Metabolic

Associated Fatty
Liver Disease
(MAFLD)
dr Fita Fitrianti
1706098833
 INTRODUCTION
• Metabolic associated fatty liver
disease (MAFLD)~(formerly
known as non-alcoholic fatty liver
disease (NAFLD)) is the principal
worldwide cause of liver disease
and afects nearly a quarter of the
global population, with differences
according to the diagnostic method,
age, sex and ethnicity.
• Prevalence has risen and placing
an enormous burden on
individuals and health care
systems.
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
APASL CPG MAFLD. Hepatol Int 2020.
 Prevalence of NAFLD/MAFLD and NASH

• Globally, the total prevalence of MAFLD has been cited at 25%, while the prevalence of NASH has been estimated to range
from 1.5% to 6.45% with the global prevalence of NASH among persons with type 2 diabetes estimated at 37.3%.
• In Asia-Pacific region, prevalence of MAFLD is 29.62% ; 50.9 cases per 1000 person-years varies widely because of
genetic background, nutrition, physical activity, lifestyle, and sedentary behaviour.

Younossi ZM et al. Hepatology. 2016;64:73-84, Younossi ZM. J Hepatol. 2019;70:531-544.

 DEFINITION AND DIAGNOSIS OF MAFLD
• MAFLD
• Detection of liver steatosis (liver histology, non-invasive
biomarkers or imaging) together with the presence of at least
one of three criteria that includes ;
• overweight or obesity,
• Type 2 diabetes mellitus (T2DM)
• or clinical evidence of metabolic dysfunction, such as an increased
waist circumference and an abnormal lipid or glycemic profle.

APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.

Definition of NAFLD

• 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

• According to the National Institute on Alcohol Abuse and Alco- holism (NIAAA), a
standard alcoholic drink is any drink that contains about 14 g of pure alcohol
 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

 Pathophysiology of MAFLD

Younossi ZM et al. Hepatology. 2016;64:73-84, Younossi ZM. J Hepatol. 2019;70:531-544.

 Natural history of MAFLD

• Globally, 54.3% of deaths due to cirrhosis and 72.7% of deaths due to hepatocellular
carcinoma (HCC) occurred in the Asia–Pacifc region in 2015.
• (CVD) followed by cancer and liver failure are the main causes of death in MAFLD

Younossi ZM et al. Hepatology. 2016;64:73-84, Younossi ZM. J Hepatol. 2019;70:531-544.

Diagnosis and impact of MAFLD in the setting
of other liver disease
• MAFLD is no longer a diagnosis of
exclusion and is based on the
presence of metabolic dysfunction,
it is now possible to diagnose its
coexistence with other liver
diseases such as:
• Alcoholic liver disease (ALD),
• Chronic hepatitis B virus
infection (CHB),
• Chronic hepatitis C virus
infection (CHC),
• Primary biliary cholangitis,
• Primary hemochromatosis,
especially in Asian populations.
APASL CPG MAFLD. Hepatol Int 2020
 RISK FACTORS FOR MAFLD

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

APASL CPG MAFLD. Hepatol Int 2020
APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.
APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.
 .
APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020
 Noninvasive assessment of advanced fibrosis in
patients with MAFLD
• The commonly investigated noninvasive tools for
the presence of advanced fibrosis in MAFLD 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)

APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.

EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
 Non-invasive tests
• Abdominal ultrasonography  recommended 1st line
diagnostic modality for imaging of MAFLD, usually suficient for
the detection of hepatic steatosis.
• If available, vibration-controlled transient elastography
(VCTE),more sensitive to US.
• If imaging modalities are not available or feasibleserum
biomarkers and scores such as the fatty liver index (FLI)
• GOLD STANDARD  MRI-PDFF and proton-MRS

APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.

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
 NAFLD
Fibrosis Score
 Indications for liver biopsy in patients
Liver biopsy with suspected MAFLD

• Uncertain diagnosis and evaluation for dual

• Remains an important diagnostic etiologies.
test to rule out other liver • Non-invasive tests showing indeterminate or
diseases, especially when the nonconcordant results.
clinical picture is atypical. • During cholecystectomy and bariatric surgery.
• Approved research
• MAFLD is common in patients
with gallstones and morbid
obesity, it is reasonable to offer
liver biopsy during laparoscopic
or open surgery in at risk
patients.

APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.

EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
LIVER BIOPSY
Treatment
 Components of a lifestyle approach to
MAFLD
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
Coffee consumption • Strictly below 30 g men
and 20 g women
• No liver-related limitations Comprehensive
lifestyle approach

Macronutrient composition Physical activity

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

APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.

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 MAFLD.
• Life style modification is also adjusted to the existing comorbidities, particularly
cardiovascular problem, the most common cause of death in MAFLD

APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.

EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
 Alcohol Use
• Patients with MAFLD should not consume heavy amounts of
alcohol.
• There are insufficient data to make recommendations with
regard to nonheavy consumption of alcohol by individuals with
MAFLD

APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.

EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
 Evidence for current drug therapies
• Several anti-diabetic medications are reported to be benefcial for
patients with MAFLD
• Pioglitazone
• RCT conducted by Belfort et al :
• improved hepatic steatosis, ballooning necrosis, and infammation in
steatohepatitis patients with prediabetes or T2DM  6months
treatment
• signifcantly improved hepatic fbrosis in steatohepatitis patients with
prediabetes or T2DM  18months treatment
• Side effect : Weight gain, edema, the development of bladder
cancer, and a decrease in bone mineral density  not widely used

APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.

 Evidence for current drug therapies (2)
• Glucagon-like peptide 1 (GLP-1)
• induce insulin secretion and reduce production of glucagon.
• Has been reported to improve hepatic histology including fbrosis in a
RCT and meta-analyses.
• Reduced body weight
• GLP-1a  gastrointestinal adverse efects including loss of appetite
which can result in poor patient-reported outcomes
• SGLT2i has been reported to reduce hepatic fat content, but efects
on hepatic fibrosis require further studies
• Importantly, both GLP-1a and SGLT2i have been shown to be
benefcial in cardiovascular outcome in patients with T2DM

APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.

Evidence for current drug therapies (3)
Metformin
• Does not improve hepatic histology in patients with MAFLD
• However, metformin improves IR and reduces the risk of HCC in patients with MAFLD

Vitamin E
• Vitamin E administered at a daily dose of 800 IU/day in nondiabetic adults,has been reported
to be effective in improving hepatic histology in patients with steatohepatitis may be considered
for this patient population.
• The development of prostate cancer is a possible concern of vitamin E

Statins
• did not show any benefecial effects on hepatic histology However, statins reduced cardiovascular
morbidity should be considered in all patients with MAFLD with hyperlipidemia.

Patients with MAFLD are at a high risk of hepatic fbrosis, HCC, cardiovascular events, and cancer.
Metabolic risk factor modifcation to improve long-term outcomes is an essential part of holistic
management.

APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.

EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
 Monitoring progress and response
to treatment
• Patients without fibrosis can be monitored at intervals of 2 or 3
years in the absence of worsening of metabolic risk factors
using a combination of non-invasive scores and liver stifness
measurement.
• Patients with fibrosis should be monitored on an annual basis
using a combination of non-invasive scores and liver stifness
measurement
• Patients with cirrhosis should undergo monitoring at 6-month
intervals including surveillance for hepatocellular carcinoma

APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.

 BARIATRIC SURGERY
• Bariatric (metabolic) surgery reduces liver fat and improves the
histological lesions of MAFLD, including fibrosis
• Due to the high risk of post-operative complications from bariatric
(metabolic) surgery in patients with cirrhosis, the decision should be
individualized.
• Bariatric surgery can be considered for MAFLD only if the following
two criteria are met:
• Presence of other indications [e.g., BMI>35 kg/ m2 [>30 kg/m2 in Asian
people)]
• Absence of liver cirrhosis or evidence of compensated cirrhosis without
concomitant portal hypertension.

APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.

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

• Post-transplant survival for MAFLD patients is equivalent to that of

other liver diseases in appropriately selected patients. Liver
transplantation should be considered for MAFLD patients with
decompensated liver disease or hepatocellular carcinoma.
• Patients with MAFLD cirrhosis have a high prevalence of pre-
existing cardiovascular disease and should be thoroughly
evaluated prior to listing for transplantation.

APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.

EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
 The pipeline of new
treatments
• The drugs that have so far
progressed to phase 3
development include:
• obeticholic acid (OCA),
• elafbranor,
• selonsertib,
• cenicriviroc,
• resmetirom,
• aramchol.

APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.

EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
 • Cenicriviroc (CVC), a CCR2/CCR5
chemokine receptor blocker aims to
reduce the drivers of infammation and
fibrosis
• A multicentre, randomised, double-
blind, placebo-controlled study of
cenicriviroc for the treatment of fbrosis
in MAFLD (AURORA) is currently
Cenicriviroc underway.
• The primary outcome is improvement
of fbrosis without worsening of
steatohepatitis.

APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.

EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
 • A dual peroxisome proliferator-
activated receptor alpha/delta
agonist (PPARα/δ)
• PPARα is an important player in the
context of steatohepatitis: it
Elafibranor modulates fatty acid transport and β-
oxidation in the liver  induce
resolution of steatohepatitis without
worsening of fibrosis in the
GOLDEN Study 2b Trial

APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.

EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
 • OCA is a farnesoid X receptor agonist
whose potential actions include
decreasing hepatic steatosis,
infammation, and fibrosis and an
increase of insulin sensitivity.

Obeticholic • Being tested at two diferent doses

(10 mg/day and 25 mg/ day) in the
acid ongoing phase 3 Randomized Global
Phase 3 Study to Evaluate the Impact
on NASH with Fibrosis of Obeticholic
Acid Treatment (REGENERATE) trial.

APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.

EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
 Management of MAFLD-related HCC
• Control of diabetes and obesity could be beneficial in MAFLD-
related HCC patients
• Metformin may be a beneficial treatment in MAFLD related HCC
patients with T2DM
• Serum albumin level is a prognostic factor and nutritional
therapy focusing on protein metabolism is important for the
management of patients with MAFLD-related HCC

APASL Clinical Practice Guideline of MAFLD. Hepatol Int 2020.

EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
Liver transplantation for MAFLD
• Post-transplant survival for MAFLD patients is equivalent to that
of other liver diseases in appropriately selected patients. Liver
transplantation should be considered for MAFLD patients with
decompensated liver disease or hepatocellular carcinoma
• Patients with MAFLD cirrhosis have a high prevalence of pre-
existing cardiovascular disease and should be thoroughly
evaluated prior to listing for transplantation
CONCLUSION
• The burden of MAFLD is rapidly increasing in the Asia–Pacifc; in this region dual
etiology disease particularly with viral hepatitis and alcohol is common.
• MAFLD is a leading cause of chronic liver disease and increasingly of HCC on
the one hand and is a contributor to the various associated systemic
complications such as T2DM, CVD, and CKD.
• Fibrosis is the major determinant of all the complications of MAFLD and liver
biopsy remains the reference standard
• Patients with cirrhosis should be considered for surveillance for varices and HCC.
• Lifestyle intervention remains the cornerstone of management but it is expected
that over the next decade, drug treatments will be approved and added to the
armamentarium of therapeutic choices.
THANK YOU