Nonalcoholic Fatty Liver Disease

It has been 35 years since the term nonalcoholic steatohepatitis (NASH) was first coined to describe “a poorly understood and hitherto unnamed liver disease that histologically mimics alcoholic hepatitis and that also may progress to cirrhosis…” for which “…currently, we know of no effective therapy.”[1] Since then, the recognition that fatty liver disease occurring in the absence of high alcohol consumption represents a broader spectrum of severity, from steatosis, through NASH to fibrosis/cirrhosis and on to hepatocellular carcinoma (HCC) has led to the term nonalcoholic fatty liver disease (NAFLD) being widely adopted to encompass all grades and stages of disease. Importantly, in the intervening years it has also become apparent that NAFLD is no minor condition whose description is restricted to small case series; it has rapidly become the most common cause of liver dysfunction in many developed and developing countries,[2] [3] and is projected to be the principal underlying etiology for liver transplantation within a decade.[4] [5] Indeed, evidence from North America indicates that this may already have occurred in some populations.[6] It is however salutatory to note that, although there are currently several promising agents in trials, it remains true that there still are no established pharmacological treatments available.

Recognition of the importance of NAFLD and the increasing health care burden associated with the treatment of affected patients has prompted formation of large international consortia to address the need for better understanding of pathophysiology, development of tools for diagnosis/risk stratification, and targeted therapies. These include the NIDDK NASH Clinical Research Network (www.jhuccs1.us/nash/) in the United States, and in Europe first the FLIP: Fatty Liver Inhibition of Progression Consortium and subsequently the EPoS: Elucidating Pathways of Steatohepatitis consortium (www.epos-nafld.eu). This latter consortium is notable in that it unites clinician–scientists drawn from several relevant medical specialties (including hepatology, metabolic medicine, and diabetology) with basic scientists to address key translational knowledge gaps. The authorship list from this edition of Seminars in Liver Disease includes international experts, many of whom are members of these consortia, each providing a state-of-the-art review of their respective fields. Rather than listing the articles in the order that they appear, we will here briefly summarize them and highlight synergies and common themes that they address, with reference to the scientific and clinical challenges that NAFLD poses.

Nonalcoholic fatty liver disease is a disease that is marked by substantial interindividual variation in disease progression, overall natural history, and outcomes.[7] Much progress has been made in our understanding of the natural history of NAFLD and its pathophysiology, from the linear two-hit hypothesis[8] to more recent data from dual-biopsy studies[9] [10] and histologically based long-term follow-up studies.[11] These suggest that the transition from steatosis to steatohepatitis is bidirectional and much more dynamic than had previously been considered, with long-term studies suggesting that it is fibrosis stage rather than presence of steatohepatitis that has the greatest prognostic value.[11] [12] The current understanding of disease natural history and the relevance of progression from steatosis or steatohepatitis to fibrosis are discussed by Satapathy and Sanyal,[13] whereas Pocha et al consider the role of NAFLD as a premalignant condition leading to the development of HCC.[14] Expanding these themes, it is noteworthy that the majority of patients that have NAFLD will die not of liver disease, but of extrahepatic diseases (e.g., cardiovascular disease and renal disease).[7] This may perhaps explain why NAFLD has for some time been erroneously regarded as simply an epiphenomenon of the metabolic syndrome by many diabetologists. Vanni et al review the literature describing extrahepatic manifestations of NAFLD and in particular the association with metabolic syndrome, type 2 diabetes, and cardiovascular disease.[15] They also highlight how in recent years this perspective has altered through the combined research efforts of researchers drawn from all relevant disciplines, determining that NAFLD itself confers an increased risk of developing metabolic syndrome and its complications beyond established predictors. Concluding this section, Vacca et al focus on the early events of the pathophysiology of NASH, dissecting the metabolic and nutritional pathways involving fatty acids and glucose sensors that can modulate lipid accumulation in the liver but also condition the progression to cirrhosis and HCC.[16]

Underlying the variation in disease outcomes that have been discussed, NAFLD is best considered a complex disease trait that occurs when environmental exposures (including diet and the intestinal flora) act upon a susceptible polygenic background composed of multiple independent modifiers. Of the many technological advances that have occurred since NASH was first described, the publication of the draft human genome heralded major advances in our understanding of human genomic variation, and through efforts such as the International HapMap Project, paved the way for the genome-wide association studies (GWASs) that followed. The two best-validated genetic variants that contribute to the observed interindividual variation in NAFLD progression lie within the genes PNPLA3 and TM6SF2. Variants in both genes have been robustly associated with disease progression from steatosis to advanced fibrosis/cirrhosis,[17] [18] [19] [20] [21] whereas PNPLA3 has also been associated with increased HCC risk.[22] The function of these genes and the pathophysiological consequences of the variant forms are the subject of considerable ongoing research interest, which we review in detail.[23] Complementary to this is the exciting and relatively new field exploring “our other genome,” the intestinal microbiome.[24] Similar technological advances to those that have underpinned the study of human genetics, have enabled this field of study through the development of rapid, high-throughput sequencing systems that permit the identification of all of the microbial constituents of the gut and the advent of supporting metagenomic and metabolomic approaches.[25] Quigley et al provide a comprehensive translational review of this field and its relevance to NAFLD.[26]

Completing this special issue of the journal, four clinically focused articles discuss diagnosis/risk stratification and clinical management. Since Ludwig et al first described NASH,[1] characteristic histopathological features of hepatic fat accumulation and steatohepatitis have been recognized; however, clear definitions of histopathological components have been lacking and have led to significant interobserver variations in making a diagnosis of steatohepatitis. As well as providing an introduction to the issue, the article by Burt et al[27] addresses these points and provides an update on histopathological prognostic factors, the robust clinically relevant grading and staging systems available, and also addresses the role of liver biopsy in contemporary clinical care of patients with NAFLD. A major challenge that has hampered the identification of patients with NAFLD and the conduct of clinical trials in this field has been the reliance on invasive testing by liver biopsy to secure a diagnosis and accurately grade/stage the disease.[28] The current state of noninvasive testing for NAFLD, to characterize degree of steatosis, presence of steatohepatitis and stage of fibrosis are comprehensively reviewed by Castera.[29] Finally, two articles, the first by Nguyen and George addressing the role of lifestyle modification through dietary and exercise interventions,[30] and the second by Gawrieth and Chalasani discussing the current options for pharmacotherapy,[31] provide detailed and authoritative overviews of these important aspects of management. Together they offer insights into what evidence-based therapeutic options should already be implemented to improve disease outcomes and the possible new drug therapies that are in development.

This issue of Seminars in Liver Disease is timely. From a public health perspective, there is a pressing need to address the increasing and often undiagnosed disease burden due to NAFLD in the general population so that health care resources can be appropriately targeted to best effect. To mitigate against this are our increasing understanding of the pathophysiology of the underlying condition and the international collaborative research efforts involving both academia and industry that are underway to better understand these processes. The challenge remains to exploit our knowledge so that it is truly available in the clinic. Much remains to be done, but we do live in interesting times.

• References

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• 2 Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 2010; 53 (2) 372-384
• 3 Das K, Das K, Mukherjee PS , et al. Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease. Hepatology 2010; 51 (5) 1593-1602
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• 9 McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol 2015; 62 (5) 1148-1155
• 10 Pais R, Charlotte F, Fedchuk L , et al; LIDO Study Group. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol 2013; 59 (3) 550-556
• 11 Ekstedt M, Hagström H, Nasr P , et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015; 61 (5) 1547-1554
• 12 Angulo P, Bugianesi E, Bjornsson ES , et al. Simple noninvasive systems predict long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2013; 145 (4) 782-9.e4
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• 19 Kozlitina J, Smagris E, Stender S , et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2014; 46 (4) 352-356
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• 21 Dongiovanni P, Petta S, Maglio C , et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 2015; 61 (2) 506-514
• 22 Liu YL, Patman GL, Leathart JB , et al. Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J Hepatol 2014; 61 (1) 75-81
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