This document provides an overview of non-alcoholic fatty liver disease (NAFLD) including its definitions, risk factors, pathogenesis, diagnosis, complications, screening recommendations, and treatment options. It discusses how NAFLD is the most common liver disease in Western countries, closely linked to metabolic syndrome. The key aspects are that lifestyle modifications targeting 7-10% weight loss are the first-line treatment. Pharmacotherapy with pioglitazone or vitamin E may be considered for patients with NASH, especially those with significant fibrosis. Ongoing research is exploring additional novel pharmacologic treatments.

1. MANAGEMENT
OF
NON ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
Dr.Debprosad Adhikary
MD(Gastroenterology)
Registrar(Medicine)
Satkhira Medical College Hospital

2. INTRODUCTION
• Leading cause of chronic liver disease in Western
nations.
• Hepatic manifestation of the metabolic syndrome.
• Cardiovascular disease is the leading cause of death.

3. METABOLIC SYNDROME

4. DEFINITIONS OF NAFLD, NAFL AND NASH
;
†Daily alcohol consumption of ≥30 g for men and ≥20 g for women
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
NAFLD
• 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
Definitive diagnosis of NASH requires a liver biopsy

5. NAFLD
Isolated
Fatty liver
>80%
NASH
<20%
Cirrhosis
11% over
15 year
Decompensa
tedCirrhosis
31% over 8
year
HCC
7% over 6.5
year
NATURAL
HISTORY

6. EPIDEMIOLOGY
• 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
• NAFLD is also present in 7%
of normal-weight (lean)
individuals2
• Middle age during the fourth
to sixth decades of life
• More common in men than
women
• Increasing frequency in
children and adolescents
• Ethnicity:
• Hispanics (45%)
• Caucasians(33%)
• African Americans(24%)

7. RISK FACTORS
• Increased consumption of
fructose
• Sugar-containing sodas
• Sedentary lifestyle
• Genetic influences-
Patatin-like phospholipase
domain-containing
protein-3 (PNPLA3)

8. RISK FACTORS FOR ADVANCED NAFLD

9. MECHANISM OF ACCUMULATION OF FAT IN
LIVER

10. PATHOGENESIS-THE “TWO HIT”
HYPOTHESIS

11. CLINICAL ASSOCIATION
• Metabolic syndrome including DM
• Cardiovascular disease
• OSA(Obstructive sleep apnea)
• Vitamin D deficiency
• Colonic adenomas
• Hypothyroidism
• Chronic kidney disease
• Polycystic ovarian syndrome

12. CLINICAL AND LABORATORY FEATURES

13. DIAGNOSIS
• Alcohol-associated liver disease must be excluded
• Diagnosis of NAFLD should be entertained only in the
absence of significant alcohol use (consumption
of<30gm/d for men, < 20 gm/d for women)

14. DIAGNOSIS: PROTOCOL FOR EVALUATION
OF NAFLD
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
• 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
1. Alcohol intake: <20 g/day (women), <30 g/day (men)
2. Personal and family history of diabetes, hypertension and CVD
3. BMI, waist circumference, change in body weight
4. Hepatitis B/hepatitis C virus infection
5. History of steatosis-associated drugs
6. Liver enzymes (ALT, AST, GGT)
7. Fasting blood glucose, HbA1c, OGTT, fasting insulin
8. Complete blood count
9. Serum total and HDL cholesterol, triacylglycerol, uric acid
10. Ultrasonography (if suspected for raised liver enzymes)
Extended
evaluation
1. Ferritin and transferrin saturation
2. Tests for coeliac and thyroid diseases, polycystic ovary syndrome
3. Tests for rare liver diseases (Wilson, autoimmune disease)

15. IMAGING

16. NEW IMAGING TECHNIQUE
• Vibration-controlled transient elastography (VCTE or
FibroScan)
• Ease of use
• Patient acceptance
• Cutoff score of 9.9 kPa-Advanced fibrosis
• Acoustic radiation force impulse(ARFI) elastography
• Supersonic sheer imaging
• Magnetic resonance elastography (MRE)
• Comparatively higher cost
• Limited availability

17. ROLE OF NON-INVASIVE ASSESSMENTS
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
• Non-invasive markers should aim to:
• Identify the risk of NAFLD among individuals with increased
metabolic risk
• Identify those with a worse prognosis
• E.g. severe NASH
• Monitor disease progression
• Predict response to therapeutic interventions
Achieving these aims could reduce the need for liver biopsy

18. NON-INVASIVE ASSESSMENT OF STEATOSIS
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
Recommendations
US is the preferred first-line diagnostic procedure for imaging
of NAFLD, as it provides additional diagnostic information
Whenever imaging tools are not available or feasible serum
biomarkers and scores are an acceptable alternative for the
diagnosis of steatosis
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

19. NON-INVASIVE ASSESSMENT OF FIBROSIS
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
• 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
Biomarkers/scores PLUS transient elastography might confer additional
diagnostic accuracy and reduce need for liver biopsy
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

20. CLINICAL SCORING SYSTEMS
• FibroTest (FibroSure)
• FibroMeter
• NAFLD fibrosis score
• Age, BMI, hyperglycemia,
AST/ALT ratio, platelet count,
and serum albumin level
(http://gihep.com/calculators/
hepatology/nafld-fibrosis-
score/)
• AST-to-platelet ratio Index (APRI)
• BARD (BMI,AST/ALT ratio,
• Fibrosis-4 (FIB-4)
• Platelet count, age, AST,and
ALT
(http://gihep.com/calculators/
hepatology/fibrosis-4-score)
• Enhanced Liver Fibrosis(ELF) score
(TIMP-1, amino-terminal
propeptide of type III
procollagen [PIIINP], hyaluronic
acid)
• NashTest
• AST/ALT ratio

21. LIVER BIOPSY
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
• 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
Recommendations
NASH has to be diagnosed by a liver biopsy showing steatosis, hepatocyte
ballooning and lobular inflammation

22. HISTOLOGY

23. HISTOLOGY

24. NAFLD ACTIVITY SCORE (NAS)

25. Metabolic risk factors
present
Ultrasound (steatosis
biomarkers)/
liver enzymes
Steatosis present Steatosis absent
Normal
liver enzymes
Abnormal
liver enzymes
Serum fibrosis
markers
Low risk
Follow-up/
2 years
Liver enzymes, fibrosis biomarkers
Medium
/
high
risk
Specialist referral
Identify other chronic liver diseases
In-depth assessment of disease
severity
Decision to perform liver biopsy
Initiate monitoring/therapy
Follow-up/
3–5 years
Ultrasound/
liver enzymes
Diagnostic
flow-chart

26. COMPLICATIONS: CVD
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
• Prevalence and incidence of CVD is higher in NAFLD than in matched controls
• 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

27. COMPLICATIONS: HCC
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
• 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 rs738409 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 rs738409 C>G polymorphism, no recommendation can be currently made on
the timing of surveillance and its cost effectiveness

28. NAFLD & T2DM
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
Recommendations
In individuals with NAFLD, screening for diabetes is mandatory, by fasting
or random blood glucose or HbA1c…
…and if available, by the standardized 75 g OGTT in high-risk groups
Look for NAFLD in patients with T2DM, irrespective of liver enzyme levels, due
to high risk of disease progression

29. SCREENING
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
Recommendations
Patients with IR and/or metabolic risk factors (i.e. obesity or
MetS) should undergo procedures for the diagnosis of NAFLD
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

30. SCREENING
*Aged >50 years, T2DM, MetS
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
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
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

31. TREATMENT
• Treatment strategy:
• Weight loss
• Removal of offending drugs and toxins
• Control of associated metabolic disorders, including DM and
hyperlipidemia
• Treatment options:
• Lifestyle modification
• Surgical interventions for weight loss
• Pharmacotherapy

32. TREATMENT: DIET AND LIFESTYLE
CHANGES
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
• 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
Patients without NASH or fibrosis should receive counselling for healthy
diet and physical activity but no pharmacotherapy
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

33. COMPONENTS OF A LIFESTYLE APPROACH
TO NAFLD
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
Comprehensive
lifestyle approach
Macronutrient composition
• Low-to-moderate fat
• Moderate-to-high carbohydrate
• Low-carbohydrate ketogenic diets or
high protein
• Consider omega-3 fatty acid
replacement
Fructose intake
• Avoid fructose-
containing
food and drink
Daily alcohol intake
• Strictly below 30 g men
and 20 g women
Coffee consumption
• 2-3 cups/day
Physical activity
• Aerobic and/or resistance training 3-4
times per wk
Energy restriction
• Calorie restriction (5001,000/day)
• 710% weight loss target
• Long-term maintenance approach
• Eliminate or reduce SFAs

34. TREATMENT: PHARMACOTHERAPY
*Age > 50 years, diabetes, MetS, increased ALT
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
• Treatment should be indicated in:
• Progressive NASH
• Early-stage NASH with risk of fibrosis progression*
• Active NASH with high necroinflammatory activity
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

35. TREATMENT: PHARMACOTHERAPY
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
• Insulin sensitizers
• Little evidence of histological efficacy with metformin( Currently not recommended)
• PPAR agonist pioglitazone(30-45 mg/d) better than placebo
• Improved all histological features except fibrosis
• Achieved resolution of NASH more often
• GLP-1 mimetics (Exenetide,Liraglutide)-Shows benefit in small trial.Further study needed.
• Antioxidants
• Vitamin E(800 IU/d) 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
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

36. TREATMENT: PHARMACOTHERAPY
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
• Lipid-lowering agents
• Statins have not been adequately tested in NASH
• Ezetimibe -Modest benefit in pilot trial
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

37. ROLE OF CYTOPROTECTIVE AGENTS
• Thought to prevent apoptosis and down-regulate the
inflammatory cascade.
• UDCA
• Not currently recommended for the treatment of NAFLD or
NASH.
• Pentoxifylline (PTX)
• Varying degrees of histologic improvement
• Improvements in liver biochemical test levels and insulin
resistance
• Improvement in the NAS but not in fibrosis with PTX for 1
year and lifestyle modification compared with lifestyle
modification alone.

38. NOVEL PHARMACOTHERAPY
• Obetocholic acid
• FxR agonist
• Improves lipid metabolism
and glucose homeostasis.
• Decreases fibrosis and
increases insulin
sensitivity.
• Antifibrotics
• Cenicriviroc, emricasan,
selonsertib, GR-MD-02
• PPAR-α/δ agonist
• Elafibranor

39. LT
NASH cirrhosis is the second most common indication for
LT
• Indicated in advanced cirrhosis
• Comorbid conditions limit eligibility for transplantation

40. TREATMENT: PAEDIATRIC NAFLD
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
• 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

41. TREATMENT: SURGERY
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
• 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
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

42. TAKE HOME MESSAGE
• NAFLD is very common disease
• Fatty liver is associated with increased overall
mortality
• Cardiovascular diseases are the leading cause of death
in NAFLD but probably it is underestimated.
• Diagnosis depends on exclusion of other common
causes of CLD
• No specific drug is approved for NASH