This document provides an overview of current treatment and updates on non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). It begins with definitions of NAFLD and NASH. It then discusses the prevalence of NAFLD globally and in Asian countries. Risk factors and the pathogenesis involving the gut microbiota and a potential role in lean NASH are reviewed. Current methods for diagnosis including laboratory tests, imaging, serum biomarkers, and liver biopsy are summarized. Current treatment options including lifestyle modifications, metformin, pioglitazone, and vitamin E are mentioned. Several newer potential treatment approaches are also listed. The role of transient elastography in management is

1. CURRENT TREATMENT AND
UPDATE ON NAFLD AND NASH
DR.AKANKSHA GUPTA
CONSULTANT MEDICINE

2. INDEX
Introduction
Prevalence
Risk Factor
New Nomenclature MAFLD
Pathogenesis
Gut Microbiota, LEAN NASH
Diagnosis
Current Treatment –Metformin ,
Pioglitazone, VIT E, UDCA
August 25, 2023
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Newer approaches
• OCA
• Lubiprostone
• DMR
• DPP4
• Saroglitazar
• Elafibrinor
• Empagliflozin
• Fecal Microbiota
Transplantation
• Current and Potential future
drugs

3. Definitions (1/2)
Non-alcoholic Fatty Liver Disease (NAFLD)
Accumulation of fat in the liver in the absence of recent or ongoing intake of significant
amount of alcohol (alcohol intake up to 20 g/day both for males and females)
NAFLD
Primary
NAFLD is primary if
other secondary causes
of hepatic steatosis have
been excluded
Secondary
Hepatitis C virus, various
inborn errors of
metabolism, total
parenteral nutrition,
various medications,
surgical procedures etc.
Duseja J, et al. J Clin Exp Hepatol. 2015;5(1):51-68.

4. Definitions (2/2)
Shutterstock ID: 286407365
Fat Deposition in
Liver
The macrovesicular
steatosis that
occupies at least 5%
of the hepatocytes
Simple Steatosis
Presence of fat in the
liver with or without
the presence of
lobular inflammation
on histology
Non-alcoholic Steatohepatitis or NASH
Steatosis and inflammation are associated with the
presence of one of the following 3 additional features on
liver histology:
Ballooning of hepatocytes
Mallory hyaline bodies
Fibrosis
Duseja J, et al. J Clin Exp Hepatol. 2015;5(1):51-68.

5. Global Prevalence
13.48%
30.45%
24.13%
31.79%
23.71% 27.37%
Overall Prevalence of NAFLD Is 25.24%
Shutterstock ID: 760209577
Younossi ZM, et al. Hepatology. 2016;64(1):73-84. NAFLD, non-alcoholic fatty liver disease.

6. Prevalence in Asian Countries
Prevalence (%) of NAFLD in different Asian
countries are as follows1:
Prevalence of NASH in patients with biopsy-proven
NAFLD is 63.5%3
China 15%-40%
India 30%
Japan 25%-30%
Korea 27%
Affects around a quarter of the Asian adult population.1
NAFLD
epidemic in
Asia1,2
Obesity
Metabolic
syndrome
Urbanisation
Sedentary lifestyle
Western diet
1. Fan JG, et al. J Hepatol. 2017;67(4):862-873.
2. Pati GK, et al. Euroasian J Hepatogastroenterol. 2016;6(2):154-162.
3. Younossi ZM, et al. Hepatology. 2016;64(1):73-84.
NAFLD, non-alcoholic fatty liver disease;
NASH, non-alcoholic steatohepatitis.

7. Natural history of NAFLD

8. Risk Factors of NAFLD
Calzadilla Bertot L, et al. Int J Mol Sci. 2016;17(5):774.
NAFLD, non-alcoholic fatty liver disease;
NASH, non-alcoholic steatohepatitis.
Source: Patel V, 2016.

9. Is it a New Nomenclature??
August 25, 2023 9

10. The two most important and significant
differences between MAFLD and NAFLD are,
MAFLD diagnosis does not require exclusion of
patients with alcohol intake, or other chronic liver
diseases and the presence of metabolic abnormality
is necessary for diagnosis of MAFLD
MAFLD = NAFLD Journal of Hepatology 2020 vol. 73 : 202–209

11. NAFLD: Pathogenesis
August 25, 2023
| 11

12. Normal
Liver
NASH
NAFL
“Simple
Steatosis”
Cirrhosi
s
Clin Med (Lond). 2015 Apr
• Sedentary lifestyle
• High fat diet
• Insulin resistance
• Obesity
• Oxidative Stress
• Mitochondrial Dysfunction
• Inflammatory Cytokines
• Gut Dysbiosis, Endotoxins
1 2
“Two Hit” Hypothesis

13. “Multi-hit” Hypothesis
Multiple insults acting together on genetically predisposed patient (insulin
resistance, altered gut bacteria, inflammatory cytokines..etc)
Not necessarily a linear progression from simple steatosis to NASH
Currently most accepted understanding of NAFLD

14. Gut microbiota :Pathogenesis of NAFLD
(1) increased production and absorption of gut short-chain fatty acids;
(2) altered dietary choline metabolism by the microbiota;
(3) altered bile acid pools by the microbiota;
(4) increased delivery of microbiota derived ethanol to liver;
(5) gut permeability alterations and release of endotoxin
(6) interaction between specific diet and microbiota
August 25, 2023 14

15. LEAN NASH
• The underlying pathophysiology of lean NAFLD may be quite different.
• Genetic predispositions, fructose- and cholesterol-rich diet, visceral adiposity and
dyslipidaemia have potential roles in the pathogenic underpinnings.
• Lean NAFLD may pose a risk for metabolic disturbances, cardiovascular
morbidity or overall mortality.
• Secondary causes of hepatic steatosis are also needed to be ruled out in lean
subjects with NAFLD.
• The effectiveness of various treatment modalities, such as exercise and
pharmacotherapy, on lean NAFLD is not known.
• Weight loss is expected to help lean NAFLD patients who have visceral obesity
• Further investigation is needed for many aspects of lean NAFLD, including
mechanistic pathogenesis, risk assessment, natural history and therapeutic
approach
August 25, 2023 15

17. Always Look for Diabetic Liver
• Up to 75% patients with NASH have diabetes mellitus
• Obese, middle-aged females with DM – more likely to have fatty liver changes on
ultrasonography (upto 70%)
• History of DM associated with a 2.6 fold increase in the risk of NASH
• Diabetes and body mass index are associated with fibrosis progression
1. Dabhi AS. JIACM. 2008; 9(1): 36 – 41
2. Yu AS. Rev. Gastroenterol. Disord. 2002; 2(1): 11 - 19

18. Diagnosis of NAFLD
NAFLD, non-alcoholic fatty liver
1. Dyson JK, et al. Frontline Gastroenterol. 2014;5(3):211-218.
2. Duseja A, et al. J Clin Exp Hepatol. 2015;5(1):51-68.
Stock vector ID: 551095132

19. Laboratory Investigations
Liver Function Tests1,2
•Mildly elevated
transaminases (ALT>AST)
and/or GGT
•However, majority (79%)
have normal ALT levels
•ALT levels are poor
predictors of NAFLD
Other Blood Tests3
•Fasting and postprandial
blood glucose
•Testing for insulin resistance
– HOMA-IR or 2-hour
glucose tolerance test
•Serum triglycerides
•HDL
•Hepatitis B surface antigen
•Antibodies to hepatitis C
virus
Further Work-up Depending
on the Age of the Patient3
•Autoimmune markers – ANA
and ASMA
•Coeliac disease work-up
•Serum iron profile
•Serum ceruloplasmin
Stock photo ID: 749463244 Stock photo ID: 441264445
1. Dyson JK, et al. Frontline Gastroenterol. 2014;5(3):211-218.
2. Browning JD, et al. Hepatology. 2004;40(6):1387-1395.
3. Duseja A, et al. J Clin Exp Hepatol. 2015;5(1):51-68.
ALT, alanine transaminase; ANA, antinuclear antibody; ASMA, anti-smooth
muscle antibody; AST, aspartate aminotransaminase; GGT, gamma glutamyl
transferase; HDL, high density lipoprotein; HOMA-IR, homoeostatic model
assessment-insulin resistance; NAFLD, non-alcoholic fatty liver disease.

20. Noninvasive Imaging of Steatosis (1/2)
Abdominal ultrasound1,2
First-line investigation for patients with suspected hepatic steatosis
Qualitative assessment of fatty infiltration of liver
Presence of >33% fat on liver biopsy, optimal for detection of
steatosis by ultrasound
Characteristic sonographic features3:
Attenuation of image quickly within 4 to 5 cm
of depth, making deeper structures, difficult
to decipher
• Echogenic diffusely but particularly
important to note brightness within the
first 2 to 3 cm of depth
• Liver is uniformly heterogeneous
• Thick subcutaneous depth (>2 cm)
• Liver fills entire field with no edges visible
(viewed as helpful but not necessary for
diagnosis)
Attenuation of image (green arrow),
diffuse echogenicity, uniform heterogeneous
liver, thick subcutaneous depth (yellow arrow)
and enlarged liver filling the entire field.
Source: Khov N, 2014.
1. Dyson JK, et al. Frontline Gastroenterol. 2014;5(3):211-218.
2. Saadeh S, et al. Gastroenterology. 2002;123(3):745-50.
3. Khov N, et al. World J Gastroenterol. 2014;20(22):6821-6825.

21. • Computed tomography scan abdomen1
• Not routinely used
• Magnetic resonance imaging and proton magnetic resonance
spectroscopy2,3
• Used to quantify fat content
• Provides a good accuracy for grading severity of steatosis
However, none of the imaging modalities can differentiate between steatosis and NASH.4
Noninvasive Imaging of Steatosis (2/2)
NASH, non-alcoholic steatohepatitis.
1. Dyson JK, et al. Frontline Gastroenterol. 2014;5(3):211-218.
2. Schwenzer NF, et al. J Hepatol. 2009;51(3):433-445.
3. McPherson S, et al. J Hepatol. 2009;51(2):389-397.
4. Duseja A, et al. J Clin Exp Hepatol. 2015;5(1):51-68.

22. Serum Biomarkers
• Biomarkers can be used in differentiating simple
steatosis from NASH1
• But, biomarkers are still under evaluation1
• Potential biomarkers: cytokeratin-18 and terminal
peptide of procollagen III1
NASH, non-alcoholic steatohepatitis.
1. Dyson JK, et al. Frontline Gastroenterol. 2014;5(3):211-218.
2. J Hepatol. 2016;64(6):1388-1402.
Stock photo ID: 615791984
Serum biomarkers can be an acceptable alternative for diagnosis of steatosis when
imaging modalities are not available.2

23. Noninvasive Tests of Fibrosis
Staging of hepatic fibrosis is necessary in all patients with NAFLD1
1. Dyson JK, et al. Frontline Gastroenterol. 2014;5(3):211-218.
2. Duseja A, et al. J Clin Exp Hepatol. 2015;5(1):51-68.
3. Rockey DC. Gastroenterology. 2008;134(1):8-14.
ALT, alanine transaminase; AST, aspartate transaminase;
NAFLD, non-alcoholic fatty liver disease.
Transient elastography1,2,3
• It is the only imaging modality that
can detect liver fibrosis
• It gives the measurement of liver
stiffness which correlates well with
degree of fibrosis
Simple noninvasive tests of
fibrosis1
The following scores can be used
to exclude advanced fibrosis and
can identify patients with mild
disease:
• NAFLD fibrosis score: age,
hyperglycaemia, body mass
index, platelet count, albumin,
AST/ALT ratio
• BARD score: body mass index,
AST/ALT ratio, type 2 diabetes
mellitus
• FIB-4 score: age, AST, ALT
Source: Rockey DC, 2008

25. Fibroscan
Transient elastography that evaluates liver stiffness using pulse-echo ultrasound
Non invasive
More sensitive than serologic markers
Evaluates a larger part of liver
Main weakness is interference with by steatosis with wave velocity
Might be unreliable in obese

27. In patients with normal ALT and liver stiffness value <6.0
kPa, no treatment is required, whereas those with liver
stiffness values >9.0 kPa should be considered for
treatment.
In patients with ALT 1-5x ULN, those patients with liver
stiffness value <7.5 kPa can be observed, whereas those
with value >12.0kPa should be considered for treatment.
In patients with liver stiffness values outside these criteria,
liver biopsy should be considered.

28. Liver Biopsy
Indications for liver biopsy1
Age >45 years
Female gender
AST/ALT ratio >1
High AST/platelet ratio index
Diabetes mellitus or metabolic
syndrome
High CK 18
High NAFLD fibrosis score
High liver stiffness measurement
Histological definition of adult
NASH2,3
Combination of 3 lesions
(steatosis, ballooning and
lobular inflammation) within a
characteristic topographical
distribution, mainly
centrilobular, zone 3 of the acini
It is the only useful modality for assessing severity of disease in patients with NAFLD.1
Haematoxylin and Eosin image of NASH; Ballooned
hepatocytes (long arrow) and mixed inflammation including
neutrophils (short arrow).4
Source: Spengler EK, 2015.
NAFLD, non-alcoholic fatty liver
disease; NASH, non-alcoholic
steatohepatitis.
1. Duseja A, et al. J Clin Exp Hepatol. 2015;5(1):51-68.
2. Ratziu V, et al. J Hepatol. 2010;53(2):372-384.
3. J Hepatol. 2016;64(6):1388-1402.
4. Spengler EK, et al. Mayo Clinic Proc. 2015;90(9):1233-1246.

29. NAFLD Activity Score or NAS
Diagnosis of NASH
• NAS score ≥5 with steatosis and ballooning
• Lower NAS scores in the presence of steatosis and ballooning also
indicates NASH
NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.
Dyson JK, et al. Frontline Gastroenterol. 2014;5(3):211-218.

30. Management of NAFLD
• Exercise1
 Exercise regimen for a minimum of 45 minutes, 5 days per week
 Achieve a target heart rate of 60% to 70% of the maximal heart rate
 Exercises can include brisk walking, jogging or rhythmic aerobic
exercises
 Weight reduction2
 10% of the body weight to be reduced in 6 to 8 months
1. Duseja A, et al. J Clin Exp Hepatol. 2015;5(1):51-68.
2. Farrell GC, et al. Nat Rev Gastroenterol Hepatol. 2013;10(5):307-318.
Successful outcome depends on a behavioural change in the patient who needs to follow it on a
long-term basis.2
Lifestyle modifications
NAFLD, non-alcoholic fatty liver
disease.

31. Role of LSM in NAFLD
LSM IS THE CORNERSTONE OF NAFLD MANAGEMENT
EXERCISE AND
CALORIC
RESTRICTION
INDUCING
WEIGHT LOSS
ARE NEEDED TO
IMPROVE NAFLD

32. Pharmacotherapy of NASH
1. Ratziu V, et al. J Hepatol. 2010;53(2):372-384.
2. J Hepatol. 2016;64(6):1388-1402.
3. Duseja A, et al. J Clin Exp Hepatol. 2015;5(1):51-68.
4. Gawrieh S, et al. Semin Liver Dis. 2015;35(3):338-348.
• Indications of pharmacotherapy1,2
1. NASH with significant fibrosis (stage F2 and higher)
2. Early-stage NASH with increased risk of fibrosis progression (age: >50 years, diabetes,
metabolic syndrome and increased ALT)
3. Active NASH with high necro-inflammatory activity
• Pharmacotherapy is not recommended for bland steatosis and NASH with no or minimal
fibrosis (stage 0 or 1).1
• Placebo controlled RCTs have tested drugs for NAFLD as an add on to LSM,
demonstrating better response with LSM + Pharmacotherapy vs LSM alone
NASH, non-alcoholic steatohepatitis.

33. Pharmacotherapy of NASH
1. Ratziu V, et al. J Hepatol. 2010;53(2):372-384.
2. J Hepatol. 2016;64(6):1388-1402.
3. Duseja A, et al. J Clin Exp Hepatol. 2015;5(1):51-68.
4. Gawrieh S, et al. Semin Liver Dis. 2015;35(3):338-348.
Drugs - I
• Vitamin E
• Pioglitazone
• These are Recommended
for non-diabetic patients
with histological NASH
Drugs - II
• Ursodeoxycholic acid
• Metformin
• Pentoxifylline
• Angiotensin antagonists
• Long-chain
polyunsaturated fatty
acids
• Fibrates
NASH, non-alcoholic steatohepatitis.

34. Pioglitazone and Vitamin E (1/2)
1. Sanyal AJ, et al. N Engl J Med. 2010;362(18):1675-1685.
2. Gawrieh S, et al. Semin Liver Dis. 2015;35(3):338-348.
3. Boettcher E, et al. Aliment Pharmacol Ther. 2012;35(1):66-75.
A total of 247 patients with NASH and without diabetes were involved;
they were classified into groups such as pioglitazone 30 mg daily, vitamin
E 800 IU daily or placebo for 96 weeks1
However, a meta-analysis (2012) of 4 good-quality RCTs showed that pioglitazone might
reverse fibrosis in NASH.3
Vitamin E and pioglitazone were associated with reduction in steatosis, lobular inflammation
and NAFLD activity scores; there was no effect on fibrosis scores.1,2
Source: Gawrieh S, 2015
HB, hepatocyte ballooning; LI, lobular inflammation; NAFLD,
non-alcoholic fatty liver disease; NASH, non-alcoholic
steatohepatitis; RCTs, randomised controlled trials.

35. Safety Concerns
• Might increase all-cause mortality at
dose >400 IU/day1
• Increases risk of haemorrhagic stroke2
• Increases risk of prostate cancer
(randomised controlled trial)3
Vitamin E1,2,3
• Causes weight gain
• Evidence on long-term efficacy and
safety is lacking
Pioglitazone4,5
Stock photo ID: 527363797
1. Miller ER 3rd, et al. Ann Intern Med. 2005;142(1):37-46.
2. Schurks M, et al. BMJ. 2010;341:c5702.
3. Klein EA, et al. JAMA. 2011;306(14):1549-1556.
4. Sanyal AJ, et al. N Engl J Med. 2010;362(18):1675-1685.
5. Gitto S, et al. Gastroenterol Res Pract. 2015;2015:732870.

36. Ursodeoxycholic Acid
1. Duseja A, et al. J Clin Exp Hepatol. 2015;5(1):51-68.
2. Duseja A, et al. Dig Dis Sci. 2007;52(9):2368-2374.
3. Ratziu V, et al. J Hepatol. 2011;54(5):1011-1019.
• Protects against hepatocyte injury by decreasing bile acids1
• Reduces oxidative stress in patients with NAFLD1
Duseja A (2007)
• Prospective study
• A total of 74% of patients with NAFLD achieved biochemical response
with ursodeoxycholic acid (300 mg twice a day) and lifestyle
modifications
ALT, alanine transaminase; NAFLD,
non-alcoholic fatty liver disease; NASH,
non-alcoholic steatohepatitis.

37. Ratziu V (2011)
• Randomised controlled trial (UDCA 28-35 mg/kg/day)
• High dose of ursodeoxycholic acid (28-35 mg/kg/day) versus placebo in NASH
patients for 12 months
• Reduced mean ALT levels from baseline and serum fibrosis markers
(P<.001)
• Improved markers of glycaemic control and insulin resistance
Ursodeoxycholic Acid

38. • UDCA significantly improves liver function tests in NAFLD.
• High doses of UDCA is seen to cause significant improvements in ALT,
GGT and liver fibrosis in NASH patients
• Pharmacological therapy for NASH could be a 1- to 2-year therapy with
glitazones or Vitamin E in combination with high-dose UDCA.
Ursodeoxycholic Acid – API recommendations

39. Ursodeoxycholic Acid - Systematic Review Analysis
Monotherapy with
UDCA
•Significantly improved liver function in 5 studies and even improved steatosis and
fibrosis in 2 of them.
•Alleviated metabolic markers in NASH patients.
Combination
therapies with UDCA
•Significantly improved liver function while there was improvement in steatosis and
inflammation in 2 of them
High-dose UDCA
•Significantly improved ALT, ¥GT, and liver fibrosis.
•Reduces serum glucose, glycosylated haemoglobin, and insulin concentrations and
triglycerides
UDCA monotherapy
and in combination
with vitamin E
•Significant improvement in ALT while the latter also led to alleviation of steatosis.
Xiang_2013

40. Indian experience with UDCA:
Three Indian Studies
2 Prospective & 1 Retrospective Study
•UDCA (300 mg BID) studied in 100
patients for 6 months
• 38% underwent biopsy,
•Outcome : biochemical response
•74% achieved biochemical response
• High dose UDCA (600 mg BID) in
23 NASH patients for 6 months
• All patients had Liver Biopsy
•Outcome measures were
improvement in ALT and liver
histology
•Biochemical improvement in all
•Histological in 13/23
• 57 NAFLD patients retrospectively
studied from 1996 and 2004
• Histologically confirmed NAFLD &
elevated ALT were included
• Comparator arms included Lifestyle
interventions, Lifestyle interventions
+ UDCA and Lifestyle interventions +
UDCA + Vitamin E
• UDCA dose: 300 mg BID
•All patients in combo group had
histological improvement
1. Duseja A, et al. The Clinicopathological Profile of Indian Patients with Nonalcoholic Fatty Liver Disease (NAFLD) is Different from That in the West. Dig Dis Sci 2007; 52:2368–2374.
2. Singh SP, et al. A pilot study of high dose UDCA in the treatment of NASH. Indian J Gastroenterol . 2007; Volume 26, Supplement 2.
3. Madan K, et al. Vitamin E-based therapy is effective in ameliorating transaminasemia in nonalcoholic fatty liver disease. Indian J Gastroenterol 2005;24:251-255
Study 2 Study 3
Study 1

41. Metformin
Haukeland JW, et al. Scand J Gastroenterol. 2009;44(7):853-860. ALT, alanine aminotransferase; AST, aspartate
aminotransferase; NAFLD, non-alcoholic fatty liver disease.
Randomised controlled trial, 48 patients with biopsy-proven NAFLD,
metformin 500 mg/day (up to maximum 2500 or 3000 mg) versus placebo
No significant differences were observed between placebo and metformin in terms of change
in steatosis or liver enzyme levels.

42. Effects of Interventions in NAFLD
Weight Loss Insulin
Resistance
Liver Enzymes Inflammat
ion
Fibrosis
Lifestyle interventions Yes Yes Yes Yes Unproven
Vitamin E No No Yes Yes No
Pioglitazone Weight gain Yes Yes Yes Might be
beneficial
Ursodeoxycholic acid No Yes Yes Yes Might be
beneficial
Metformin Yes Yes No No No
Gitto S, et al. Gastroenterol Res Pract. 2015;2015:732870.

43. New
approaches
in NAFLD
drug
therapy
Journal of
Hepatology 2018
vol. 68 j 362–375

44. New therapeutic strategies in
nonalcoholic fatty liver disease: a focus
on promising drugs for nonalcoholic
steatohepatitis
New therapeutic strategies in nonalcoholic fatty liver disease: a focus
on promising drugs for nonalcoholic steatohepatitis
Natalia Pydyn 2020

45. Effects of OCA due to its binding to FXR in NAFLD/NASH
Florucci et al 2004 The Nuclear Receptor SHP Mediates Inhibition of Hepatic
Stellate Cells By FXR and Protects Against Liver Fibrosis

46. Phase 2 trial in NASH (FLINT)
Farnesoid X nuclear receptor ligand obeticholic acid for
non-cirrhotic, non-alcoholic steatohepatitis (FLINT):
a multicentre, randomised, placebo-controlled trial 2014

47. Phase 3 trial in NASH (Regenerate)
August 25, 2023
Enter title via "insert>header and footer>footer" | 47
REGENERATE: Design of a pivotal, randomised, phase 3 study evaluating
the safety and efficacy of obeticholic acid in patients with fibrosis due to
nonalcoholic steatohepatitis
https://www.globenews
wire.com/news-
release/2019/11/08/194
3921/0/en/New-
REGENERATE-Interim-
Analysis-Data-Presented-
at-The-Liver-Meeting-
Report-OCA-Impr

48. CDSCO APPROVAL
August 25, 2023
Enter title via "insert>header and footer>footer" | 48
CDSCO approval 2020 11/03/2020

49. LIVER INJURY IN RODENTS -2019
August 25, 2023
MECHANISM OF ACUTE LIVER DECOMPENSATION CAUSED BY
OBETICHOLIC ACID IN CHOLESTASIS IS FXR DEPENDENT
Adriana CarinoEnter title via "insert>header and footer>footer" |
49

50. Liver injury to CLD patient treated with OCA-2020
August 25, 2023
Liver Injury in Patients With Cholestatic
Liver Disease Treated With Obeticholic
Acidr title via "insert>header and footer>footer" |
50
The goal of this paper is to raise awareness of the
potential hepatotoxicity of OCA and add a note of caution to the use of OCA in
patients with decompensated disease.
Patients with PBC/PSC cirrhosis
with deterioration in liver function following OCA
use appear to develop jaundice without an impressive increase in liver enzymes.
About half of the patients progressed to liver failure, requiring liver
transplantation due to ACLF.
The long latency period presumably related to the dosing strategy raises the
possibility that this event may be dose-related. The current case series does not
allow us to estimate the incidence of DILI from OCA in comparison
to age, gender, and severity-matched PBC patients, but we anticipate that such
information would be available from the ongoing phase 4 COBALT study
(https://clini caltr ials.gov:/ct2/show/NCT02 308111).
Additional safety, efficacy, and pharmacology data are
needed before OCA is used in cirrhosis from PBC or
PSC.

51. Pruritus with OCA therapy
August 25, 2023
Practical strategiesfor pruritus
managementin the obeticholic acidtreated
patient with PBC: proceedings
from the 2018 expert panelEnter
51
After 1 year of treatment,
pruritus was reported by 56% of patients in the
5–10 mg group and 68% of patients in the 10 mg
group,
compared with 38% in the placebo group
Conclusion
Pruritus is a common symptom in patients with PBC
and may be exacerbated by PBC pharmacotherapy.
OCA has
shown a sustained efficacy and safety profile at 48
months, effectively improving liver biochemical
parameters in PBC. Pruritus associated with OCA
therapy is dose-dependent
and often manageable, and clinical studies show
that treatment discontinuation can be minimised
when pruritus is managed effectively.

52. OCA IMPACT ON LIPOPROTIEN PROFILE
August 25, 2023
tImpact of obeticholic acid on the lipoprotein profile in
patients with non-alcoholic steatohepatitiser title via "insert>header and footer>footer" | 52
This study included 196 patients (99 OCA group and
97 placebo group) who were enrolled in the FLINT trial and
had samples available for lipid analysis and liver biopsies at
enrollment and end-of-treatment (EOT) at 72 weeks. Very low-
density lipoprotein (VLDL), low-density lipoprotein (LDL), and
high-density lipoprotein (HDL) particles were evaluated at
baseline, 12 and 72 weeks after randomization, and 24 weeks
following EOT.
Conclusion: OCA therapy is associated with increases in
small
VLDL particles, large and small LDL particles, and a
reduction
in HDL particles at 12 weeks. These lipoprotein
concentrations
reverted to baseline values 24 weeks after drug
obeticholic acid
(OCA), a farnesoid X receptor agonist, improved liver disease but
led to an increase in cholesterol

53. OCA increase the risk of gallstone
August 25, 2023
Obeticholic acid may increase the risk of gallstone
formation in susceptible patientsEnter title via "insert>header and footer>footer" |
53
OCA in Animal and human study has
shown pharmacological activation of the
farnesoid X receptor increased the risk of
gallstone formation.
Reason could be
FGF19 might trigger relaxation and filling of the
gallbladder which, in combination with increased
cholesterol saturation and BA
hydrophobicity, both decreasing cholesterol
solubility in bile. This would enhance the risk of
gallstone development.

54. FDA LETTER ON OBETICOLIC ACID 29 JUNE 2020
•The predicted benefit of OCA based on a surrogate histopathologic
endpoint remains uncertain and does not sufficiently outweigh the
potential risks to support accelerated approval for the treatment of
patients with liver fibrosis due to NASH
•Additional post-interim analysis efficacy and safety data is needed from
the ongoing REGENERATE study .
•The long-term outcomes phase of the study should continue.

55. Efficacy, safety, and tolerability of lubiprostone for the treatment of non-
alcoholic fatty liver disease in adult patients with constipation: The
LUBIPRONE, double-blind, randomised, placebo-controlled study
design.( ONGOING STUDY)
• LUB is a type 2 chloride channel activator used as a laxative for the treatment
of patients with constipation.
• LUB suppresses gut permeability induced by non-steroidal anti-inflammatory
drugs in healthy volunteers and lowers blood endotoxin levels.
• There have been no clinical studies of LUB for NAFLD/NASH patients.

56. Contd …
Method
The study plans to enrol adult patients (20-85 years, planned enrolment, n = 150;
planned sample size, n = 120) with NAFLD and constipation, alanine
aminotransferase ≥40 IU/L, equivalent steatosis grade ≥1, and equivalent fibrosis
stage <4 measured using non-invasive vibration-controlled transient elastography
and magnetic resonance imaging. Participants will be randomly allocated into
three groups: LUB 12 μg, LUB 24 μg, and a placebo group
Results : primary endpoint will be changes in alanine aminotransferase from
baseline at 12 weeks. The main secondary endpoint will be changes in intestinal
permeability from baseline at 12 weeks using the lactulose mannitol ratio.
Conclusions: This study will determine whether LUB improves gut permeability
in NAFLD patients with constipation

57. Duodenal Mucosal Resurfacing
Procedure Improves NASH and
Diabetes Markers
5
7
• DMR catheter to reach the duodenum (a
tube is inserted down through the esophagus)
to lift the submucosal lining of the organ and
use heated liquid to strip away the excessive
growth of the mucosal layer.
• This promotes healthy regrowth of the lining
of the duodenum within 12 weeks with the goal
of reducing insulin resistance and excess insulin
in the blood.
August 25, 2023

58. Endoscopic duodenal mucosal resurfacing improves
glycaemic and hepatic indices in type 2 diabetes: 6-
month multicentre results
• 85 patients with T2DM who received endoscopic DMR treatment were
enrolled from 5 centres and followed up for 6 months.
• Assessed safety in all patients. Efficacy was evaluated in patients who
received at least 9 cm of duodenal ablation (n = 67).
• Endpoints included HbA1c, fasting plasma glucose, weight and
aminotransferase levels. Metabolomic analysis was conducted in a subgroup
(n = 14). Data were analysed using paired t test or ANOVA for repeated
measures with Bonferroni correction and correction for initial weight loss if
applicable.
August 25, 2023 58

59. Results and Conclusion
• The DMR procedure was completed with no intraprocedural complications in the entire cohort
• HbA1c was lower 6 months after DMR than at baseline (7.9 ± 0.2% vs. 9.0 ± 0.2% [mean ±
SE], p ≪0.001).
• Fasting plasma glucose was also significantly lower 6 months after DMR compared to baseline (161 ± 7
mg/dl vs. 189 ± 6 mg/dl, p = 0.005).
• Body weight decreased slightly.
• At 6 months, alanine aminotransferase had decreased from 41 ± 3 IU/L to 29 ± 2 IU/L (p ≪0.001) and
aspartate aminotransferase had decreased from 30 ± 2 IU/L to 23 ± 1 IU/L (p ≪0.001).
• Metabolomic analysis demonstrated that DMR had key lipid-lowering, insulin-sensitizing and anti-
inflammatory effects, as well as increasing antioxidant capacity. Mean FIB-4 was also markedly
decreased.
Conclusion : Hydrothermal ablation of the duodenum by DMR elicits a beneficial metabolic
response in patients with T2DM. DMR also improves hepatic indices, potentially through an
insulin-sensitizing mechanism. These encouraging data deserve further evaluation in
randomized controlled trials.
August 25, 2023
Endoscopic duodenal mucosal resurfacing improves glycaemic and hepatic indices in type 2 diabetes: 6-
month multicentre results
59

60. GLP-1 Analogoues and DPP-4 Inhibitors
Incretin, GLP-1
Exenatide, liraglutide Lowering of blood
glucose
Stimulates
insulin release
Inhibitis
glucagon release
DPP-4
Enzyme
inactivates
GLP-1
DPP-4 inhibitors (linagliptin, vildagliptin)
block DPP-4 and decrease glucose
Wight loss: delay gastric
emptying and centrally
supress appetite

61. LEAN Study
•AASLD: Still too few evidence to recommend use

62. The Liraglutide Efficacy and Action in Non-
alcoholic Steatohepatitis (LEAN)
Results of the LEAN trial
a P<.05; b P = .05, remaining comparisons P>.05.
LI, lobular inflammation
Gawrieh & Chalasani . Treatments for Nonalcoholic Fatty Liver Disease Clin Liver Dis - (2017)
http://dx.doi.org/10.1016/j.cld.2017.08.013

64. )

65. ALP reduction induced by Elafibranor
•Elafibranor in NASH:
• Effects on ALP and GGT increase with the level at baseline
• Effects consistent in all Phase 2 trials in cardiometabolic patients
Vlad Ratziu e tal Gastroenterology 2016;150:1147–1159

66. Sodium Glucose Cotransporter 2 Inhibitors-Empagliflozin

67. Baseline & Posttreatment Changes in Liver Fat
Empaglifozin Vs Control

69. Current and Potential Future Pharmacological Interventions
Savinda Liyanagedera 1 , Robert Patrick Williams 1 , Silvio Veraldi 2 3 , Valerio Nobili 2 3 , Jake P Mann 4 5
Affiliations PMID: 28803504 DOI: 10.1080/17512433.2017.1365599

70. Conclusion
All patients with high risk of NASH should be identified especially those with
metabolic risk factors.
There is long period of approx 15 years for an individual to progress from NASH
to cirrhosis so timely intervention and screening can arrest this progression.
Dietary and lifestyle modifications scores over pharmacotherapy .