NAFLD: Old Issues and Emerging Concepts

This volume of Seminars is devoted to some issues that have emerged recently with regard to nonalcoholic fatty liver disease (NAFLD). Recognized as a distinct entity 30 years ago, NAFLD remains a hot research topic due to its wide dissemination and its deep cardiometabolic entanglements, and almost every issue once held as a cornerstone has been repeatedly challenged over time.

In the first article, pathologists David Kleiner and Elizabeth Brunt revisit basic concepts regarding histologic patterns in NAFLD and nonalcoholic steatohepatitis (NASH). NASH is a pathologic definition and as such, the criteria should be reproducible and have prognostic value, allowing reliable identification of patients at increased risk of progressive liver disease. This need has always had to confront the paucity of prospective studies assessing the natural history of NAFLD histologic subtypes.[1] Evidence emerging in 2011 questioned the widespread use of the NAFLD activity score (NAS), a composite score of steatosis, lobular inflammation and hepatocyte ballooning severity, ranging from 0 to 8, to define NASH. Specifically, new studies demonstrated that a NAS ≥ 5 does not predict liver disease progression to cirrhosis and liver-related mortality, thereby suggesting this cutoff should not be used to select NAFLD patients at higher liver-related risk for therapeutic trials.[2] [3] The NAS score was created to monitor treatment response and not as a diagnostic category for NASH, which consists of a specific pattern of elementary histologic lesions. In an attempt to redirect future research, a recent consensus stated the primary endpoints for clinical trials in NASH should be resolution of steatohepatitis or a minimum of 2-point improvement in NAS, with at least one point improvement in more than one category and no worsening of fibrosis.[4] Importantly, NASH resolution can be achieved in < 50% of patients with available treatments,[5] and the prognostic value of a two-point improvement in whatever category of NAS is currently uncertain, as different histologic features of NASH may differentially affect liver disease progression in these patients.

In the second article, Professor Yilmaz from Istanbul discusses the evidence and pathogenic connections of NAFLD unrelated to metabolic syndrome. Traditionally thought to be the hepatic manifestation of the metabolic syndrome (MetS), NAFLD can be encountered without the MetS in 20 to 80% of cases, and recent evidence provided by this author and his associates clearly showed that MetS-unrelated NAFLD may have distinct epidemiology, putative pathogenetic mechanisms, and risk factors for disease progression. The finding of increased hemoglobin levels as a predictor of liver disease severity is intriguing and warrants confirmation in independent cohorts of different ethnicities.

In the third article, Professor Chalasani and colleagues provide a comprehensive overview of lipid-lowering drugs in NAFLD. Although lipid metabolism affects many aspects of liver disease pathogenesis and of NAFLD-related cardiovascular risk, to date very few trials assessed the effects of lipid-lowering drugs on liver disease activity in NASH.[5] The recent experimental evidence that cholesterol synthesis and absorption affects liver damage in NASH and data from large randomized trials, including the GREACE trial, suggest that lipid-lowering drugs may warrant assessment in a large randomized controlled trial with histologic endpoints.[6] [7]

In the next review, Torres and Harrison from Fort Sam Houston, Texas, provide a state-of-the art review on the emerging problem of hepatocellular carcinoma (HCC) in noncirrhotic NASH. The incidence rates of HCC are exponentially growing all over the world and are only partially attributable to increased numbers of NASH cirrhotics. Recent evidence suggested NAFLD may directly promote hepatic carcinogenesis independent of cirrhosis, through mechanisms that are comprehensively discussed by the authors.

Next, Patrick Northup et al, from the Coagulation in Liver Disease Study Group, provides a balanced and comprehensive overview of the evidence, mechanisms, and therapeutic implications of coagulation disorders in NAFLD. When considering cardiovascular risk in NAFLD, we commonly think of arteriosclerosis and arterial vascular events, but the chronic low-grade inflammation may also predispose to venous thrombosis, even in noncirrhotic patients. Possible methods to assess thrombophilic risk of these patients are also discussed.

In the sixth review, Musso, Olivetti, Cassader, and Gambino from Turin discuss the evidence and mechanisms connecting chronic intermittent hypoxia (CIH) and obstructive sleep apnea syndrome (OSAS) to the pathogenesis and severity of NAFLD. The relevance of OSAS for the pathogenesis and aggravation of diabetes, hypertension, and cardiovascular disease has been recently recognized and animal models suggest CIH may represent a silent, hidden, injurious, and fibrogenic factor in NASH. Despite growing experimental evidence connecting these two conditions, the extensive heterogeneity in methods and definitions in human studies prevents any firm causal inference at present, but indicate a need for future study.

The last two reviews in the volume are devoted to two therapeutic measures placed at the opposite extremes of NASH treatment, which can complement each other[8]: physical exercise and bariatric surgery.

Physical exercise improves cardiometabolic profile independently of weight loss in at-risk populations, and evidence from a recent randomized trial suggests it also independently decreases liver fat content, although effects on liver histology remain unknown.[5] In their article, Johnson et al from the Sydney group review the effect of acute and regular exercise on metabolism, including hepatic and extrahepatic glucose and lipid homeostasis, and the available human trials in NAFLD. They also highlight the challenges in implementing exercise programs in daily clinical practice and suggest possible solutions.

Finally, Rabl and Campos discuss the effects of bariatric surgery in NASH. Bariatric surgery has proven to be safe and highly effective at ameliorating obesity, diabetes, and cardiovascular risk, and retrospective evidence also suggests that it leads to histologic improvement in NASH. The authors discuss data from human studies, and detail the impact of different techniques on liver disease. They also thoroughly review proposed mechanisms of action of bariatric surgery in NAFLD, which include not only weight loss, but a rearrangement in gut, pancreatic, and adipocyte hormone networks. Clearly, further well-designed prospective randomized trials are warranted to clarify the place of surgery in the treatment of NASH.

In closing, I greatly enjoyed working on this issue. I want to thank the authors and Editor, Professor Berk, for their commitment to improving the health of patients with NAFLD. Their efforts to match routine clinical work with research, two activities, which although often hard to reconcile, are complementary, and are likely to yield the greatest benefit for patients.

• References

• 1 Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011; 43 (8) 617-649
• 2 Ekstedt M, Franzén LE, Mathiesen UL, Kechagias S. Low clinical relevance of the nonalcoholic fatty liver disease activity score (NAS) in predicting fibrosis progression. Scand J Gastroenterol 2012; 47 (1) 108-115
• 3 Younossi ZM, Stepanova M, Rafiq N , et al. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology 2011; 53 (6) 1874-1882
• 4 Sanyal AJ, Brunt EM, Kleiner DE , et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 2011; 54 (1) 344-353
• 5 Musso G, Cassader M, Rosina F, Gambino R.. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia 2012; ; January 27 [Epub ahead of print] DOI 10.1007/s00125-011-2246-4
• 6 Enjoji M, Nakamuta M. Is the control of dietary cholesterol intake sufficiently effective to ameliorate nonalcoholic fatty liver disease?. World J Gastroenterol 2010; 16 (7) 800-803
• 7 Athyros VG, Tziomalos K, Gossios TD , et al; GREACE Study Collaborative Group. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet 2010; 376 (9756) 1916-1922
• 8 Livhits M, Mercado C, Yermilov I , et al. Exercise following bariatric surgery: systematic review. Obes Surg 2010; 20 (5) 657-665