Non-Alcoholic Fatty Liver Disease

Ivan Banjuradja
 Introduction

• The number 1 cause of liver disorder in Western countries, affecting

17–46% of adults.
• The prevalence of NAFLD, pooled for Asian countries, was estimated
to be 27.4%
• The prevalence of NAFLD in Indonesia was estimated around 30%,
this condition related to the increased incidence of metabolic disorders.

1. World gastroenterology organisation global guidelines nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J clin gastroenterol volume 48, number 6, July 2014
2. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the american gastroenterological association, american association for the study of liver diseases, and americancollege of gastroenterology
3. EASL-EASD-EASO clinical practice guidelines for the management ofnon-alcoholic fatty liver disease
4. Pharmacological and non-pharmacological treatment in non-alcoholic fatty liver disease the indonesian journal of gastroenterology, hepatology and digestive endoscopy.
Introduction

• Parallels the prevalence of metabolic syndrome (MetS) and its

components which also increase the risk of more advanced disease
• Pitfall!
• NAFLD is also present in 7% of normal-weight (lean) individuals
Definition of NAFLD
 Definitions
• AASLD: >21 standard drinks per week in men and
>14 standard drinks per week in women over a 2-
year period preceding baseline liver histology.
• EASL: daily alcohol consumption 30 g for men and
20 g for women

Metabolic risk factors/components of Metabolic Syndrome:

• Waist circumference ≥94/ ≥ 80 cm for Europid men/women
• Arterial pressure ≥ 130/85 mmHg or treated for hypertension.
• Fasting glucose ≥ 100 mg/dl or treated for T2DM.
• Serum triacylglycerols >150 mg/dl
• HDL cholesterol <40/50 mg.dl for men/women

1. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the
american gastroenterological association, american association for the study of liver diseases, and
americancollege of gastroenterology
2. EASL-EASD-EASO clinical practice guidelines for the management ofnon-alcoholic fatty liver
disease
 NAFLD
• Excessive hepatic fat accumulation with IR
• Steatosis in >5% of hepatocytes*
• Exclusion of secondary causes and AFLD†

NAFL
• Pure steatosis NASH HCC
• Steatosis and mild lobular inflammation

Early Fibrotic Cirrhotic

F0/F1 fibrosis ≥F2 to ≥F3 fibrosis F4 fibrosis

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
NAFL VS NASH
 Spectrum of NAFLD and concurrent disease
Sub-classification of NAFLD* Most common concurrent diseases
NAFL AFLD†
• Pure steatosis Drug-induced fatty liver disease†
• Steatosis and mild lobular inflammation HCV-associated fatty liver disease (GT 3)†
Others†
• Haemochromatosis
• Autoimmune hepatitis
NASH
• Coeliac disease
• Early NASH (no or mild fibrosis)
• Wilson disease
• Fibrotic NASH (significant/advanced
• A/hypo-betalipoproteinaemia lipoatrophy
fibrosis)
• Hypopituitarism, hypothyroidism
• NASH cirrhosis
• Starvation, parenteral nutrition
• Inborn errors of metabolism
HCC‡ – Wolman disease (lysosomal acid lipase
deficiency)

*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
Pathogenesis

• A Western diet/lifestyle has been associated with weight gain and

obesity, and NAFLD
• Several genetic modifiers of NAFLD have been identified
• PNPLA3 I148M and TM6SF2 E167K carriers have a higher liver fat
content  increased risk of NASH
 Progressive liver disease in NAFLD

Byrne CD, Targher G. J Hepatol 2015;62:S47–64

Copyright © 2014 European Association for the Study of the Liver Terms and Conditions
Clinical Feature

• It is important to remember that NAFLD remains a diagnosis of

exclusion, so other causes of chronic liver disease must be ruled out,
especially alcoholic liver disease, HCV and Wilson’s disease (in
young patients).
• NAFLD patients are usually asymptomatic until the condition
progresses to liver cirrhosis
• Value of screening for NAFLD in the community is limited
Who should be screened for NAFLD?
 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 1. Alcohol intake: <20 g/day (women), <30 g/day (men)
evaluation 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 [HOMA-IR])
8. Complete blood count
9. Serum total and HDL cholesterol, triacylglycerol, uric acid
10. Ultrasonography (if suspected for raised liver enzymes)
Extended* 1. Ferritin and transferrin saturation
evaluation 2. Tests for coeliac and thyroid diseases, polycystic ovary syndrome
3. Tests for rare liver diseases (Wilson, autoimmune disease, AATD)

*According to a priori probability or clinical evaluation

EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
 Diagnosis: diagnostic flow-chart
Metabolic risk factors present

Ultrasound (steatosis biomarkers)*/

• Metabolic work-up must carefully assess liver enzymes†

all components of MetS Steatosis present Steatosis absent

Normal Abnormal Normal

liver enzymes liver enzymes‡ liver enzymes
• Obesity/T2DM or raised liver enzymes in
patients with metabolic risk factors should Serum fibrosis
markers§
prompt non-invasive screening to predict
steatosis, NASH and fibrosis Low risk‖
Medium/
high risk‖

Follow-up/ Follow-up/
Specialist referral
2 years 3–5 years

Identify other chronic liver diseases

Liver enzymes,
In-depth assessment of disease severity Ultrasound/
fibrosis
Decision to perform liver biopsy liver enzymes
*Steatosis biomarkers: Fatty Liver Index, SteatoTest, NAFLD Fat score; biomarkers
Initiate monitoring/therapy
†
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
Potential algorithm for non-invasive assessment: prediction rules
and blood-based biomarkers

*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
FIB-4 Score
Diagnostic
option
Noninvasive assessment of advanced fibrosis in
patients with NAFLD

• The commonly investigated noninvasive tools for

the presence of advanced fibrosis in NAFLD include
clinical decision aids
• NAFLD fibrosis score
• FIB-4 index
• Aspartate aminotransferase [AST] to platelet ratio index [APRI])
• Serum biomarkers (Enhanced Liver Fibrosis [ELF] panel
• Fibrometer, FibroTest, and Hepascore), or
• Imaging (eg, TE, MR elastography [MRE], acoustic radiation force impulse imaging, and supersonic shear
wave elastography)
NAFLD
Fibrosis Score
Comparison of recommendation about non-
invasive evaluation
Algorithm
liver biopsy
(Patient
suspect
NAFLD)
Gold Standard

• Liver biopsy becomes the gold standard

in establishment of NAFLD diagnosis,
particularly in differentiating pure
steatosis and steatohepatitis.
• NAFLD is generally suspected in
individual with transaminase elevation
with no apparent reason and no history
of alcohol consumption
Histological
criteria
Treatment
 Components of a lifestyle approach to
NAFLD Fructose intake
Energy restriction • Avoid fructose-containing
• Calorie restriction (5001,000/day) food and drink
• 710% weight loss target
• Long-term maintenance approach
Daily alcohol intake
• Strictly below 30 g men
Coffee consumption
• No liver-related limitations Comprehensive and 20 g women

lifestyle approach

Macronutrient composition Physical activity

• Low-to-moderate fat • 150200 min/week moderate intensity
• Moderate-to-high carbohydrate in 35 sessions
• Low-carbohydrate ketogenic diets or high • Resistance training to promote
protein musculoskeletal fitness and improve
metabolic factors

EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

 Treatment
• 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

*Age > 50 years, diabetes, MetS, increased ALT

EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
 Management (Non-Pharmacological)

• Life style intervention

• Aerobic exercise with the intensity equal to walking 30 minutes per day or 5 km per
day 3 times a week
• Calorie restriction up to 30 kcal/kg/day with lower composition of saturated and trans
fatty acid, also simple sugar
• Decrease of 10% body weight in 6 months and not so fast because it may aggrevated
NAFLD.
• Life style modification is also adjusted to the existing comorbidities, particularly
cardiovascular problem, the most common cause of death in NAFLD
Alcohol Use

• Patients with NAFLD should not consume heavy amounts of

alcohol. There are insufficient data to make recommendations with
regard to nonheavy consumption of alcohol by individuals with
NAFLD
• Insulin sensitizer
• Metformin
• Glitazon : insulin sensitizer working in skeletal muscle and liver,
increasing glucose uptake by improving peripheral insulin resistance

• Recommendation
• Metformin is not recommended for treating NASH in adult patients.
• Pioglitazone improves liver histology in patients with and without T2DM
with biopsy-proven NASH.
Therefore, it may be used to treat these patients. Risks and benefits should
be discussed with each patient before starting therapy.
• Until further data support its safety and efficacy, pioglitazone should not
be used to treat NAFLD without biopsy-proven NASH
• GLUCAGON-LIKE PEPTIDE-1 ANALOGUES : It is premature to consider
GLP-1 agonists to specifically treat liver disease in patients with NAFLD or
NASH
• VITAMIN E
• Vitamin E administered at a daily dose of 800 IU/day improves liver
histology in nondiabetic adults with biopsy-proven NASH and therefore
may be considered for this patient population. Risks and benefits should be
discussed with each patient before starting therapy.
• Until further data supporting its effectiveness become available, vitamin E
is not recommended to treat NASH in diabetic patients, NAFLD without
liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis.
URSODEOXYCHOLIC ACID, OMEGA-3 FATTY
ACIDS, AND MISCELLANEOUS AGENTS

• UCDA is not recommended for the treatment of NAFLD or NASH.

• Omega-3 fatty acids should not be used as a specific treatment of NAFLD or
NASH, but they may be considered to treat hypertriglyceridemia in patients
with NAFLD.
• Statins have not been adequately tested in NASH
BARIATRIC SURGERY

• Foregut bariatric surgery can be considered in otherwise eligible obese individuals

with NAFLD or NASH.
• It is premature to consider foregut bariatric surgery as an established option to
specifically treat NASH.
• The type, safety, and efficacy of foregut bariatric surgery in otherwise eligible obese
individuals with established cirrhosis attributed to NAFLD are not established. In
otherwise eligible patients with compensated NASH or cryptogenic cirrhosis, foregut
bariatric surgery may be considered on a case-by-case basis by an experienced
bariatric surgery program.
MANAGEMENT OF CVD AND
DYSLIPIDEMIA

• Patients with NAFLD are at high risk for cardiovascular morbidity and
mortality. Thus, aggressive modification of CVD risk factors should be
considered in all patients with NAFLD.
• Patients with NAFLD or NASH are not at higher risk for serious liver injury
from statins. Thus, statins can be used to treat dyslipidemia in patients with
NAFLD and NASH. While statins may be used in patients with NASH
cirrhosis, they should be avoided in patients with decompensated cirrhosis.
 Liver Transplantation

• Liver transplantation is an accepted procedure in NASH patients with

end-stage liver disease, with comparable overall survival to other
indications, despite a higher cardiovascular mortality. NASH patients
with liver failure and/or HCC are candidates for liver transplantation
Management
algorithm
Prognosis
Terima Kasih