1) The document discusses MASLD (Metabolic dysfunction associated steatotic liver disease), formerly known as NAFLD. It provides epidemiological data showing a high prevalence of 38.6% in Indian adults. 2) Pathogenesis involves insulin resistance leading to increased free fatty acid flux to the liver and mitochondrial dysfunction. Lifestyle interventions including weight loss through diet and exercise can help resolve steatosis and improve fibrosis. 3) For patients at high risk of progression, pharmacotherapy with vitamin E, pioglitazone or saroglitazar may be considered. Bariatric surgery can be effective for weight loss but is not routinely recommended for NASH currently. Surveillance is advised for those

1. MASLD (Fatty Liver)
Recent Advances in
Management
Dr GOPI SRIKANTH

2. Dr GOPI SRIKANTH
MD (PGIMER, Chandigarh)
DM & Fellowship (AIIMS, New Delhi)
EUS Fellowship (WISE, WEO)
Ex Faculty AIIMS, New Delhi
Current designation:
Consultant in Gastroenterology,
Hepatology and Advanced Endoscopy
Yashoda Hospitals (Hitec-city),
Hyderabad

3. Real life case scenario
• 55 year old male
• Non-smoker, No history of alcohol consumption
• Editor by profession
• Presented to us with painless hematemesis – 4 episodes from last 4
hours

4. Emergency UGIE – Active bleed from the esophageal varices
Endoscopic variceal band ligation done
Hemostasis achieved

5. • Triphasic CT abdomen – Features of cirrhosis with no ascites or liver SOL
• HBsAg and Anti-HCV - negative
• Percutaneous liver biopsy – features of cirrhosis with steatohepatitis
Final diagnosis: Esophageal variceal bleed
Portal hypertension
Cirrhosis
Etiology: MASLD (fatty liver)

6. What is fatty liver
• ≥5% of hepatocytes display macrovesicular steatosis (fatty infiltration)
• In the absence of a readily identified alternative cause of steatosis
Nomenclature:
- Fatty liver
- NAFLD (Non-alcoholic fatty liver disease)
- MAFLD (Metabolic dysfunction associated fatty liver disease)
- MASLD (Metabolic dysfunction steatotic liver disease) – accepted terminology

7. Obesity in India
Journal of Clinical and Diagnostic Research, 2018, Nov, Vol-12(11): LC01-LC05

8. MASLD Epidemiology - India
• 50 studies
• Pooled prevalence:
Adults: 38.6% (32-45.5)
Children: 35.4% (18.2-54.7)
• Males = Females
• Urban : 40% / Rural: 29.2%
8
J Clin Exp Hepatol. 2022 May-Jun; 12(3): 818–829

9. MASLD –
Pathogenesis

10. Alcohol consumption – Liver disease

11. Consensus Nomenclature
11
The NAFLD nomenclature is changing.

12. 12
CARDIOMETABOLIC RISKS

13. Fatty liver Spectrum
Journal of Hepatology 2019 vol. 70 j 151–171
Low risk
NASH
At risk NASH
(≥ F2 fibrosis)

14. Liver – Regenerative capacity

15. Persistent injury - Point of no return

16. Liver function test – Blood

17. Normal ALT :
Males - 29 to 33 IU/l
Females - 19 to 25 IU/l
Levels above this should be assessed

18. Asymptomatic elevated ALT/AST
• 18% - elevated aminotransferase ( ALT > 31 or AST > 24)
• Multivariate analysis association - age, hypertriglyceridemia, hyperglycemia and
higher BMI
Annasamy C et al, Biomed Pharmacol J 2017

19. To remember
• Don’t rely on lab upper limits for LFT interpretation
ALT >33 (Male)
ALT > 25 (Female)
Red-flag
Assess cause

20. Non-invasive tests for NAFLD evaluation

21. Transient
Elastography

22. NITs in patients observed in primary care
EASL clinical practice guidelines on NIT, 2021
Hepatology 2019;0:1-10

23. Risk stratification– Whom to screen
J CLIN EXP HEPATOL 2023;13:273–302
Additional causes of hepatic
steatosis:
1. Alcohol
2. Chronic Hepatitis C
3. Drugs
4. Malnutrition
5. Long term TPN
6. Hypobetalipoproteinemia
7. Wilson
8. Celiac ds
9. lysosomal acid lipase
deficiency

24. Risk stratification - Whom to refer
J CLIN EXP HEPATOL 2023;13:273–302
To identify “At risk NASH”

25. FIB-4 caveats
• Age >65 - cutoff >2.0
• Age < 35 - low accuracy
Age <35 + metabolic risks or elevated liver enzymes – TE
• not be used in acutely ill

26. Risk stratification
J CLIN EXP HEPATOL 2023;13:273–302
Identify “At risk NASH” by
Transient Elastography

27. MASLD – Indications for liver biopsy
• To assess stage of fibrosis if :
1. Discordant or indeterminate NITs
2. Discordance between NITs and clinical / imaging / lab features
• To confirm diagnosis if:
1. Competing or concomitant possible diagnoses (eg, autoimmune
hepatitis, DILI)
2. Persistent elevation (>6 mo) in liver chemistries

28. Treatment of MASLD
Systemic disorder
Needs Multimodality treatment
Treatment of all individual aspects

29. Management
• Lifestyle Interventions
• Pharmacotherapy
• Bariatric procedures
• Management of metabolic risk factors / modifiers

30. Weight loss – Key component

31. Lifestyle Interventions and
MASH Resolution/ Fibrosis improvement
Romero-Gomez M et al. J Hepatol 2017

32. • Paired liver biopsies - 261 patients (Out of 293) - lifestyle interventions in clinical
practice for 52 weeks – Single arm non-interventional study
• Overall-
• 72 (25%) - resolution of NASH
• 138 (47%) - reduction in NAS
• 56 (19%) - regression of fibrosis.
• Weight loss at week 52
• 88 (30%) – at least 5% of their weight
• 29 (10%) - ≥ 10%
• Degree of weight loss - independently associated with improvements in all NASH-
related histologic parameters (odds ratios = 1.1- 2.0; P < .01).

33. Diet
• Calorie restriction appears to be more important than the specific type of diet
• Daily calorie restriction by 30% or 500-1000 Kcal/day to achieve the target weight loss
• Total fat should not exceed 30% of total energy intake. Intake of saturated fats should be
<10% of total energy intake
• Limit intake of free sugars
• >2 cups of caffeinated coffee per day in NAFLD (Indian habit of sweetening their coffee -
? Counterproductive)
J CLIN EXP HEPATOL 2023;13:273–302

34. • 23 studies - 24 aerobic and 7 resistance exercise protocols .
• Twelve articles including 13 aerobic and 4 resistance exercise protocols
were selected for the comparative analysis.
• Both aerobic and resistance exercise reduce hepatic steatosis with
similar frequency, duration, and period of exercise (40–45 min/session 3
times/week for 12 weeks)
• Intensity and energy consumption - significantly lower for resistance
than for aerobic exercise.
• Resistance exercise - more feasible than aerobic exercise for patients
with poor cardiorespiratory fitness or for those who cannot tolerate or
participate in aerobic exercise.
Hashida R et al. J Hepatol 2017

35. Exercise
• Moderate intensity aerobic or resistance exercises 30-45
minutes/day at least 5 days in a week (at least 200 minutes per
week) in all patients with NAFLD irrespective of body weight
• Moderate intensity aerobic exercises include brisk walking, jogging,
running, swimming, cycling etc
J CLIN EXP HEPATOL 2023;13:273–302

36. Issues with lifestyle interventions
Vilar-Gomez E et al. Gastroenterology 2015

37. Who require pharmacotherapy for NASH ?
J CLIN EXP HEPATOL 2023;13:273–302

38. Vitamin E and Pioglitazone – Improvement in NAS
Sanyal AJ. et al. N Eng J Med 2010

39. Vitamin E and Pioglitazone – Improvement in Fibrosis
Sanyal AJ. et al. N Eng J Med 2010

40. Fatty acid catabolism
Insulin secretion
Wound healing / Cancer
Inflammation
Placenta development
PPAR PPAR 
PPAR
Fatty acid catabolism
(circadian regulation)
Inflammation
Detoxification
Sexual dimorphism
Adipogenesis
Fatty acid storage
Glucose metabolism
Inflammation
Placenta development
Fibrates
Thiazolidinediones
Pioglitazone
Dual PPAR Agonists
Saroglitazar
Elafibranor
IVA337-Lanifibranor/ Bezafibrate
Grygiel-Górniak B. Nutritional Journal 2014

41. Gawrieh S et al. Hepatology 2021

42. • 102 adult patients – at 10 centres in India.
• Biopsy proven NASH (F1-3)
• NAFLD activity score (NAS) of ≥4
• Score of at least 1 in each
• steatosis, lobular inflammation
hepatocyte ballooning
• Randomized - 2:1
• Saroglitazar 4mg and placebo
• At week 52 - Proportion of patients
• Decrease in NAS ≥2
• Spread across 2 of NAS components
• Without worsening of fibrosis
Saroglitazar- Phase III (EVIDENCES II)
Sarin SK, Sharma , Koradia P, Duseja A et al, APASL 2020

43. Safety and Tolerability of Recommended Therapies
(Off Label)
Vitamin E (800 IU/day)
• Possible all-cause mortality risk at
> 800 IU/day
• Increased hemorrhagic stroke risk
• Also shows reduced ischemic stroke risk
• Increased prostate carcinoma risk
(HR vs placebo: 1.17; 99% CI: 1.004-1.36;
P = .008)
Pioglitazone
• Edema, weight gain (~ 2-3 kg over
2-4 yrs)
• Risk of osteoporosis in women[5]
• Equivocal bladder cancer risk
• Increased in some studies
• No association in most studies
Use of these agents should be personalized for selected patients
with histologically confirmed NASH after careful consideration of risk/benefit ratio

44. N Engl J Med 2021; 385:1547-1558

45. Incretins
45
James Armstrong et al. LANCET 2016

46. - subcutaneous injections of 1.8mg liraglutide OD
- 48-week treatment
- 26 in each group
- Primary end-point (NASH resolution) - 39% vs 9% (p=0.019)
- Progression of fibrosis - 9% vs 36% (p=0.03)

47. N Engl J Med 2021; 384:1113-1124

48. Obeticholic Acid: FXR Agonist
• FXR central to multiple key pathways in animal models
Hepatology. 2014;59:2286.
↑ Cholesterol
↓ Bile acids
CYP7a1
↓ Fibrosis
↓ Hepatic
triglycerides
↑ Glucose tolerance
Multiple mechanisms
via ↓ SREPB-1C
RXR
via ↑ β-oxidation
↓ Stellate cell
activation
via ↑ iNOS
↓ Portal
pressure
FXR agonist
(eg, obeticholic acid)

49. Younossi Z et al. Lancet 2019

50. Failed to show direct benefit in NASH (RCTs)
• Statins
• Metformin
• Elafibranor

51. Surgical Interventions for weight loss
• Lifestyle interventions
• Not all patients are obese
• Less than one third - ≥ 5% weight loss
• Less than 10% - ≥ 10% weight loss
• Pharmacological approach
• Increase weight loss by 3-9%, Unfavorable side effects
• Weight recidivism with both – difficult to sustain
• Bariatric Surgery
• Effective, No RCTs, not recommended in NASH
• Less than 1% - who qualify undergo surgery
• Cost, preference, access, morbidity, mortality
• Endoscopic Bariatric and Metabolic Therapy (EBMT) – Less invasive
• Limited data
• No RCTs, not recommended in NASH
J CLIN EXP HEPATOL 2023;13:273–302

52. - Total bodyweight loss - 13·6% ESG group and 0·8% for
control group (p<0·0001)
- At 52 weeks, 80% of 51 participants in the ESG group had an
improvement in one or more metabolic comorbidities,
compared with the control group in which 45% of 62
participants had similar improvement
- At 104 weeks, 68% of 60 participants in the ESG group
maintained 25% or more of EWL.
- ESG-related serious adverse events: 2% (no mortality or
need for intensive care or surgery)

53. Modifiers of NAFLD
Gastroenterology 2020;158:1851–1864

54. MASLD Lifestyle changes
Aggressive risk factor modification (like HTN,
Dyslipidemia)
Assess
cardiometabolic
risk factor
Assess for
“At risk MASLD”
Low risk At risk Cirrhotic
Obesity
Present Absent
Is he eligible for
bariatric procedure
Yes No DM Yes
No
Consider Vit. E/ Saroglitazar /
?Pioglitazone
Prefer Pioglitazone /
?Semaglutide
Bariatric option

55. Precancerous conditions of liver cancer (HCC)
• Cirrhosis
• Non-cirrhotic chronic hepatitis B
• Non-cirrhotic fatty liver with advanced fibrosis

56. Surveillance with USG liver+ serum AFP
every 6 months
in all cirrhosis cases
- Can detect HCC early
To remember

57. "Be Vigilant, Do Regular Liver Check-Up,
Fatty Liver Can Affect Anyone”
- World Liver Day 2023 theme

58. Let’s Live Strong with Live(r) Strong
Department of Gastroenterology, Hepatology,
and Advanced Interventional Endoscopy
Yashoda Hospitals, Hi-tec city, Hyderabad