New treatment options for

NAFLD

Dr. P.Karthikeyan M.D.,D.M

Consultant Gastroentrerologist &
Hepatologist
Royal care Super Speciality Hospital
Coimbatore
 What is NAFLD ?
• Fatty liver – sustainable fat in hepatocytes
• NAFLD – no more than 70g ethanol/ week
• Most common denominator is Diabetes
• Other common accompaniment – obesity,
Met S
• Metabolic steatohepatitis
Fatty liver
 NAFLD
DISTRIBUTION OF FAT MACRO VESICULAR FAT
 Causes of fatty liver

Alcohol

Drug induced steatosis Tamoxifen, amiodarone, methotrexate

Insulin resistant syndromes Familial and acquired lipodystrophies
PCOD
Hypernutrition in adults TPN, intravenous glucose
Altered anatomy Jejuno- ileal bypass
Rapid weight loss Cachexia, bulemia, starvation
Bacterial over growth Jejunal diverticulum
Congenital Abetalipoproteinemia
Copper toxicity Wilson disease, indian childhood cirrhosis
 Metabolic association with NASH
Central obesity Waist hip ration > 0.85 women
0.90 in males

Overweight BMI > 25

Obesity BMI > 30
Insulin resistance IGT
Type 2 DM
Atherogenic dyslipidemia Low HDL
High LDL
High TGL

Hypertension
Metabolic syndrome IDF definition
Family history
Diabetes in India
NAFLD IN INDIA
 Routine Clinical Biochemistry (LFTs)?
• Liver enzymes may be normal in ~ 80% of
NAFLD pts
– Transaminases are not a sensitive test for
NAFLD/NASH
– Poor correlation between ALT and histology
– ALT typically decreases with advanced fibrosis
– As NASH progresses, ALT/AST ratio may reverse to
ALT < AST
• Severity of histology in NAFLD similar for pts
with normal vs abnormal LFTs
References in slidenotes. Slide credit: clinicaloptions.c
New treatment options for
NAFLD

Dr. P.Karthikeyan M.D.,D.M

Consultant Gastroentrerologist &
Hepatologist
Royal care Super Speciality Hospital
Coimbatore
 What is NAFLD ?
• Fatty liver – sustainable fat in hepatocytes
• NAFLD – no more than 70g ethanol/ week
• Most common denominator is Diabetes
• Other common accompaniment – obesity,
Met S
• Metabolic steatohepatitis
Fatty liver
 NAFLD
DISTRIBUTION OF FAT MACRO VESICULAR FAT
 Causes of fatty liver

Alcohol

Drug induced steatosis Tamoxifen, amiodarone, methotrexate

Insulin resistant syndromes Familial and acquired lipodystrophies
PCOD
Hypernutrition in adults TPN, intravenous glucose
Altered anatomy Jejuno- ileal bypass
Rapid weight loss Cachexia, bulemia, starvation
Bacterial over growth Jejunal diverticulum
Congenital Abetalipoproteinemia
Copper toxicity Wilson disease, indian childhood cirrhosis
 Metabolic association with NASH
Central obesity Waist hip ration > 0.85 women
0.90 in males

Overweight BMI > 25

Obesity BMI > 30
Insulin resistance IGT
Type 2 DM
Atherogenic dyslipidemia Low HDL
High LDL
High TGL

Hypertension
Metabolic syndrome IDF definition
Family history
Diabetes in India
NAFLD IN INDIA
Obesity and Insulin Resistance as Pathogenic
Drivers
Central
Obesity
Thromboph Hyperten
ilia sion

Macrovasc Insulin
Hyperurice
ular Resistan mia
Disease ce

Hyperglyc Dyslipide
emia mia
NAFL
D
Slide credit: clinicaloptions.c
 NAFLD as a Complex Disease Trait: Genetic
and Environmental Modifiers
Environment
Norm Sedentary lifestyle
al Snacking, fast food
Saturated fats
Trans fats
Processed red meat
Steatos
is

NASH

Genes
PNPLA3
TM6SF2
GCKR
Cirrhosi
SOD2 s
MBOAT7
Slide credit: clinicaloptions.c
 NAFLD Natural History
25% to 35% of general population has Only a minority will ever progress beyond
NAFLD NAFL

An important paradox exists:

A substantial proportion of the population has NAFLD but only a minority
progresses
to advanced liver disease or morbidity/mortality
Fazel Y, et al. Metabolism. 2016;65:1017-1025. Slide credit: clinicaloptions.c
 NAFLD Disease Progression
Histological Change in
Subtypes[1,2] Fibrosis*[3,4]
NAFLD Regression:
70% to 75% 25% to 18%-22%
30%

Isolated Steatosis NASH Stable:

steatosis with 40%-43%
mild
inflammation

Cirrhosis Fibrosis Progression:

34-42%

*N = 108 pts with NAFL/NASH and median

6.6 yrs follow-up (data from serial
1. Ludwig J, et al. Mayo Clin Proc. 1980;55(7):434-438.
biopsies).
2. Kleiner DE, et al. Hepatology. 2005;41(6):1313-1321.
3. McPherson S, et al. J Hepatol. 2015;62:1148-1155.
4. Singh S, et al. Clin Gastroenterol Hepatol. 2015 Slide credit: clinicaloptions.com
Apr;13(4):643-54
 NAFLD Natural History

How does NAFLD progress?

Serial biopsy studies

What histologic features predict that pts will experience

significant events or reach clinically relevant endpoints?

Long-term prospective
follow-up studies

Slide credit: clinicaloptions.c

 NAFLD and NASH . . . Finding the
“At-Risk” Patient
Is this steatosis

?
How much
or
fibrosis is
steatohepatitis
there?
?
 NAFLD Presentation
• Symptoms • Common scenarios
– Usually asymptomatic, – Statin monitoring
majority discovered by – “Annual reviews” in
chance
T2DM/lipid/
– Fatigue frequently present
hypertension clinics
• Often an “incidental finding”
– Medical
– Incidental abnormal LFTs
insurance/occupational
– Incidental “bright liver” on
health checks
imaging
– Incidental hepatomegaly

De Alwis NM, et al. Dig Dis. 2016;34:19-26. Slide credit: clinicaloptions.c

 Pathogenesis
• Direct hepatotoxixity/ • Insulin resistance
lipotoxicity • Genetic polymorphism/
• Oxidative stress epigenetic contributions
• ER stress • TLR 9/ TLR 2
• Senesence • Adipokinins
• Hepatocyte cell death/ • Cannabinoid receptors
apoptosis • Autophagy
• Inate immunity • Microbiome
 Routine Clinical Biochemistry (LFTs)?
• Liver enzymes may be normal in ~ 80% of
NAFLD pts
– Transaminases are not a sensitive test for
NAFLD/NASH
– Poor correlation between ALT and histology
– ALT typically decreases with advanced fibrosis
– As NASH progresses, ALT/AST ratio may reverse to
ALT < AST
• Severity of histology in NAFLD similar for pts
with normal vs abnormal LFTs
References in slidenotes. Slide credit: clinicaloptions.c
 Normal ALT Does Not Rule Out
Progressive Disease in NAFLD or NASH
• Persistently elevated ALT can be
associated with disease
progression[1]
• Patients with normal ALT levels can
also develop progressive disease[2-4]
– Up to 80% of NAFLD patients can have
normal ALT[5]
• No designated ALT cutoff for
prediction
1. Ekstedt of2006;44:865-873.
M, et al. Hepatology. NASH or 2. advanced
Maximos M, et al. Hepatology. 2015;61:153-160. 3.
Mofradfibrosis in
P, et al. Hepatology. NAFLD pts
2003;37:1286-1292.
Amarapurkar DN, Patel ND. Trop Gastroenterol.
4.[6]

2004;25:130-134. 5. Dyson JK, et al. Frontline Slide credit: clinicaloptions.com

Gastroenterol. 2014;5:211-218. 6. Verma S, et al. Liver Int.
Noninvasive Diagnosis of Liver Fibrosis
in NAFLD
Clinical or Laboratory Tests Imaging
Simple Complex Elastography
 AST/platelet  NASH  VCTE
ratio index FibroSure FibroScan
 FIB-4 index  ELF  MR
 NAFLD fibrosis  HepaScore elastography
score
 BARD score  ARFI

Slide credit: clinicaloptions.com

 Fibrosis Assessment for Pts With NAFLD
Blood Tests Assessing Fibrosis Stage in
Category
NAFLD

 NAFLD fibrosis
 AST/ALT ratio
score 
“Simple” lab/clinical  FIB-4 score BARD
indices[6-10]  APRI
 Ferritin levels
 BAAT
 IgA levels

“Expanded” lab  FibroTest†

indices[4,5]  FibroMeter
*Assays HA, PIIINP, and TIMP-1; F3/4 fibrosis, AUC: 0.90 (95% CI: 0.84-0.96).
Direct fibrosis markers GGT, α2-macroglobulin,
ELF test* ApoA1, and haptoglobin, corrected for
[1-
†
Includes total bilirubin,
3]
age and sex; F3/4 fibrosis, AUC:  0.88
PIIINP
(95% CI: 0.82-0.92).

Routine LFTs do not differentiate NAFL vs NASH or accurately stage fibrosis

References in slidenotes. Slide credit: clinicaloptions.c

 Tools for Diagnosis of NAFLD
Method Sensitivity Specificity Comments

Liver enzymes
 GGT[1] 63% 65% Not reliable for diagnosis

Ultrasound[2] 85% 94% Inexpensive and accessible,

 Any degree[3] 61% 100% but cannot distinguish
 Cutoff ≥ 20%[3] 100% 90% fibrosis/steatosis
CT without contrast[4] Better in morbid obesity, but
 Cutoff > 30% 79% 97% affected by iron, fibrosis, and
less accurate with less
steatosis
MRI[5] Detects mild steatosis,
 Cutoff PDFF 6.4%, gr ≥ 86% 83% quantifies hepatic fat most
1 64% 96% accurately
 Cutoff PDFF 17.4%, gr ≥
2 90-96% 87-100%
MRS[6] 92-100% 92-97%
 Cutoff ≥ 5%
 Cutoff > 33%

Liver biopsy Gold standard, but invasive

References in slidenotes. Slide
and credit: clinicaloptions.com
subject to sampling error
 How Reliable Is Noninvasive Imaging
Assessment of Liver Fibrosis in NAFLD?

Reprinted by permission from Macmillan Publishers Ltd:

Brunt EM, et al. Nat Rev Dis Primers. 2015;1:15080, Slide credit: clinicaloptions.com
copyright (2015).
Diagnostic Performance of Supersonic
Shear Imaging, FibroScan, and ARFI
AUROC (95% Best Accuracy, %
Fibrosis Stage
CI) (n/N)
Supersonic shear
imaging
 ≥ F2 0.86 (0.79-0.90) 80 (185/232)
 ≥ F3 0.89 (0.83-0.92) 85 (196/232)
 F4 0.88 (0.82-0.92) 87 (202/232)

FibroScan (M probe
only)
 ≥ F2 0.82 (0.76-0.87) 77 (172/223)
 ≥ F3 0.86 (0.80-0.90) 79 (175/223)
 F4 0.87 (0.79-0.92) 89 (198/223)

ARFI
 ≥ F2 0.77 (0.70-0.83) 74 (175/236)
 ≥ F3 0.84 (0.78-0.89) 79 (186/236)
 F4 0.84 (0.78-0.89) 84 (199/236)

Cassinotto C, et al. Hepatology. 2016;63:1817-1827. Slide credit: clinicaloptions.com

Magnetic Resonance Elastography

Stiffness[1]

Low High

Simple Steatosis Inflammation Fibrosis

,
 But No accuracy for fibrosis vs transient
In NAFLD, higher diagnostic
elastography and CPRs,
Fibrosis
[2,3]
can accurately predict advanced fibrosis[4]
 Inflammation can increase stiffness values in the absence of
fibrosis[1]
Reprinted, with permission, from Radiology 2011;259:749-
756. ©RSNA. References in slidenotes. Slide credit: clinicaloptions.com
Fibrosis Staging in NASH
F1: Perisinusoidal F2: Perisinusoidal + Portal

F3: Bridging Fibrosis F4: Cirrhosis

Slide credit: clinicaloptions.com

 Grading severity of NASH
Grade Steatosis Balloning Lobular Portal
inflammation inflammation

1. Mild Upto 33% Minimal <4 foci None

2. Moderate More than 33% Present zone 3 2-4 foci Mild

3. Severe More than 66% Severe > 4 foci Moderate

Brunt EM et al : Am J Gastroenterol 1999

Risk Stratification in Pts With Suspected
NAFLD
Hepatic steatosis on
imaging
± elevated serum ALT
levels
Evaluate alcohol Confirm NAFLD Exclude alternate
consumption causes of ↑ALT
levels

High-risk profile
Low-risk profile  AST level > AST
 BMI < 29.9 Intermediate-risk
 Age < 40 yrs profile level
 BMI > 29.9*  Platelets <
 No T2DM or
 Age > 40 yrs 150,000
metabolic  Multiple  Noninvasive
syndrome
features of the fibrosis
features
 Noninvasive metabolic estimation:
syndrome* • FIB-4 > 2.67
fibrosis  Noninvasive • APRI > 1.5
estimation:
fibrosis • NFS >
• FIB-4 < 1.30
estimation: 0.675
• APRI < 0.5  FibroScan > 11
• FIB-4 1.30- Consider liver
• NFS < -1.455
Follow and
 FibroScan 2.67 kPabiopsy or
<5
reassess as risk • APRI 0.5-1.5
Consider liver confirmatory
kPa
factors evolve • NFS -1.455-
biopsy testing for cirrhosis
*Risk factors in our patient. 0.675 (eg, MRE)
 FibroScan
Rinella ME, Sanyal AJ. Nat Rev Gastroenterol 6-11
Hepatol.
2016;13:196-205. kPa Slide credit: clinicaloptions.com
Reprinted by permission from Macmillan Publishers Ltd.
 Lifestyle Changes in NAFLD
• Foundation of any treatment plan
• Difficult to achieve and sustain
• Not enough for morbidly obese pts

Hannah WN, et al. Dig Dis Sci. 2016;61:1365-1374. Slide credit: clinicaloptions.com
 Lifestyle Guidelines in NASH
AASLD 20181 EASL 20162 APASL 20203
Program Lifestyle modification including dietary change, weight loss, and structured exercise
intervention
500-1000 kcal energy deficit to induce a weight loss of 500-1000 g/wk
 Prospective trials
Diet  Exclusion of NAFLD-promoting components
comparing
macronutrient diets in (processed food, added fructose)
 Mediterranean diet suggested
NAFLD are limited
Weight 7% to %10% weight loss is the target of lifestyle interventions to improve NASH and
Loss fibrosis
 Exercise alone may
prevent/ reduce hepatic 
steatosis Both aerobic exercise and resistance training
Exercise ‒ Effect on other reduce liver fat
‒ Tailor to patient preferences
aspects of liver
histology unknown
Bariatric  Reduces liver fat, improves histologic lesions of NASH, including fibrosis
Surgery  Individualize decision in cirrhosis

1. Chalasani. Hepatology. 2018;67:328. 2. EASL, EASD, EASO. J Hepatol. 2016;64:1388. 3. Eslam. Hepatol Slide credit: clinicaloptions.c
Intern. 2020;14:889.
Percentage of Weight Loss Associated With
Histological Improvement in NAFLD
• Analysis of data from 4 randomized studies
Weight loss ≥ 10%
Fibrosis
regression
(45% of pts)
Weight loss ≥ 7%
NASH
resolution
(64% to 90% of
pts)*
Weight loss ≥ 5%

Ballooning/inflammation
(41% to 100% of pts)*

Weight loss ≥ 3%
Steatosis
(35% to 100% of pts)*

*Depending on degree of weight loss.

Hannah WN, et al. Clin Liver Dis. 2016;20:339-350. Slide credit: clinicaloptions.com
 Recommendation

Hypocaloric diet Moderate

Sustained
(daily reduction
by 500-1000 kcal)
+ intensity
exercise
= weight loss

Slide credit: clinicaloptions.com

 Low-Carbohydrate Diet: Meta-analysis of
Effect on Intrahepatic Lipid Content in NAFLD
Studies Results
• Meta-analysis of 10 • Low-carbohydrate diets
international clinical trials associated with significant
reduction in intrahepatic lipid
of low-carbohydrate
content by
(<50%) diets in patients -11.53% (95% CI: -18.10% to
with NAFLD -4.96%; I2 = 83.2%)
– 10 evaluated ALT (n = • Nonsignificant reductions in
238) serum ALT, AST, GGT
– 9 evaluated AST (n = 216) • An updated meta-analysis did
– 5 evaluated GGT (n = 91) not find a difference between
– 4 evaluated intrahepatic low-carbohydrate diet and
lipid content (n = 50) low-fat diet
Haghighatdoost. J Res Med Sci. 2016;21:53. Ahn. Clin Nutr. 2019;38:2023. Bueno. Clin Nutr. Slide credit: clinicaloptions.c
2020;39:P310.
 Low-Carbohydrate and Intermittent Calorie Restriction
Diets: Effect on Reducing Steatosis in NAFLD

• Open-label, randomized, controlled trial of 12 wk of standard

of care vs intermittentStanda
calorie
5:2
restriction
Low
(5:2) vs low-
carbohydrate, high-fatrddiet
of in patients
Carb, with NAFLD (N = 74)
Care (n = High
0 (n = 25) Fat
24) (n =
25)
 5:2 diet associated
with a decrease in
Relative Change

-20
in MR-Fat (%)

LDL levels and

-
16. fewer adverse
8 events vs low-carb,
-40 high-fat diet

-60 - -
Holmer. JHEP Reports. 2021;3:100256. 50.9 53.1 Slide credit: clinicaloptions.c
 Sustained Weight Loss Through
Lifestyle Modification
Outcome Among Patients Patients
Weight Loss Achieving Weight Loss Sustaining Weight
Loss at 1 Yr1

≥10%1 Fibrosis <10%

regression

≥7%1 NASH resolution 18%

≥5%1-3 Ballooning/inflammation improvement 30%

≥3%1-4 Steatosis improvement Not reported

1. Vilar-Gomez. Gastroenterology. 2015;149:367. 2. Promrat. Hepatology. 2010;51:121.

3. Harrison. Hepatology. 2009;49:80. 4. Wong. J Hepatol. 2013;59:536. Slide credit: clinicaloptions.c
Fibroscan in NASH- cirrhosis