scopus (31) Google Scholar]. This is a big change from the previously held perception of NASH as a disease without a clear regulatory approval process. By ensuring technical feasibility of the registration pathway, it will certainly provide a big boost to all stakeholders in the industry-sponsored drug development programs. But most importantly, it will provide confidence to patients and caregivers that therapeutic options will be available to those who need them.Table 2Progress and continuing challenges facing the NASH pipeline. Open table in a new tab NAFLD patients have unhealthy dietary intakes characterized by overconsumption of fructose and soft drinks, lower consumption of fiber, overconsumption of meat, saturated fat and cholesterol, lower consumption of fish or omega-3 fatty acids or PUFA, and low consumption of some vitamins [6Zelber-Sagi S. Nitzan-Kaluski D. Goldsmith R. Webb M. Blendis L. Halpern Z. et al.Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population based study.J Hepatol. 2007; 47: 711-717Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 32Zelber-Sagi S. Ratziu V. Oren R. Nutrition and physical activity in NAFLD: an overview of the epidemiological evidence.World J Gastroenterol. 2011; 17: 3377-3389Crossref PubMed Scopus (95) Google Scholar, 33Ouyang X. Cirillo P. Sautin Y. McCall S. Bruchette J.L. Diehl A.M. et al.Fructose consumption as a risk factor for non-alcoholic fatty liver disease.J Hepatol. 2008; 48: 993-999Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar]. A high fructose consumption, possibly industrial fructose only (not fruit fructose) [[34]Petta S. Marchesini G. Caracausi L. Macaluso F.S. Cammà C. Ciminnisi S. et al.Industrial, not fruit fructose intake is associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients.J Hepatol. 2013; 59: 1169-1176Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar], increases the risk of fibrosis in NASH patients [[35]Abdelmalek M.F. Suzuki A. Guy C. Unalp-Arida A. Colvin R. Johnson R.J. et al.Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease.Hepatology. 2010; 51: 1961-1971Crossref PubMed Scopus (224) Google Scholar]. There seems to be some controversy, however, as to whether the excess risk is not in fact conferred by an excess caloric intake (irrespective of the type of sugars) [36Chiu S. Sievenpiper J.L. de Souza R.J. Cozma A.I. Mirrahimi A. Carleton A.J. et al.Effect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials.Eur J Clin Nutr. 2014; 68: 416-423Crossref PubMed Scopus (50) Google Scholar, 37Sievenpiper J.L. de Souza R.J. Mirrahimi A. Yu M.E. Carleton A.J. Beyene J. et al.Effect of fructose on body weight in controlled feeding trials: a systematic review and meta-analysis.Ann Intern Med. 2012; 156: 291-304Crossref PubMed Google Scholar] or confounded by an unhealthy lifestyle pattern that includes smoking, lack of exercise, diets rich in fat and poor in fiber etc [[38]Chiavaroli L. Ha V. Kendall C.W. Sievenpiper J.L. Is industrial fructose just a marker of an unhealthy dietary pattern?.J Hepatol. 2014; 61: 172-173Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Well designed, prospective studies accounting for multiple confounders are necessary to better establish the epidemiological basis for this association. Nonetheless, interventional data in animals have shown that while high fat diet alone only induces steatosis, high fat diet + high sucrose diets induce steatohepatitis, inflammation oxidative stress and fibrosis [[39]Ishimoto T. Lanaspa M.A. Rivard C.J. Roncal-Jimenez C.A. Orlicky D.J. Cicerchi C. et al.High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinase.Hepatology. 2013; 58: 1632-1643Crossref PubMed Scopus (41) Google Scholar]. In overweight/obese individuals, dietary fructose specifically increases de novo lipogenesis, promotes dyslipidemia, increases insulin resistance and increases visceral adiposity [[40]Stanhope K.L. Schwarz J.M. Keim N.L. Griffen S.C. Bremer A.A. Graham J.L. et al.Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans.J Clin Invest. 2009; 119: 1322-1334Crossref PubMed Scopus (615) Google Scholar]; other studies however did not confirm that fructose is metabolically more deleterious than other sugars like glucose [[41]Johnston R.D. Stephenson M.C. Crossland H. Cordon S.M. Palcidi E. Cox E.F. et al.No difference between high-fructose and high-glucose diets on liver triacylglycerol or biochemistry in healthy overweight men.Gastroenterology. 2013; 145: e1012Google Scholar]. There are very few RCTs of dietary interventions on liver injury in NASH patients. In a well conducted but small RCT, 32 NASH patients were randomized to receive complex, intensive lifestyle intervention or basic education about a healthy lifestyle (controls) over a 48-week period [[42]Promrat K. Kleiner D.E. Niemeier H.M. Jackvony E. Kearns M. Wands J.R. et al.Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.Hepatology. 2010; 51: 121-129Crossref PubMed Scopus (370) Google Scholar]. The active arm e