Clinical Practice GuidelinesEASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease☆
Introduction
The Clinical Practice Guidelines propose recommendations for the diagnosis, treatment and follow-up of non-alcoholic fatty liver disease (NAFLD) patients and are the product of a joint effort by the European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) and European Association for the Study of Obesity (EASO). They update a position statement based on the 2009 EASL Special Conference [1].
The data have been retrieved by an extensive PubMed search up to April 2015. The final statements are graded according to the level of evidence and strength of recommendation, which are adjustable to local regulations and/or team capacities (Table 1) [2]. In particular, screening for NAFLD in the population at risk should be in the context of the available resources, considering the burden for the national health care systems and the currently limited effective treatments. The document is intended both for practical use and for advancing the research and knowledge of NAFLD in adults, with specific reference to paediatric NAFLD whenever necessary. The final purpose is to improve patient care and awareness of the importance of NAFLD, and to assist stakeholders in the decision-making process by providing evidence-based data, which also takes into consideration the burden of clinical management for the healthcare system.
Section snippets
Definition
NAFLD is characterised by excessive hepatic fat accumulation, associated with insulin resistance (IR), and defined by the presence of steatosis in >5% of hepatocytes according to histological analysis or by a proton density fat fraction (providing a rough estimation of the volume fraction of fatty material in the liver) >5.6% assessed by proton magnetic resonance spectroscopy (1H-MRS) or quantitative fat/water selective magnetic resonance imaging (MRI). NAFLD includes two pathologically
Prevalence and incidence
NAFLD is the most common liver disorder in Western countries, affecting 17–46% of adults, with differences according to the diagnostic method, age, sex and ethnicity [4]. It parallels the prevalence of MetS and its components, which also increases the risk of more advanced disease, both in adults and in children. NAFLD is also present in 7% of normal-weight (lean) persons [5], more frequently in females, at a younger age and with normal liver enzymes. Their liver disease may nonetheless be
Pathogenesis: Lifestyle and genes
A high-calorie diet, excess (saturated) fats, refined carbohydrates, sugar-sweetened beverages, a high fructose intake and a Western diet [9] have all been associated with weight gain and obesity, and more recently with NAFLD. High fructose consumption may increase the risk of NASH and advanced fibrosis, although the association may be confounded by excess calorie intake or by unhealthy lifestyles and sedentary behaviour [10], which are more common in NAFLD [11].
Liver biopsy
Liver biopsy is essential for the diagnosis of NASH and is the only procedure that reliably differentiates NAFL from NASH, despite limitations due to sampling variability [19].
NAFL encompasses: a) steatosis alone, b) steatosis with lobular or portal inflammation, without ballooning, or c) steatosis with ballooning but without inflammation [20]. The diagnosis of NASH requires the joint presence of steatosis, ballooning and lobular inflammation [20], [21], [22]. Other histological features can be
Non-invasive assessment
Non-invasive markers should aim to: i) in primary care settings, identify the risk of NAFLD among individuals with increased metabolic risk; ii) in secondary and tertiary care settings, identify those with worse prognosis, e.g. severe NASH; iii) monitor disease progression; iv) predict response to therapeutic interventions. Achieving these objectives could reduce the need for liver biopsy.
Common metabolic disorders related to NAFLD
NAFLD is tightly associated with IR not only in the liver, but also in muscle and adipose tissues [44], and also with the MetS, defined as the cluster of any three of the following five features associated with IR: impaired fasting glucose (IFG) or T2DM, hypertriglyceridaemia, low high-density lipoprotein (HDL)-cholesterol (gender-adjusted), increased waist circumference (ethnicity adjusted) and high blood pressure [45]. As all components of MetS correlate with liver fat content, independently
Diagnostic algorithm and follow-up
The incidental discovery of steatosis should lead to comprehensive evaluation of family and personal history of NAFLD-associated diseases and the exclusion of secondary causes of steatosis. Metabolic work-up has to include a careful assessment of all components of MetS [63]. Similarly, the presence of obesity/T2DM or the incidental finding of raised liver enzymes in patients with metabolic risk factors should prompt non-invasive screening to predict steatosis, NASH and fibrosis (Table 3).
Disease progression
In general, NAFLD is a slowly progressive disease, both in adults and in children, but fibrosis rapidly progresses in 20% of cases [68]. The rate of progression corresponds to 1 fibrosis stage every 14 years in NAFL and every 7 years in NASH, and is doubled by arterial hypertension [68]. NASH is associated with an increased standardized mortality ratio compared with the general population [69] and liver disease is the third most common cause of death after CVD and cancer. US-diagnosed NAFLD is
Treatment
Rationale. Successful treatment of NASH should improve outcomes, i.e. decrease NASH-related mortality, reduce progression to cirrhosis or HCC. The resolution of the histological lesions defining NASH is now accepted as a surrogate endpoint, particularly in clinical trials. Only a few properly designed randomized controlled trials (RCTs) are available, with improvement/regression of hepatic necroinflammation and/or fibrosis as primary outcomes [83], [84], [85], [86], [87], [88], [89], [90], [91]
Liver transplantation
NAFLD-associated cirrhosis is among the top three indications for liver transplantation. The 3- and 5-year survival is not different in NAFLD vs. no-NAFLD; NAFLD carries a higher risk of death from cardiovascular complications and sepsis, whereas the risk of graft failure is lower [145], [146]. The overall mortality is associated with BMI and diabetes, with 50% of cases with BMI >35 kg/m2 dying within 1-year of transplantation [147]. Transplant failure (10% and 45% at 10 and 20 years,
Conflict of interest
Giulio Marchesini declares he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Christopher P. Day declares he has been a consultant/advisor for Abbott Laboratories and Genfit and completed sponsored lectures for Abbott Laboratories.
Jean-François Dufour declares he has been a consultant/advisor for Intercept and Genfit.
Ali Canbay declares he does not have anything to disclose regarding funding or conflict of interest with respect to
Acknowledgements
We would like to thank the reviewers of this Clinical Practice Guideline for their time and critical reviewing: Professor Elisabetta Bugianesi (Department of Medical Sciences, University of Turin, Turin, Italy), Professor Helena Cortez-Pinto (Unidade de Nutrição e Metabolismo, Faculdade de Medicina de Lisboa, Lisbon, Portugal) and Dr. Stephen Harrison (Brooke Army Medical Center, San Antonio, Texas, USA).
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Contributors: Coordinator EASL: Giulio Marchesini; Panel members: Christopher P. Day, Jean-François Dufour, Ali Canbay, Valerio Nobili, Vlad Ratziu, Herbert Tilg; Coordinator EASD: Michael Roden; Panel members: Amalia Gastaldelli, Hannele Yki-Järvinen, Fritz Schick; Coordinator EASO: Roberto Vettor, Panel members: Gema Frühbeck, Lisbeth Mathus-Vliegen.
These Guidelines were developed by the EASL, EASD and the EASO, and are published simultaneously in the Journal of Hepatology, Diabetologia and Obesity Facts.