1. Clinical Practice Guidelines
Non-alcoholic fatty liver disease

2. About these slides
These slides give a comprehensive overview of the EASL clinical practice guidelines on non-alcoholic fatty liver disease
The guidelines were published in full in the June 2016 issue of the Journal of Hepatology
The full publication can be downloaded from the Clinical Practice Guidelines section of the EASL website
Please cite the published article as: EASL–EASD–EASO 2016 Clinical Practice Guidelines on the management of non-alcoholic fatty liver disease. J Hepatol 2016;64:1388–402
Please feel free to use, adapt, and share these slides for your own personal use; however, please acknowledge EASL as the source

3. About these slides
Definitions of all abbreviations shown in these slides are provided within the slide notes
When you see a home symbol like this one: , you can click on this to return to the outline or topics pages, depending on which section you are in
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These slides are intended for use as an educational resource and should not be used in isolation to make patient management decisions. All information included should be verified before treating patients or using any therapies described in these materials

4. Guideline panel Chairs Panel members Reviewers EASL: Giulio Marchesini
EASD: Michael Roden
EASO: Roberto Vettor
Panel members
EASL: Christopher P Day, Jean-François Dufour, Ali Canbay, Valerio Nobili, Vlad Ratziu, Herbert Tilg
EASD: Amalia Gastaldelli, Hannele Yki-Järvinen, Fritz Schick
EASO: Gema Frühbeck, Lisbeth Mathus-Vliegen
Reviewers
Elisabetta Bugianesi, Helena Cortez-Pinto, Stephen Harrison
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

5. Outline Methods Background Guidelines
Grading evidence and recommendations
Methods
Definitions of NAFLD, NAFL and NASH
Background
Key topics and recommendations
Guidelines
NAFL, non-alcoholic fatty liver; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

6. Methods
Grading evidence and recommendations

7. Grading evidence and recommendations
Grading is adapted from the GRADE system1
Grade of evidence
A: High quality
Further research is very unlikely to change our confidence in the estimate effect
B: Moderate quality
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate effect
C: Low/very low quality
Further research is very likely to have an important impact on our confidence in the estimate of effect and may change the estimate effect. Any estimate of effect is uncertain
Grade of recommendation
1: Strong
Factors influencing the strength of the recommendation included the quality of the evidence, presumed patient-important outcomes, and cost
2: Weaker
Variability in preferences and values, or more uncertainty: more likely a weak recommendation is warranted. Recommendation is made with less
certainty; higher cost or resource consumption
GRADE, Grading of Recommendations Assessment Development and Evaluation
1. Chalasani N, et al. Hepatology 2012;55:200523;
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

8. Background Definitions of NAFLD, NAFL and NASH
NAFL, non-alcoholic fatty liver; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis

9. Definitions of NAFLD, NAFL and NASH
Excessive hepatic fat accumulation with IR
Steatosis in >5% of hepatocytes*
Exclusion of secondary causes and AFLD†
NASH
NAFL
Pure steatosis
Steatosis and mild lobular inflammation
Cirrhotic
F4 fibrosis
Fibrotic
≥F2 to ≥F3 fibrosis
Early
F0/F1 fibrosis
HCC
AFLD, alcoholic fatty liver disease; HCC, hepatocellular carcinoma; IR, insulin resistance; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NAFL, non-alcoholic fatty liver; NASH, non-alcoholic steatohepatitis
Definitive diagnosis of NASH requires a liver biopsy
*According to histological analysis or proton density fat fraction or >5.6% by proton MRS or quantitative fat/water-selective MRI;
†Daily alcohol consumption of ≥30 g for men and ≥20 g for women
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

10. Spectrum of NAFLD and concurrent disease
Sub-classification of NAFLD*
Most common concurrent diseases
NAFL
Pure steatosis
Steatosis and mild lobular inflammation
AFLD†
Drug-induced fatty liver disease†
HCV-associated fatty liver disease (GT 3)†
Others†
Haemochromatosis
Autoimmune hepatitis
Coeliac disease
Wilson disease
A/hypo-betalipoproteinaemia lipoatrophy
Hypopituitarism, hypothyroidism
Starvation, parenteral nutrition
Inborn errors of metabolism
Wolman disease (lysosomal acid lipase deficiency)
NASH
Early NASH (no or mild fibrosis)
Fibrotic NASH (significant/advanced fibrosis)
NASH cirrhosis
HCC‡
AFLD, alcoholic fatty liver disease; GT, genotype; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HDL, high-density lipoprotein; MetS, metabolic syndrome; NAFL, non-alcoholic fatty liver; NASH, non-alcoholic steatohepatitis; T2DM, type 2 diabetes mellitus
*Also called primary NAFLD and associated with metabolic risk factors/components of MetS: 1. Waist circumference ≥94/≥80 cm for Europid men/women; 2. Arterial pressure ≥130/85 mmHg or treated for hypertension; 3. Fasting glucose ≥100 mg/dl (5.6 mmol/L) or treated for T2DM; 4. Serum triacylglycerols >150 mg/dl (>1.7 mmol/L); 5. HDL cholesterol <40/50 mg/dl for men/women (<1.0/<1.3 mmol/L); †Also called secondary NAFLD. Note that primary and secondary NAFLD may coexist in individual patients. Also NAFLD and AFLD may coexist in subjects with metabolic risk factors and drinking habits above safe limits; ‡Can occur in the absence of cirrhosis and histological evidence of NASH, but with metabolic risk factors suggestive of ‘‘burned-out” NASH
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

11. Multiple organs are likely to be involved in NAFLD
Pathogenesis of NAFLD probably involves inter-organ crosstalk
Adipose tissue, pancreas, gut, and liver
DAMP, damage-associated molecular pattern; FFA, free fatty acid; HSC, hepatic stellate cell; PAMP, pathogen-associated molecular pattern
Image sourced from Nobili et al. J Hepatol 2013;58:
Nobili, V et al. J Hepatol 2013;58:121829
Copyright © 2013 European Association for the Study of the Liver Terms and Conditions

12. Lipids induce hepatic IR and inflammation
AGAT, acylglycerol- cyltransferase; AGPAT, acylglycerol phosphate acyltransferase; CGI-58, comparative gene identification-58; CYP 2E1, cytochrome P450 2E1; DAG, di-acylglycerol; DGAT, di-acylglycerol acyltransferase; IKKb, IjB kinase b; IR, insulin resistance; IRS-2-P, insulin receptor substrate-2 phosphorylation; JNK, c-Jun N-terminal kinase; LPA, lysophosphatidic acid; GPAT, glycerol-3-phosphate acyltransferase; LCFA, long-chain fatty acid; MAG, mono-acyl glycerol; mTOR, mechanistic target of rapamycin; mTORC-2, mechanistic target of rapamycin complex-2; PA, phosphatidic acid; PAP, phosphatidate phosphohydrolase; PKCe, protein kinase Ce; TAG, tri-acylglycerol; TGRLP, triglyceride-rich lipoprotein; VLDL, very-low-density lipoprotein
Lipid-induced mechanisms contributing to hepatic insulin resistance and inflammation in NAFLD
Synthesis of lipid intermediates from long-chain fatty acids (LCFAs), e.g., ceramide, lyso-phosphatidic acid, phosphatidic acid (PA), di-acylglycerol (DAG), tri-acylglycerol (TAG) and very-low-density lipoprotein (VLDL) secretion. Synthesis of various species of DAG in particular may promote hepatic insulin resistance and inflammation. Synthesis of ceramide may also increase resistance to insulin action by decreasing efficient insulin signaling. (AGAT, acyl glycerol acyl transferase; AGPAT, acylglycerol phosphate acyltransferase; CGI-58, Comparative Gene Identification-58; Cytochrome P450 2E1; CYP 2E1; DGAT, di-acyl glycerol acyl transferase; IKKβ, IκB kinase β; IRS-2-P, insulin receptor substrate-2 phosphorylation; JNK, c-Jun N-terminal kinase; LPA, lysophosphatidic acid; GPAT, glycerol-3-phosphate acyltransferase; MAG, mono-acyl glycerol; mTOR, mechanistic target of rapamycin; mTORC-2, mechanistic target of rapamycin complex-2; PA, phosphatidic acid; PAP, phosphatidate phosphohydrolase; PKCε, protein kinase Cε; TGRLPs, triglyceride-rich lipoproteins).
From: Byrne CD and Targher G. J Hepatol 2015;62:S47-S64
Copyright © 2014 European Association for the Study of the Liver Terms and Conditions
Byrne CD, Targher G. J Hepatol 2015;62:S47–64
Copyright © 2014 European Association for the Study of the Liver Terms and Conditions

13. Guidelines
Key topics and recommendations

14. Click on a topic to skip to that section
Topics
Screening, prevalence and incidence
Pathogenesis: lifestyle and genes
Liver biopsy
Non-invasive assessments
Common related metabolic disorders
Diagnosis
Natural history and complications
Treatment
Diet and lifestyle changes
Drug treatment
Paediatric NAFLD
Surgery
Click on a topic to skip to that section
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

15. Screening, prevalence and incidence
NAFLD is the most common liver disorder in Western countries, affecting 17–46% of adults1
Parallels the prevalence of metabolic syndrome (MetS) and its components, which also increase the risk of more advanced disease
NAFLD is also present in 7% of normal-weight (lean) individuals2
Recommendations
Patients with IR and/or metabolic risk factors (i.e. obesity or MetS) should undergo procedures for the diagnosis of NAFLD A 1
Screen individuals with steatosis for secondary causes of NAFLD, including a careful assessment of alcohol intake. Always consider the interaction between moderate amounts of alcohol and metabolic factors in fatty liver
Identify other chronic liver diseases that may coexist with NAFLD as these might result in more severe liver injury B
Grade of evidence
Grade of recommendation
IR, insulin resistance
1. Vernon G, et al. Aliment Pharmacol Ther 2011;34:27485; 2. Younossi ZM, et al. Medicine 2012;91:31927; EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

16. Screening, prevalence and incidence
Value of screening for NAFLD in the community is limited
High direct and indirect costs
Low predictive value of non-invasive tests
Risks associated with liver biopsy
Lack of effective treatments
Diagnosis of NASH provides important diagnostic information
Points to increased risk of fibrosis progression, cirrhosis and possibly HCC
Recommendations
All individuals with steatosis should be screened for features of MetS, independent of liver enzymes. All individuals with persistently abnormal liver enzymes should be screened for NAFLD A 1
In subjects with obesity or MetS, screening for NAFLD should be part of routine work-up. In high-risk individuals* case finding of advanced disease is advisable 2
Grade of evidence
Grade of recommendation
HCC, hepatocellular carcinoma; MetS, metabolic syndrome; NASH, non-alcoholic steatohepatitis; T2DM, type 2 diabetes mellitus
*Aged >50 years, T2DM, MetS
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

17. Pathogenesis: lifestyle and genes
A Western diet/lifestyle has been associated with weight gain and obesity, and NAFLD1
High calorie intake
Obesity
NAFLD
Excess (saturated) fat
High fructose intake
Sedentary behaviour
Recommendation
Unhealthy lifestyles play a role in the development and progression of NAFLD. The assessment of dietary and physical activity habits is part of comprehensive NAFLD screening A 1
Grade of evidence
Grade of recommendation
1. Barrera F, George J. Clin Liver Dis 2014;18:91–112;
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

18. Pathogenesis: lifestyle and genes
Several genetic modifiers of NAFLD have been identified1
A minority have been robustly validated
PNPLA3 I148M and TM6SF2 E167K carriers have a higher liver fat content*
Increased risk of NASH
NAFLD not systematically associated with features of IR
Recommendation
Genotyping may be considered in selected patients and clinical studies but is not recommended routinely B 2
Grade of evidence
Grade of recommendation
IR, insulin resistance; NASH, non-alcoholic steatohepatitis
*Grade of evidence B, grade of recommendation 2
1. Anstee QM, et al. Nat Rev Gastroenterol Hepatol 2013;10:330–44;
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

19. Progressive liver disease in NAFLD
DAG, di-acylglycerol; Di-P PA, di-palmitoyl phosphatic acid; HCC, hepatocellular carcinoma; LCFA, long-chain fatty acid; TAG, tri-acylglycerol
The influences of visceral ectopic fat accumulation, adipose tissue inflammation, type 2 diabetes, diet and intestinal dysbiosis to promote the development of progressive liver disease in NAFLD
Visceral ectopic fat accumulation, which often occurs with inflammation and type 2 diabetes, causes resistance to insulin action and hepatic necro-inflammation (by Kupffer cell activation) with activation of hepatic stellate cells and increased production of collagen matrix and progression of liver disease. Progression of liver disease over an ill-defined period of time causes advanced liver fibrosis, cirrhosis and, in some cases, hepatocellular carcinoma. Poor diet (particularly high fat and high fructose intakes) along with genetic factors (e.g., PNPLA3 polymorphisms) may also play a role in NAFLD progression increasing hepatic lipid accumulation and increasing risk of liver fibrosis. Alternations in the diet may cause dysbiosis of the gut microbiota with hepato-toxic effects from secondary bile acids. Dysbiosis may alter the production of short-chain fatty acids (from fermentation of dietary carbohydrate), and increase the production of lipopolysaccharide into the portal circulation (from egress of intestinal bacteria caused by increased intestinal permeability). Such effects create a pro-inflammatory hepatic stimulus that increases risk of progression of NAFLD. (DAG, di-acylglycerol; HCC, hepatocellular carcinoma; LCFA, long-chain fatty acid; PNPLA3, patatin-like phospholipase domain-containing 3).
From: Byrne CD, Targher G. J Hepatol 2015;62:S47–64
Copyright © 2014 European Association for the Study of the Liver Terms and Conditions
Byrne CD, Targher G. J Hepatol 2015;62:S47–64
Copyright © 2014 European Association for the Study of the Liver Terms and Conditions

20. Natural history of NAFLD over 8–13 years
Steatosis
NASH 
F1F2
fibrosis
HCC
Death/
LTx
Cirrhosis
Advanced F3
1240%
510%
050% 8%
13%
2550%
14%
25% 7%
HCC, hepatocellular carcinoma; NASH, non-alcoholic steatohepatitis; LTx, liver transplantation
de Alwis NMW, Day CP. J Hepatol 2008;48:S104–12
Copyright © 2008 European Association for the Study of the Liver Terms and Conditions

21. Liver biopsy Liver biopsy is essential for the diagnosis of NASH
Clinical, biochemical or imaging measures cannot distinguish NASH from steatosis
NAFL encompasses
Steatosis alone plus ONE of lobular or portal inflammation OR ballooning
NASH requires
Steatosis AND
Lobular or portal inflammation AND
Ballooning
NAS scoring indicates disease severity*
NAFL, non-alcoholic fatty liver; NASH, non-alcoholic steatohepatitis; NAS, NAFLD Activity Score
Image from Journal of Hepatology 2013 vol. 59 :131–137
Recommendations
NASH has to be diagnosed by a liver biopsy showing steatosis, hepatocyte ballooning and lobular inflammation A 1
Grade of evidence
Grade of recommendation
*Should not be used for initial diagnosis
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

22. Role of non-invasive assessments
Non-invasive markers should aim to:
Identify the risk of NAFLD among individuals with increased metabolic risk in primary care
Identify those with a worse prognosis in secondary and tertiary care
E.g. severe NASH
Monitor disease progression
Predict response to therapeutic interventions
Achieving these aims could reduce the need for liver biopsy
NASH, non-alcoholic steatohepatitis
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

23. Non-invasive assessment of steatosis
Steatosis should be documented whenever NAFLD is suspected
Predicts future T2DM, cardiovascular events and arterial hypertension
Quantification of fat content is of limited clinical relevance
Except as a surrogate of treatment effectiveness
Recommendations
US is the preferred first-line diagnostic procedure for imaging of NAFLD, as it provides additional diagnostic information A 1
Whenever imaging tools are not available or feasible serum biomarkers and scores are an acceptable alternative for the diagnosis of steatosis B 2
A quantitative estimation of liver fat can only be obtained by 1H-MRS. This technique is of value in clinical trials and experimental studies, but is expensive and not recommended in the clinical setting
Grade of evidence
Grade of recommendation
1H-MRS, proton magnetic resonance spectroscopy; T2DM, type 2 diabetes mellitus; US, ultrasound
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

24. Non-invasive assessment of fibrosis
Fibrosis is the most important prognostic factor in NAFLD
Correlates with liver-related outcomes and mortality
Advanced fibrosis indicates thorough investigation
Recommendations
Biomarkers, fibrosis scores, and transient elastography, are acceptable non-invasive procedures to identify those at low risk of advanced fibrosis/cirrhosis A 2
Biomarkers/scores PLUS transient elastography might confer additional diagnostic accuracy and reduce need for liver biopsy B
Monitoring of fibrosis progression may rely on biomarkers/scores and transient elastography, although this strategy requires validation C
The identification of advanced fibrosis or cirrhosis by serum biomarkers/scores and/or elastography is less accurate and needs to be confirmed by liver biopsy, according to the clinical context
In selected patients at high risk of liver disease progression, monitoring should include a repeat biopsy after 5-year follow-up
Grade of evidence
Grade of recommendation
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

25. Potential algorithm for non-invasive assessment: prediction rules and blood-based biomarkers
ALT, alanine aminotransferase; ELF, enhanced liver fibrosis; GGT, gamma-glutamyl transferase; MRE, magnetic resonance elastography; NFS, NAFLD fibrosis score; NPV, negative predictive value; PPV, positive predictive value; VCTE, vibration-controlled transient elastography
Citation for image: Vilar-Gomez and Chalasani J Hepatol 2018: 68:305–15
*Estimated prevalence for low-, intermediate- and high-risk groups
Vilar-Gomez E, Chalasani N. J Hepatol 2018;68:30515
Copyright © 2017 European Association for the Study of the Liver Terms and Conditions

26. Non-invasive assessment of paediatric NAFLD
NAFLD should always be suspected in obese children
Exclude other causes
Evaluate elevated aminotransferase levels and liver hyperechogenicity
Due to the poor sensitivity in overweight/obese children, non-invasive markers and imaging techniques are the first diagnostic step
ALT, alanine aminotransferase; ARFI, acoustic radiation force impulse; CNS, central nervous system
Progression to pediatric NAFLD: what are the possible contributory factors? In this cartoon the normal child (circle; red triangular liver) becomes obese (ellipse indicating central obesity) with a fatty liver (yellow liver) and later more obese with a damaged liver (yellow heterogeneous liver). Initial factors are diet elicting hyperinsulinemia; secondary factors include genetic and environmental (contributing to less physical activity). Determining the relative contribution of direct hepatocellular damage and inflammation in the progression from simple steatosis to chronic liver damage requires more data; likewise the mechanistic importance of decreased serum adiponectin needs further investigation. In principle, this disease mechanism can apply to the normal child who develops fatty liver without becoming technically overweight/obese (circle; yellow liver).
Recommendations
In children, predictors of fibrosis, including elastometry, ARFI imaging and serum biomarkers might help reduce the number of biopsies B 2
Grade of evidence
Grade of recommendation
Roberts EA. J Hepatol 2007;46:113342
Copyright © 2007 European Association for the Study of the Liver Terms and Conditions
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

27. Common related metabolic disorders
NAFLD is closely associated with:
IR in the liver as well as adipose and muscle tissue
MetS
Three of: impaired fasting glucose or T2DM, hypertriglyceridaemia, low HDL-C,* increased waist circumference,† high blood pressure
All components of MetS correlate with liver fat content:
Evaluate risk of NAFLD in patients with MetS
Evaluate MetS in patients with NAFLD
HDL-C, high-density lipoprotein cholesterol; IR, insulin resistance; MetS, metabolic syndrome; T2DM, type 2 diabetes mellitus
*Gender-adjusted; †ethnicity-adjusted
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

28. Common related metabolic disorders
In individuals without diabetes, HOMA-IR can be considered as a surrogate for IR
HOMA-IR:
Fasting glucose (mmol/L) + insulin (mU/ml)
22.5
Recommendations
HOMA-IR can be recommended if proper reference values have been established A 1
HOMA-IR is of limited use for NAFLD diagnosis in patients with metabolic risk factors. It could confirm altered insulin sensitivity, thereby favouring a diagnosis of IR-associated NAFLD in cases of diagnostic uncertainty* B 2
During follow-up, HOMA-IR might help identify patients at risk of NASH or fibrosis progression in selected cases. Improvement of HOMA-IR during weight loss may indicate metabolic improvement C
Grade of evidence
Grade of recommendation
HOMA-IR, Homeostatic Model Assessment of Insulin Resistance; IR, insulin resistance; US, ultrasound
*E.g. US-defined steatosis with normal body weight
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

29. Common related metabolic disorders: obesity
BMI and waist circumference are positively related to NAFLD
Predictors of advanced disease, particularly in the elderly
Recommendations
Follow up is mandatory in obesity, which is the major phenotype and risk condition for NAFLD, driven by IR, and also increases the risk of advanced disease A 1
Most lean individuals with NAFLD display IR and altered body fat distribution even though they have less severe metabolic disturbance than overweight NAFLD. Follow-up is nonetheless required because of possible disease progression B 2
Grade of evidence
Grade of recommendation
BMI, body mass index; IR, insulin resistance
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

30. Common related metabolic disorders: T2DM
Irrespective of liver enzymes, diabetes risk and T2DM are closely associated with:
Severity of NAFLD
Progression to NASH
Presence of advanced fibrosis
Development of HCC
Recommendations
In individuals with NAFLD, screening for diabetes is mandatory, by fasting or random blood glucose or HbA1c… A 1
…and if available, by the standardized 75 g OGTT in high-risk groups B
Look for NAFLD in patients with T2DM, irrespective of liver enzyme levels, due to high risk of disease progression 2
Grade of evidence
Grade of recommendation
HbA1c, glycated haemoglobin; HCC, hepatocellular carcinoma; NASH, non-alcoholic steatohepatitis; OGTT, oral glucose tolerance test; T2DM, type 2 diabetes mellitus
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

31. Diagnosis: protocol for evaluation of NAFLD
Incidental discovery of steatosis indicates comprehensive evaluation
Family and personal history of NAFLD-associated diseases
Exclusion of secondary causes of steatosis
Level
Variable
Initial evaluation
Alcohol intake: <20 g/day (women), <30 g/day (men)
Personal and family history of diabetes, hypertension and CVD
BMI, waist circumference, change in body weight
Hepatitis B/hepatitis C virus infection
History of steatosis-associated drugs
Liver enzymes (ALT, AST, GGT)
Fasting blood glucose, HbA1c, OGTT, (fasting insulin [HOMA-IR])
Complete blood count
Serum total and HDL cholesterol, triacylglycerol, uric acid
Ultrasonography (if suspected for raised liver enzymes)
Extended* evaluation
Ferritin and transferrin saturation
Tests for coeliac and thyroid diseases, polycystic ovary syndrome
Tests for rare liver diseases (Wilson, autoimmune disease, AATD)
AATD, α1-antitrypsin deficiency; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CVD, cardiovascular disease; GGT, gamma-glutamyl transpeptidase; HbA1c, glycated haemoglobin; HDL, high-density lipoprotein; HOMA-IR, Homeostatic Model Assessment of Insulin Resistance; OGTT, oral glucose tolerance test
*According to a priori probability or clinical evaluation
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

32. Diagnosis: diagnostic flow-chart
Metabolic work-up must carefully assess all components of MetS
Obesity/T2DM or raised liver enzymes in patients with metabolic risk factors should prompt non-invasive screening to predict steatosis, NASH and fibrosis
Steatosis absent
Normal liver enzymes
Follow-up/
3–5 years
Ultrasound/
liver enzymes
Steatosis present
2 years
Liver enzymes,
fibrosis biomarkers
Serum fibrosis
markers§
Low risk‖
Medium/ high risk‖
Metabolic risk factors present
Ultrasound (steatosis biomarkers)*/ liver enzymes†
Abnormal liver enzymes‡
Specialist referral
Identify other chronic liver diseases
In-depth assessment of disease severity
Decision to perform liver biopsy
Initiate monitoring/therapy
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ELF, enhanced liver fibrosis; GGT, gamma-glutamyl transpeptidase; MetS, metabolic syndrome; NASH, non-alcoholic steatohepatitis; T2DM, type 2 diabetes mellitus
*Steatosis biomarkers: Fatty Liver Index, SteatoTest, NAFLD Fat score;
†Liver tests: ALT AST, GGT; ‡Any increase in ALT, AST or GGT;
§Serum fibrosis markers: NAFLD Fibrosis Score, FIB-4, Commercial tests (FibroTest, FibroMeter, ELF);
‖Low risk: indicative of no/mild fibrosis; medium/high risk: indicative of significant fibrosis or cirrhosis
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

33. Natural history and complications: progression
In general, NAFLD is a slowly progressive disease, both in adults and in children
Rate of progression corresponds to 1 fibrosis stage every 14 years in NAFL and every 7 years in NASH
Rate of progression is doubled by arterial hypertension1
Progression of fibrosis is more rapid in about 20% of cases1
Paediatric NAFLD is of concern
Potential for severe liver-related complications later in life
NASH-related cirrhosis has been reported as early as 8 years of age
Recommendations
NASH patients with fibrosis associated with hypertension should receive closer monitoring because of a higher risk of disease progression B 1
Grade of evidence
Grade of recommendation
NAFL, non-alcoholic fatty liver; NASH, non-alcoholic steatohepatitis
1. Sing S et al. Clin Gastroenterol Hepatol 2015;13:643–54;
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

34. Natural history and complications: CVD
Prevalence and incidence of CVD is higher in NAFLD than in matched controls
Driven by the association between NAFLD and MetS components
CVD should be identified in NAFLD, regardless of traditional risk factors
CVD and metabolic risk factors are also reported in adolescents and children with NAFLD
Recommendations
Screening of the cardiovascular system is mandatory in all individuals with NAFLD because CV complications frequently dictate the outcome A 1
Grade of evidence
Grade of recommendation
CV, cardiovascular; CVD, cardiovascular disease; MetS, metabolic syndrome
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

35. Putative connection between NAFLD, CVD and CKD
CKD, chronic kidney disease; CRP, C-reactive protein; CVD, cardiovascular disease; FGF-21, fibroblast growth factor-21; HDL, high-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; PAI-1, plasminogen activator
inhibitor-1; TNF, tumour necrosis factor Schematic representation of the putative mechanisms underlying the contribution of NAFLD to the increased risk of CVD, CKD and other structural and arrhythmic cardiac complications.
The complex and intertwined interactions among NAFLD, abdominal obesity and insulin resistance make it extremely difficult to dissect out the specific role of the liver and the underlying mechanisms responsible for the association between NAFLD and the risk of developing CVD, CKD and other structural cardiac complications (i.e., aortic valve sclerosis, cardiac dysfunction/hypertrophy, congestive heart failure and atrial fibrillation). NAFLD might be associated with such complications either as a consequence of shared cardio-metabolic risk factors and co-morbidities or as a marker of ectopic fat accumulation in other organs. For instance, myocardial steatosis and increased pericardial fat volume as well as fatty kidney and increased renal sinus fat volume may exert local adverse effects that result in structural and functional derangements of the myocardium and kidneys. However, in this dangerous and intricate scenario, growing evidence indicates that NAFLD is not only a simple marker of vascular/cardiac and kidney damage but also may play a part in the pathophysiology of CVD, CKD and other cardiac complications. Indeed, NAFLD may directly contribute to the development and progression of these vascular/cardiac complications through the hepatic production of lipids, atherogenic lipoproteins, the induction of hepatic/peripheral insulin resistance and dysglycaemia (i.e., increased hepatic glucose production), and the systemic release of numerous potentially pathogenic mediators (i.e., pro-inflammatory biomarkers, pro-oxidant molecules, and pro-coagulant and pro-fibrogenic factors). (CRP, C-reactive protein; FGF-21, fibroblast growth factor-21; HDL, high-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; PAI-1, plasminogen activator inhibitor-1; TNF, tumour necrosis factor).
From: Byrne CD and Targher G. J Hepatol 2015;62:S47-S64
Copyright © 2014 European Association for the Study of the Liver Terms and Conditions
Byrne CD, Targher G. J Hepatol 2015;62:S47–64
Copyright © 2014 European Association for the Study of the Liver Terms and Conditions

36. Natural history and complications: HCC
Cumulative incidence of NAFLD-associated HCC varies according to study population
Large number of NAFLD cases at risk of HCC makes systematic surveillance largely impracticable
PNPLA3 rs C>G gene polymorphism is associated with increased HCC risk
However, HCC surveillance in NAFLD is not yet considered cost effective
Recommendations
Although NAFLD is a risk factor for HCC, which may also develop in the pre-cirrhotic stage, and the risk is further increased by the presence of the PNPLA3 rs C>G polymorphism, no recommendation can be currently made on the timing of surveillance and its cost effectiveness B 1
Grade of evidence
Grade of recommendation
HCC, hepatocellular carcinoma
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

37. Treatment: diet and lifestyle changes
Epidemiology suggests a close relationship between an unhealthy lifestyle and NAFLD
Diet and lifestyle changes are mandatory in all patients
Modest weight loss reduces liver fat, improves hepatic IR, and can result in NASH regression
Weight loss of 7% is associated with histological improvement
Recommendations
Structured programmes aimed at lifestyle changes towards healthy diet and habitual physical activity are advisable in NAFLD C 2
Patients without NASH or fibrosis should receive counselling for healthy diet and physical activity but no pharmacotherapy B
In overweight/obese NAFLD, a 7–10% weight loss is the target of most lifestyle interventions, and results in improvement of liver enzymes and histology 1
Grade of evidence
Grade of recommendation
IR, insulin resistance; NASH, non-alcoholic steatohepatitis
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

38. Treatment: diet and lifestyle changes
A pragmatic, individually tailored approach is required
Dietary restriction PLUS
Progressive increase in aerobic exercise/resistance training
Recommendations
Dietary recommendations should consider energy restriction and exclusion of NAFLD-promoting components (processed food, and food and beverages high in added fructose). The macronutrient composition should be adjusted according to the Mediterranean diet B 1
Both aerobic exercise and resistance training effectively reduce liver fat. The choice of training should be tailored based on patients’ preferences to be maintained in the long-term 2
Grade of evidence
Grade of recommendation
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

39. Components of a lifestyle approach to NAFLD
Fructose intake
Avoid fructose-containing food and drink
Energy restriction
Calorie restriction (5001,000/day)
710% weight loss target
Long-term maintenance approach
Daily alcohol intake
Strictly below 30 g men and 20 g women
Coffee consumption
No liver-related limitations
Comprehensive
lifestyle approach
Macronutrient composition
Low-to-moderate fat
Moderate-to-high carbohydrate
Low-carbohydrate ketogenic diets or high protein
Physical activity
150200 min/week moderate intensity in 35 sessions
Resistance training to promote musculoskeletal fitness and improve metabolic factors
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

40. Treatment: pharmacotherapy
Treatment should be indicated in:
Progressive NASH
Early-stage NASH with risk of fibrosis progression*
Active NASH with high necroinflammatory activity
Treatment should reduce NASH-related mortality and progression to cirrhosis or HCC
Resolution of NASH-defining lesions accepted as surrogate endpoint
Safety and tolerability are prerequisites
Extensive comorbidities associated with significant polypharmacy and increased likelihood of DDIs
ALT, alanine aminotransferase; DDI, drug-drug interaction; HCC, hepatocellular carcinoma; MetS, metabolic syndrome; NASH, non-alcoholic steatohepatitis
Recommendations
Pharmacotherapy should be reserved for patients with NASH, particularly for those with significant fibrosis (stage F2 and higher). Patients with less severe disease, but at high risk of disease progression could also be candidates for treatment B 1
Grade of evidence
Grade of recommendation
*Age > 50 years, diabetes, MetS, increased ALT
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

41. Treatment: pharmacotherapy
Treatment should be indicated in:
Progressive NASH
Early-stage NASH with risk of fibrosis progression*
Active NASH with high necroinflammatory activity
Treatment should reduce NASH-related mortality and progression to cirrhosis or HCC
Resolution of NASH-defining lesions accepted as surrogate endpoint
Safety and tolerability are prerequisites
Extensive comorbidities associated with significant polypharmacy and increased likelihood of DDIs
No drugs are approved for NASH
No specific therapy can be recommended
Any drug treatment is off label
ALT, alanine aminotransferase; DDI, drug-drug interaction; HCC, hepatocellular carcinoma; MetS, metabolic syndrome; NASH, non-alcoholic steatohepatitis
Recommendations
Pharmacotherapy should be reserved for patients with NASH, particularly for those with significant fibrosis (stage F2 and higher). Patients with less severe disease, but at high risk of disease progression could also be candidates for treatment B 1
Grade of evidence
Grade of recommendation
*Age > 50 years, diabetes, MetS, increased ALT
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

42. Treatment: pharmacotherapy
Insulin sensitizers
Little evidence of histological efficacy with metformin
PPAR agonist pioglitazone better than placebo
Improved all histological features except fibrosis
Achieved resolution of NASH more often
Antioxidants
Vitamin E may improve steatosis, inflammation and ballooning and resolve NASH in some patients
Concerns about long-term safety exist
Recommendations
While no firm recommendations can be made, pioglitazone* or vitamin E† or their combination could be used for NASH B 2
The optimal duration of therapy is unknown; in patients with increased ALT at baseline, treatment should be stopped if there is no reduction in aminotransferases after 6 months of therapy‡ C
Grade of evidence
Grade of recommendation
ALT, alanine aminotransferase; NASH, non-alcoholic steatohepatitis; PPAR, peroxisome proliferator-activated receptor; T2DM, type 2 diabetes mellitus
*Most efficacy data, but off-label outside T2DM; †Better safety and tolerability than pioglitazone in the short-term; ‡No recommendations can be made in patients with normal baseline ALT
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

43. Treatment: pharmacotherapy
Lipid-lowering agents
Statins have not been adequately tested in NASH
Recommendations
Statins may be confidently used to reduce LDL cholesterol and prevent cardiovascular risk, with no benefits or harm to liver disease.
Similarly, n-3 polyunsaturated fatty acids reduce both plasma and liver lipids, but there are no data to support their use specifically for NASH B 1
Grade of evidence
Grade of recommendation
LDL, low-density lipoprotein; NASH, non-alcoholic steatohepatitis
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

44. MOA of pharmacological treatments for NAFLD
ACC, Acetyl-CoA Carboxylase; AOC, amine oxidase, copper containing; ASK, Apoptosis signal-regulating kinase; DNL, de novo lipogenesis; ER, endoplasmic reticulum; FGF, fibroblast growth factor; FFA, free fatty acids; FXR, Farnesoid X receptor; IL, interleukin; LPS, lipopolysaccharide; MOA, mechanism of action; ROS, reactive oxygen species; SIM, simtuzumab; SHP, small heterodimer partner; SREBP, Sterol regulatory element binding proteins; TGF, Transforming growth factor; TLR, toll like receptor; TNF, tumor necrosis factor; TR, thyroid receptor; UPR, unfolded protein response; Jun N-terminal kinases; VLDL, very-low-density lipoprotein
Mechanism of action of pharmacologic treatments for NAFLD and NASH.
From: Konerman MA et al. J Hepatol 2018;68:362–375
Konerman MA, et al. J Hepatol 2018;68:362–75
Copyright © 2017 European Association for the Study of the Liver Terms and Conditions

45. Treatment: paediatric NAFLD
Diet and exercise training reduce steatosis, but do not affect ballooning, inflammation, and fibrosis
The long-term outcome of paediatric NASH remains poor
Drugs have shown beneficial effects but fibrotic lesions are refractory to treatment
Recommendations
Diet and physical activity improve steatosis and hepatic inflammation in paediatric NAFLD, but no beneficial effects on fibrosis have ever been demonstrated. No safe drug treatment has proven effective on fibrosis in paediatric NAFLD B 1
Grade of evidence
Grade of recommendation
NASH, non-alcoholic steatohepatitis
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

46. Treatment: surgery
Bariatric surgery is an option in patients unresponsive to lifestyle changes and pharmacotherapy
Reduces weight and metabolic complications
Stable results in the long term
NAFLD-associated cirrhosis is one of the top three indications for LTx
Recommendations for bariatric surgery
Bariatric surgery reduces liver fat and is likely to reduce NASH progression; prospective data have shown an improvement in all histological lesions of NASH, including fibrosis B 1
Recommendations for liver transplant
LTx is an accepted procedure in patients with NASH and end-stage liver disease. Overall survival is comparable to other indications, despite a higher cardiovascular mortality. Patients with NASH and liver failure and/or HCC are candidates for liver transplantation A
Grade of evidence
Grade of recommendation
HCC, hepatocellular carcinoma; LTx; liver transplantation; NASH, non-alcoholic steatohepatitis
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402