NAFLD

“PARTNERS IN CRIME”-DIABETES
& THE LIVER
Dr. Asif H. Gulam
MBChB, Mmed, FCP(ECSA)

Introduction/Epidemiology
Pathophysiology
Evaluation
Treatment options

SCOPE & DEFINITION
NAFLD
• Excessive hepatic fat accumulation with IR
• Steatosis in >5% of hepatocytes*
• Exclusion of secondary causes and AFLD†
NASH
NAFL
• Pure steatosis
• Steatosis and mild lobular inflammation
Cirrhotic
F4 fibrosis
Fibrotic
≥F2 to ≥F3 fibrosis
Early
F0/F1 fibrosis
HCC

Global prevalence estimated at 25% however it
is likely to have exceeded 30% prevalence in
most middle-income and high-income countries.
The most recent data are from Asia and suggest
that NAFLD affects 30% of the Asian population,
topping 40% in some territories.*
*Lancet Gastroenterol Hepatol 2019;4:389–98

NAFLD is closely linked with type 2 diabetes and
obesity.
NAFLD is not, however, confined to the obese
population. In the USA, 43% of people with
NAFLD are not obese, rising to 71% in Sweden.*
*Ye Q, Zou B, Yeo YH, et al. Global prevalence, incidence, and outcomes of non-obese or lean non-
alcoholic fatty liver disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol
2020;5:739–52.

Non-alcoholic steatohepatitis is becoming the most
important aetiology for advanced liver disease.
AB, AbdYounossi ZM, Koenig elatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-
Analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73–84.

It is the fastest-growing indication for liver
transplantation in the USA, accounting for more
than 25% of transplants, compared with around
5% in 2002.

HCC is not the only cancer of concern. Studies
have found people with NAFLD have an
increased risk of colorectal cancers,
cholangiocarcinoma and cancers of the breast,
stomach, pancreas, prostate and oesophagus.*
*Liu S-S, Ma X-F, Zhao J, et al. Association between nonalcoholic fatty liver disease and extrahepatic cancers: a
systematic review and meta-analysis. Lipids Health Dis 2020;19:118.

NAFLD has an incremental adverse impact on
ASCVD risk over and above traditional risk
factors (up to double the risk).
NASH and its severity is also related to chronic
kidney disease (up to 3.5 times the risk). The
relationship of NAFLD with CVD and CKD is
independent of T2DM and obesity.*
*Papademetriou M, Athyros VG, Geladari E, Doumas M, Tsioufis C, Papademetriou V. The co-existence of NASH
and chronic kidney disease boosts cardiovascular risk: are there any common therapeutic options? Curr Vasc
Pharmacol 2018;16:254-68.

Despite limitations, liver biopsy results
are predictive of patient outcomes*1
15
Fibrosis stage
determined by
liver biopsy
predicts risk of all-
cause mortality in
NAFLD patients1
Kaplan-Meier survival estimates and fibrosis
stage1
F0
F2
F4
40
0 10 20 30
Years of follow-up
Proportion
alive
1.00
0.00
0.25
0.50
0.75
Log-rank <0.001
Controls
F1
F3
Adapted from Hagström H et al. J Hepatol 2017;67:1265 –
1273
*From a retrospective cohort study of 646 biopsy-proven NAFLD patients, each matched to 10 controls
NAFLD, nonalcoholic fatty liver disease
1. Hagström H et al. J Hepatol 2017;67:1265 –1273.

• In view of the foregoing findings & trends,
morbidity/mortality related to NAFLD are
bound to increase in the foreseeable future
and therefore increased awareness and
proactive screening is vital.

Pathophysiology of NAFLD
► NAFLD is a complex disease driven by
lipotoxicity, insulin resistance and activation of
inflammatory and immune pathways, closely
linked to metabolic disorders.
► There is increasing evidence of a link
between the gut microbiome and development
of both insulin resistance and NASH.
“Multiple Hit”

Pathogenesis: lifestyle and genes
1. Barrera F, George J. Clin Liver Dis 2014;18:91–112;
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
• A Western diet/lifestyle has been associated with weight gain and obesity,
and NAFLD1
Recommendation
Unhealthy lifestyles play a role in the development and
progression of NAFLD.
The assessment of dietary and physical activity habits is part of
comprehensive NAFLD screening
A 1
Grade of evidence Grade of recommendation
Obesity
NAFLD
High calorie intake
Excess (saturated) fat
High fructose intake
Sedentary behaviour

Pathogenesis: lifestyle and genes
*Grade of evidence B, grade of recommendation 2
1. Anstee QM, et al. Nat Rev Gastroenterol Hepatol 2013;10:330–44;
• Several genetic modifiers of NAFLD have been identified1
– A minority have been robustly validated
• PNPLA3 I148M and TM6SF2 E167K carriers have a higher liver fat content*
– Increased risk of NASH
– NAFLD not systematically associated with features of IR
Recommendation
Genotyping may be considered in selected patients and clinical
studies but is not recommended routinely
B 2
Grade of evidence Grade of recommendation

Gut microbiota and NAFLD
• Researchers have identified 8 species of gut
microbes which are twice as abundant in
advanced fibrosis, and 22 species which are
twice as abundant in mild or moderate
fibrosis.
• Research could pave the way for a non-
invasive stool test to identify the progression
from NAFLD to advanced fibrosis.

One hot question is whether the terminology of
NAFLD should be changed, given that many
people have liver damage from fatty liver
,alcohol and other aetiologies. A new name of
MAFLD—metabolic-associated liver disease—
has been proposed, to include people with fatty
liver and metabolic risk factors. The proposal is
under discussion by professional bodies
worldwide

Who Should Be Screened for NAFLD?
• The European guideline recommends that all
patients with obesity or the metabolic syndrome
be screened for NAFLD because of the prognostic
implications of progressive disease.
• The Asian guidelines: screening may be
considered in at-risk groups, such as patients with
diabetes and obesity. Lean NAFLD is prevalent in
Asia, where almost a quarter of patients with
NAFLD are not obese.

• AASLD: Routine Screening for NAFLD in high-
risk groups attending primary care, diabetes,
or obesity clinics is not advised at this time
because of uncertainties surrounding
diagnostic tests and treatment options, along
with lack of knowledge related to long-term
benefits and cost-effectiveness of screening.

How Should NAFLD Be Diagnosed, and How
Should It Be Monitored?
• Liver histology: Gold standard for differentiating
steatohepatitis from simple steatosis and for
assessing fibrosis staging. Due to its invasive nature
and associated costs, all guidelines agree that liver
biopsy should be considered only in select
individuals.
• All guidelines agree that NonInvasive Tools (NITs)
should be used to stratify patients as low or high risk
for advanced fibrosis.

Diagnosis: protocol for evaluation of
NAFLD
*According to a priori probability or clinical evaluation
• Patients could be asymptomatic or complain of unexplained fatigue and RUQ
discomfort. Incidental discovery of steatosis also indicates comprehensive
evaluation
– Family and personal history of NAFLD-associated diseases
– Exclusion of secondary causes of steatosis
Level Variable
Initial
evaluation
1. Alcohol intake: <20 g/day (women), <30 g/day (men)
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*
evaluation
1. Ferritin and transferrin saturation
2. Tests for coeliac and thyroid diseases, polycystic ovary syndrome
3. Tests for rare liver diseases (Wilson, autoimmune disease, AATD)

NON-INVASIVE TESTS(NITs)
The diagnosis of NAFLD is usually made after excess liver fat is demonstrated
by ultrasound, MRI or other modality. These modalities only reveal NAFL and
not NASH/Fibrosis.
Liver biopsy may be the gold standard investigation for determining fibrosis
stage in NAFLD, but it is invasive, costly, carries a risk of complications and,
probably most importantly, is subject to sampling and inter- and intra-
observer variability.
NITs have prognostic value in predicting both mortality and liver related
complications in patients with NAFLD/NASH

Commonly used NITs
NITs, non-invasive tests
1. EASL. J Hepatol 2015;63:237–264; 2. Alkhouri N et al. Gastroenterol Hepatol (NY) 2012;8(10): 661–668; 3. Atay K et al. Biomedical Research 2017;28(2):565–570; 4. Chalasani N et al. Hepatology
2018;67(1):328–357.
• NITs use different approaches to determine liver fibrosis:1
• NITs are an area of active research and learning continues to evolve
29
ELFTM is a trademark of Siemens Healthineers
*ELFTM is not commercially available in the US, but used widely outside of the US
FibroScan® is a registered trademark of EchoSensTM, Paris
FibroTest® is a registered trademark of BioPredictive S.A.S, Paris; FibroSure® is distributed by LabCorp in the US
List of NITs provided above is not exhaustive
• FibroSure®
(FibroTest® outside of the
US)2
• ELFTM (Enhanced Liver
Fibrosis)2*
• NFS (NAFLD fibrosis
score)2
• FIB-4 (Fibrosis-4)2
• APRI (Aspartate
aminotransferase/ platelet
ratio index)3
• Simple Scores
•use information from
standard liver tests and
patient data1
Proprietary Serum Tests
test biomarkers
associated with fibrosis
stage1
• Transient elastography
(e.g. FibroScan®)2
• MRE (Magnetic resonance
elastography)4
Imaging techniques
focus on liver stiffness1

What makes a good NIT?
• A good NIT is both sensitive and specific in determining the presence or
absence of Advanced Fibrosis1
– Use of two cut-off values can maximize sensitivity and specificity compared to the use of a single cut-off value2
• An acceptable NIT also has an AUROC value closer to 1.0*1
30
*The AUROC (Area Under the Receiver Operating Characteristic curve) gives an average performance of a model (NIT) along all sensitivity thresholds. The higher the AUROC (or the closer to 1.0 or
similar) the better the model is at distinguishing between patients with disease and no disease1
AUROC, area under the receiver operating characteristic curve; NIT, non-invasive test
1. Bewick V et al. Crit Care 2004;8(6):508–512; 2. Anstee QM et al. Hepatology 2019; doi: 10.1002/hep.30842.
Indeterminate
Presence of Advanced
Fibrosis
Absence of Advanced
Fibrosis
Upper cut-off value
Lower cut-off value
Lower threshold
maximizes
sensitivity, ensuring
that patients with
Advanced Fibrosis are
not wrongly excluded2
Upper threshold
maximizes
specificity, ensuring
that patients without
not wrongly diagnosed2

Fibrosis 4 (FIB-4) can be easily calculated in office with a
simple blood test and online calculators1
31
FIB-4, fibrosis-4; URL, Uniform Resource Locator
1. Fibrosis-4 calculator. Available at: https://www.mdcalc.com/fibrosis-4-fib-4-index-liver-fibrosis. (Accessed September 2019); 2. Alkhouri N et al. Gastroenterol Hepatol (NY)
2012;8(10): 661–668.
• Based on age, platelet count, alanine aminotransferase (ALT) level and
aspartate aminotransferase (AST) level2
• Simple score that uses readily available patient data
FIB-4 =

FIB-4 can determine the presence of
Advanced Fibrosis1,2
32
• AUROC of 0.78 (95% CI:0.78–0.78)2
• Recognized by AASLD as clinically useful in identifying patients with a higher likelihood of F3
or F43
• LabCorpTM recently incorporated FIB-4, including these cut-off points, into its test report4
Indeterminate
Fibrosis
Absence of Advanced
Fibrosis
Sensitivity of 82%
18% of patients with
missed
Specificity of 93%
7% of patients are wrongly
diagnosed with Advanced
Fibrosis
FIB-4 cut-off scores and accuracy for measurement of Advanced
Fibrosis*2
≥2.67
<1.3
*FIB-4 test results are based on age, hence the accuracy of the test may vary according to age
AASLD, American Association for the Study of Liver Diseases; AUROC, area under the receiver operating curve; CI, confidence interval; F3, stage 3 fibrosis; F4, stage 4 fibrosis; FIB-4, Fibrosis-4
1. Alkhouri N et al. Gastroenterol Hepatol (NY) 2012;8(10): 661–668; 2. Anstee QM et al. Hepatology 2019; doi: 10.1002/hep.30842; 3. Chalasani N et al. Hepatology 2018;67(1):328–357; 4. Available
from https://www.labcorp.com/test-menu/46291/fib-4#. (Accessed September 2019)

FIB-4 score may predict long-term
outcomes
33
FIB-4, fibrosis-4
1. Angulo P et al. Gastroenterology 2013;145:782–789.
Cumulative probability of death/liver transplantation
is related to FIB-4 score1
1.0
Survival
probability
(%)
Duration (years)
0.0
0.2
0.4
0.6
0.8
25
20
15
10
5
0
FIB-4: >2.67
FIB-4: 1.30 to 2.67
FIB-4: <1.30
Adapted from Angulo P et al. Gastroenterology 2013;145:782–789Adapted from Hagström H et al. J Hepatol 2017;67:1265 –1273
Liver biopsy
Years of follow-up
P = 0.03
FIB-4 Liver biopsy
Charts are illustrative and not comparative due to differing patient populations described in
the studies

Nonalcoholic Fatty Liver Disease and Recent Guideline Updates
Clinical Liver Disease, Volume: 17, Issue: 1, Pages: 23-28, First published: 01 February 2021, DOI: (10.1002/cld.1045)

NAFLD Fibrosis Score (NFS) can be easily calculated in
office
with a simple blood test and online calculators1
35
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; NAFLD, nonalcoholic fatty liver disease; NFS, NAFLD fibrosis score; URL, Uniform Resource Locator
1. NAFLD fibrosis score. Available from https://www.mdcalc.com/nafld-non-alcoholic-fatty-liver-disease-fibrosis-score (Accessed September 2019); 2. Alkhouri N et al. Gastroenterol Hepatol (NY) 2012;8(10): 661–668.
• Based on age, hyperglycemia, BMI, platelet count, albumin level, and AST/ALT ratio2
• Simple score that uses readily available information
NFS =
Permission to use MDCalc logo and NAFLD URL has been kindly granted by Dr Graham Walker, Co-Creator of MDCalc
Calculator available at:
https://www.mdcalc.com

NFS can determine the presence of
Advanced Fibrosis
36
*NFS test results are based on age, hence the accuracy of the test may vary according to age
AASLD, American Association for the Study of Liver Diseases; AUROC, area under the receiver operating curve; CI, confidence interval; F3, stage 3 fibrosis; F4, stage 4 fibrosis; NAFLD, non-alcoholic
fatty liver disease; NFS, NAFLD fibrosis score
1. Anstee QM et al. Hepatology 2019; doi: 10.1002/hep.30842; 2. Chalasani N et al. Hepatology 2018;67(1):328–357.
• AUROC: 0.74 (95% CI:0.74–0.74)1
• Recognized by AASLD as clinically useful in identifying patients with a higher
likelihood of F3 or F42
Indeterminate
Fibrosis
Absence of Advanced
Fibrosis
Sensitivity of 89%
missed
Specificity of 89%
11% of patients are
wrongly diagnosed with
Advanced Fibrosis
NFS cut-off scores and accuracy for measurement of Advanced Fibrosis*1
≥0.676
<-1.455

NFS may predict long-term outcomes
37
NAFLD, nonalcoholic fatty liver disease; NFS, NAFLD fibrosis score
Cumulative probability of death/liver transplantation is related to NFS1
1.0
Survival
probability
(%)
0.0
0.2
0.4
0.6
0.8
25
20
15
10
5
0
NAFLD-FS: -1.455 to
0.676
NAFLD-FS: <-1.455
Duration (years)
NAFLD-FS:
>0.676
Adapted from Angulo P et al. Gastroenterology 2013;145:782–789Adapted from Hagström H et al. J Hepatol 2017;67:1265 –1273
Liver biopsy
Years of follow-up
P <0.001
NFS Liver biopsy
the studies

APRI (aspartate aminotransferase/platelet ratio index) can be easily
calculated in office with a simple blood test and online calculators1
• Based on AST and platelet count1
• Simple score that can be used at the bedside or in an outpatient setting1
APRI, aspartate aminotransferase/platelet ratio index; AST, aspartate aminotransferase; URL, Uniform Resource Locator
1. Kruger FC et al. S Afr Med J 2011;101:477-480.
U/L
AST
U/L
AST upper limit of normal
X109
/L
Platelet count
Norm: 1–40
40
Norm: 150–350
APRI
=
38

APRI can exclude Advanced Fibrosis
• AUROC: 0.76 (95% CI:0.74–0.79)1
APRI cut-off scores and accuracy for measurement of Advanced Fibrosis*1
Caution needed with false positives, particularly in patients with acute hepatitis2
May be more useful to exclude, rather than determine, Advanced Fibrosis3
*The study population included patients with histological findings consistent with NAFLD
APRI, aspartate aminotransferase/platelet ratio index; AUROC, area under the receiver operating curve; CI, confidence interval; NAFLD, nonalcoholic fatty liver disease
1. Siddiqui MS et al. Clin Gastroenterol Hepatol 2019; doi: 10.1016/j.cgh.2018.12.031; 2. EASL. J Hepatol 2015;63:237–264; 3. Atay K et al. Biomedical Research 2017;28(2):565–570.
Specificity of 65%
35% of patients are
Advanced Fibrosis
Sensitivity of 90%
missed
Absence of Advanced
Fibrosis
Fibrosis
Indeterminate
>0.84
<0.57
39

Cumulative probability of death/liver transplantation is
related to APRI score1
Adapted from Angulo P et al. Gastroenterology 2013;145:782–789
Liver biopsy
Years of follow-up
Adapted from Hagström H et al. J Hepatol 2017;67:1265 –1273
APRI, aspartate aminotransferase/platelet ratio index
APRI may predict long term outcomes
Liver biopsy
the studies
40
1.0
Survival
probability
(%)
Duration (years)
0.0
0.2
0.4
0.6
0.8
25
20
15
10
5
0
APRI: <0.5
APRI: 0.5 to
1.5
APRI:
>1.5
APRI

FibroSure®
can determine the presence of Advanced Fibrosis
• Proprietary serum test that combines five biomarkers: haptoglobin, α2-
macroglobulin, apolipoprotein A1, total bilirubin and gamma glutamyl-
transferase*1
• AUROC: 0.832 (SE 0.01)
Specificity of 83%
17% of patients are
Advanced Fibrosis
FibroTest® is a registered trademark of BioPredictive S.A.S, Paris; FibroSure® is distributed by LabCorpTM in the US
Sensitivity of 84%
missed
Early or no Fibrosis
Fibrosis
Moderate‡
*False positives can arise from haemolysis, Gilbert syndrome, cholestasis and inflammation due to increased levels of α2-macroglobulin and haptoglobin4
†In patients with hepatitis C
‡Moderate, F1–F2 and F2–bridging fibrosis with few septa3
AUROC, area under the receiver operating curve; SE, standard error
1. Alkhouri N et al. Gastroenterol Hepatol (NY) 2012;8(10): 661–668; 2. Poynard T et al. Comp Hepatol 2004;3:8; 3. LabCorp NASH FibroSure sample report. Available at: https://files.labcorp.com/testmenu/550140.pdf
(Accessed October 2019); 4. Lucero C and Brown RS. Gastroenterol Hepatol 2016;12(1):33–40.
>0.58
≤0.31
41

ELF (enhanced liver fibrosis) score can
determine
the presence of Advanced Fibrosis
• Combines three biomarkers of fibrosis: hyaluronic acid, tissue inhibitor of metalloproteinase 1
and amino-terminal peptide of procollagen III1
• AUROC for identifying Advanced Fibrosis (cut-off ≥9.8): 0.86 (95% CI: 0.83–0.89)2
• ELF is recommended by NICE for the diagnosis of Advanced Fibrosis in adults with NAFLD3
42
Moderate* Presence of Advanced
Fibrosis
Sensitivity of 85%
missed
Specificity of 90%
Fibrosis
ELF cut-off scores and accuracy for measurement of Advanced
Fibrosis4
Early or no fibrosis
≥9.8
<7.7
*Moderate, categorized as mild–advanced fibrosis, ELF scores of 7.7–9.79
AUROC, area under the receiver operating curve; CI, confidence interval; ELF, enhanced liver fibrosis; NAFLD, nonalcoholic fatty liver disease; NICE, National Institute for Health and Care Excellence
1. Alkhouri N et al. Gastroenterol Hepatol (NY) 2012;8(10): 661–668; 2. Siemens Healthineers. ELF instructions for use. Available at: https://doclib.healthcare.siemens.com/ (Accessed October 2019);
3. NICE. Non-alcoholic fatty liver disease (NAFLD): assessment and management. NICE guideline NG49, July 2016. Available at: https://www.nice.org.uk/guidance/ng49 (Accessed October 2019); 4.
Day J et al. JALM 2019;DOI:10.1373/jalm.2018.027359.

ELF score may predict long-term liver-
related outcomes1
43
*Kaplan–Meier survival curves for survival free of liver-related events including complications of portal hypertension, liver cancer, liver transplantation, and death for patients with ELF scores in
the ranges <7.70, 7.7–9.79, 9.80–11.29, and ≥11.30
ELF, enhanced liver fibrosis; IFU, instructions for use
1. Day J et al. JALM 2019;DOI:10.1373/jalm.2018.027359.
Cumulative probability of liver-related events is related to ELF score*1
Liver biopsy
Years of follow-up
Adapted from Hagström H et al. J Hepatol 2017;67:1265 –1273
Liver biopsy
the studies
Adapted from Day J et al. JALM 2019;DOI:10.1373/jalm.2018.027359
Time to event (years)
Cumulative
survival
1.0
0.0
0.2
0.4
0.6
0.8
10
8
6
4
2
0
ELF
≥11.30
9.8–11.29
7.70–9.79
<7.70
ELF IFU cut-offs

Transient Elastography (e.g. FibroScan®) can
determine the presence of Advanced Fibrosis
• Imaging technique that evaluates both fibrosis and steatosis:1
– Liver stiffness expressed as kPa, correlates with fibrosis
– Controlled attenuation parameter, expressed in dB/m, correlates with steatosis
• Recognized by AASLD as clinically useful for the identification of
Advanced Fibrosis in patients with NAFLD2
Fibrosis
Absence of Advanced
Fibrosis
Sensitivity of 91%
9% of patients with
missed
Specificity of 92%
Fibrosis
Indeterminate
AASLD, American Association for the Study of Liver Diseases; AUROC, area under the receiver operating curve; CI, confidence interval; kPa, kilopascal; NAFLD, nonalcoholic fatty
liver disease
1. Mikolasevic I et al. World J Gastroenterol 2016;22(32):7236–7251; 2. Chalasani N et al. Hepatology 2018 Jan;67(1):328–357; 3. Wong VWS et al. Hepatology 2010;51(2):454–462.
≥9.6 kPa
<7.9 kPa
44

Transient Elastography (e.g. FibroScan®)
measures
liver stiffness, which correlates with fibrosis1
45
BMI, body mass index
1. Grandison GA and Angulo P. Clin Liver Dis 2012;16(3):567–585; 2. Kemp W and Roberts S. Aust Fam Physician 2013;42(7):468–471.
Measures liver
stiffness over
an area
estimated to
be 100x
greater than
that of liver
biopsy1
Failure to obtain
readings is more
likely in patients
with a high BMI
(>30 kg/m2),
however, use of
XL probe may
help overcome
this limitation1
Over-estimation
of fibrosis can
occur in cases of
hepatitis,
cholestasis, liver
congestion and if
mass lesions are
present in the
liver2
FibroScan® is a registered trademark of EchoSensTM, Paris
• Liver stiffness is measured via a mechanically induced,
controlled 50 Hz frequency shear wave1
• The propagation speed of the shear wave is measured with
pulse echo ultrasound, with the results presented as
kilopascals (kPa)1

Fibrosis stage measured by
Transient Elastography is predictive of mortality
46
LSM, liver stiffness measurement; TE, transient elastography
1. Boursier J et al. J Hepatol 2016;65(3):570–578.
Cumulative probability of death is related to Transient Elastography
score1
Adapted from Boursier J et al. J Hepatol
2016;65(3):570–578
Adapted from Hagström H et al. J Hepatol
2017;67:1265 –1273
1.0
Overall
survival
Follow-up (years)
0.0
0.2
0.4
0.6
0.8
10
8
6
4
2
0
LSM fibrosis
classification:
LSM1 (F0/1)
LSM3 (F1/2)
LSM4 (F2/3)
LSM6 (F3/4)
LSM7 (F4)
P <0.001
Liver biopsy
TE
Years of follow-up
TE Liver biopsy
the studies

Magnetic resonance elastography (MRE) can
determine the presence of Advanced Fibrosis
*Moderate is classified as patients with fibrosis staging of F2
AUROC, area under the receiver operating curve; CI, confidence interval; F0–F2, stage 0–2 fibrosis; F2, stage 2 fibrosis; F3, stage 3 fibrosis; MRE, magnetic resonance elastography
1. Grandison GA and Angulo P. Clin Liver Dis 2012;16(3):567–585; 2. Hsu C et al. Clin Gastroenterol Hepatol 2019;17(4):630–637.e8.
• Imaging technique that assesses the propagation of mechanical waves through liver
tissue to estimate the degree of fibrosis1
• AUROC for identifying Advanced Fibrosis (≥F3) vs F0–2: 0.93 (95% CIs: 0.90–0.96)2
Moderate*
Fibrosis
Sensitivity of 85%
missed
Specificity of 83%
17% of patients are
Advanced Fibrosis
MRE cut-off scores and accuracy for measurement of advanced
fibrosis2
Early or No Fibrosis
>3.62
<2.97
47

MRE in clinical practice
MRE has been
shown to be
both sensitive
and specific
when
identifying
different
stages of liver
fibrosis2
Unlike other
NITs and liver
biopsy, MRE
estimates the
average
degree of
fibrosis
throughout
the entire
liver2
Limitations
include the
high cost of the
equipment and
the level of
expertise
required to
interpret
results2
MRE is recognized by AASLD as “clinically useful” for the identification of Advanced
Fibrosis*1
Inflammat
ion/
fibrosis
Healthy
liver
†
*Identification of Advanced Fibrosis in patients NAFLD1
†MRE image indicates Advanced Fibrosis (F3) – liver stiffness 6.1 kPa. Adapted from Venkatesh SK et al. J Magn Reson Imaging 2013;37:544–555
AASLD, American Association for the Study of Liver Diseases; kPa, kilopascal; MRE, magnetic resonance elastography; NAFLD, nonalcoholic fatty liver disease; NIT, non-invasive test
1. Chalasani N et al. Hepatology 2018 Jan;67(1):328–357; 2. Grandison GA and Angulo P. Clin Liver Dis 2012;16(3):567–585. 48

Summary of common tests for
determining fibrosis stage*
Test AUROC Lower cut-off to rule
out Advanced Fibrosis
Sensitivity for lower
cut-off (%)
Upper cut-off to rule in
Advanced Fibrosis
Specificity for upper
cut-off (%)
Simple scores
FIB-41 0.78 <1.3 82 ≥2.67 93
NFS1 0.74 <-1.455 89 ≥0.676 89
APRI2 0.76 <0.57 90 >0.84 65
Proprietary serum tests
FibroSure®3 0.83 ≤0.31 84 >0.58 83
ELF4,5 0.86† <7.7 85 ≥9.8 90
Imaging techniques
FibroScan®6 0.93 <7.9 kPa 91 ≥9.6 kPa 92
MRE7 0.93‡ <2.97 kPa 85 >3.62 kPa 83
Histological tests
Liver biopsy8 0.87 ≤F2 85 ≥F3 89
*For informational purposes only – not intended for comparison
†AUROC is for upper cut-off of ≥9.6 to detect patients with Advanced Fibrosis
‡AUROC is for upper cut-off of >3.62 kPa to detect patients with ≥F3 fibrosis
APRI, aspartate aminotransferase/platelet ratio; AUROC, area under the receiver operating curve; ELF, enhanced liver fibrosis; FIB-4, fibrosis 4; kPa, kilopascal; MRE, magnetic resonance elastography; NAFLD,
nonalcoholic fatty liver disease; NFS, NAFLD fibrosis score
1. Anstee QM et al. Hepatology 2019; doi: 10.1002/hep.30842; 2. Siddiqui MS et al. Clin Gastroenterol Hepatol 2019; doi: 10.1016/j.cgh.2018.12.031; 3. Poynard T et al. Comp Hepatol 2004;3:8; 4. Siemens
Healthineers. ELF instructions for use. Available at: https://doclib.healthcare.siemens.com/ (Accessed October 2019); 5. Day J et al. JALM 2019;DOI:10.1373/jalm.2018.027359; 6. Wong VWS et al. Hepatology
2010;51(2):454–462; 7. Hsu C et al. Clin Gastroenterol Hepatol 2019;17(4):630–637.e8; 8. Ratzui V et al. Gastroenterology 2005;128:1898–1906. 49

• Plasma CytoKeratin(CK-18) -emerging as one
of the promising biomarkers for the
noninvasive detection of NASH.

For patients with Advanced Fibrosis without cirrhosis,
halting progression is an important goal1,2
1. Filozof C et al. Hepatol Commun 2017; 1(7): 577–585; 2. FDA Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs
for Treatment Guidance for Industry. December 2018; 3. Angulo P et al. Gastroenterology 2015;149:389–397.
HALT/REVERSE
INFLAMMATION
FIBROSIS
• Preventing
progression to
cirrhosis is a principle
objective of
management1
PREVENT
Progression to
CIRRHOSIS
• Fibrosis stage is
associated with overall
survival and
liver-related
complications3
• Presence and severity
of fibrosis may predict
long-term outcomes3
52

With no indicated pharmacological treatments,
management options are currently limited1,2
EASD, European Association for the Study of Diabetes; EASL, European Association for the Study of the Liver; EASO, European Association for the Study of Obesity; FDA, Food and Drug
Administration; NASH, nonalcoholic steatohepatitis; US, United States
1. Chalasani N et al. Hepatology 2018;67(1):328–357; 2. EASL-EASD-EASO. J Hepatol 2016;64:1388–1402. 3. Oseini AM et al. Liver Int 2017;37 Suppl 1:97–103; 4. FDA
Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment Guidance for Industry, December 2018.
Lifestyle Modification
• Lifestyle modification, including
changes such as diet, weight loss,
and exercise, is recommended as a
first-line treatment3
• Lack of patient compliance may be a
key limitation of this approach1
• Non-indicated treatments, such as vitamin E or
pioglitazone, may be considered in select
patients1,2
• GLP1 Agonist
• Data are limited and risks and benefits should be
discussed with each patient before starting
therapy1
Non-indicated pharmacological
treatments
There is an urgent need for options for patients
with Advanced Fibrosis due to NASH3
53

The GLP1 RA semaglutide has completed a 72-
week phase II trial with 320 participants,
showing resolution of NASH with no worsening
of fibrosis for 56% of patients on 0.4 mg
compared with 20% on placebo.*
*Newsome PN, Buchholtz K, Cusi K, et al. A placebo-controlled trial of subcutaneous
Semaglutide in nonalcoholic steatohepatitis. N Engl J Med 2021;384:1113–24.

On the Horizon..
Five phase III studies are expected to complete the trial part
having surrogate, histological endpoints before the end of
2024 :
1. Aramchol
2. Resmetiron
3. Obeticholic acid
4. Belapectin
5. Lanifibranor
6. Efruxifermin.

Conclusion
The challenge of NASH remains to license a
treatment for this increasingly prevalent and
important condition. There is no shortage of
candidate drugs, but difficulties in diagnosis,
staging and monitoring the effects of
treatment have added unprecedented
complexity to the field.
Combination therapies seem promising.

Thank you for your
attention !

NAFLD

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