NASH/NAFLD Management in AfricaClinical Case Presentation
Imam Waked, MD, FRCP, FAASLDProfessor of Medicine
National Liver Institute, Egypt
Disclosures
• Investigator / Research Support: Abbvie, Gilead Sciences, Marcyrl, Novartis, Onxio, Pharco,
• Speaker Bureau: Abbvie, Eva Pharma, Gilead Sciences, Marcyrl, Takeda
+24 lbs.+10 kgs.
Obesity a global problem
Background
39,85
35,7
31,329,3
27,424,9
22,220,3
18,516,9
15,313,412
0
5
10
15
20
25
30
35
40
45
20
19
20
17
20
15
20
13
20
11
20
09
20
07
20
05
20
03
20
01
19
99
19
97
19
95
19
93
19
91
19
89
19
87
19
85
19
83
19
81
19
79
19
77
19
75
% B
MI ≥
30
Year
Overall Obesity Prevalence 1975-2019
Background- Obesity on the Increase (Egyptian Adults)
Background- Obesity on the Increase (Egyptian Adults)
CASE
• 52 year old obese woman
• BMI 42 Kg/m2
• No alcohol use
• Chronically tired
• Blood pressure 145/95 mmHg
• ALT 90 IU/L
• LDL 160 mg/dL
• TGs 200 mg/dl
• HDL 30 mg/dl
• Fasting glucose 150 mg/dL
• HbA1C 7.0%
• HBsAg and anti-HCV negative
• Ferritin normal
• Ultrasound: increased liver
echogenicity, no focal lesions, no
gall stones, normal spleen
• Mother died of cirrhosis
• Does she have NAFLD?
• Does she have the metabolic syndrome?
CASE: Questions
The Metabolic Syndrome
• NAFLD is the hepatic consequence of the metabolic syndrome
• Diagnostic criteria for metabolic syndrome: 3 of the following:
1. Abdominal obesity, waist circumference
• Men >102 cm, Women: >88 cm
2. Triglycerides ≥150 mmg/dl or treatment
3. HDL cholesterol
• Men <40 md/dl, Women <50 mg/dl or treatment
4. Blood pressure ≥130mmHg systolic and / or 85 mmHg diastolic, or
treatment
5. Fasting glucose ≥100 mg/dl or treatment
CASE
• 52 year old obese woman
• BMI 42 Kg/m2
• No alcohol use
• Chronically tired
• Blood pressure 145/95 mmHg
• ALT 90 IU/L
• LDL 160 mg/dL
• TGs 200 mg/dl
• HDL 30 mg/dl
• Fasting glucose 150 mg/dL
• HbA1C 7.0%
• HBsAg and anti-HCV negative
• Ferritin normal
• Ultrasound: increased liver
echogenicity, no focal lesions, no
gall stones, normal spleen
• Mother died of cirrhosis
Prevalence of NAFLD Increases with Obesity in T2DM
Portillo-Sanchez P, et al. J Clin Endocrinol Metab. 2015.
Even with AST/ALT ≤ 40 U/L Screened by MRS
Prevalence of Advanced Fibrosis in T2DM with NAFLD
Transient
elastography
Brill F, et al. Diabetes Care. 2017
CASE
• 52 year old obese woman
• BMI 42 Kg/m2
• No alcohol use
• Chronically tired
• Blood pressure 145/95 mmHg
• ALT 90 IU/L
• LDL 160 mg/dL
• TGs 200 mg/dl
• HDL 30 mg/dl
• Fasting glucose 150 mg/dL
• HbA1C 7.0%
• HBsAg and anti-HCV negative
• Ferritin normal
• Ultrasound: increased liver
echogenicity, no focal lesions, no
gall stones, normal spleen
• Mother died of cirrhosis
Ultrasound• NAFLD:
• Increased hepatic echogenicity
• Obscuring periportal echogenicity
• Obscuring the diaphragmatic echogenicity
• Normal liver:
• Normal echogenicity
• Visible periportal echogenicity
• Visible diaphragmatic echogenicity
Ultrasound• Grade 1: increased hepatic
echogenicity with visible
periportal and diaphragmatic
echogenicity
• Grade 2: increased hepatic
echogenicity with imperceptible
periportal echogenicity, without
obscuring the diaphragm
• Grade 3: increased hepatic
echogenicity with imperceptible
periportal echogenicity, and
obscuring the diaphragm
• Other non-invasive investigations to diagnose NAFLD?
CASE: Questions
NAFLD: Non-invasive diagnosis
• Currently, therapeutic trials in NASH require liver biopsy to
establish an initial diagnosis of NASH and to document
treatment response
• Available alternative methods can quantify fat in the liver and
assess fibrosis stage
• Non-invasive, reliable, accurate, safe and quantitative
biomarkers for NASH are needed as an alternative to liver
biopsy
Caussy C, et al Hepatology 2018; epub ahead of print
CT• Normal liver
• Minimal lipid storage
• Denser and higher Hounsfield unit (HU) than spleen
• Appears bright on contrast
• NAFLD
• Density decreases
• HU decreases
• Less than the spleen
• Appears darker on contrast
• HU <40 suggestive
HU 80 HU 15
• MRI proton density fat
fraction (MRI-PDFF) is
quantitative fat imaging
• Enables accurate
quantitative assessment of
liver fat over the entire liver
Caussy C, et al Hepatology 2018; epub ahead of print
MRI-PDFF
Caussy C, et al Hepatology 2018; epub ahead of print
• Able to assess treatment response of fat content in NASH.
• Does not assess
• Ballooning, inflammation, fibrosis
MRI-PDFF
Predicting Fibrosis: NAFLD Fibrosis Score
Score Interpretation
< -1.455No advanced fibrosis
≥-1.455 to ≤0.676
Indeterminate score
> 0.676Advanced fibrosis
• Formula for prediction of severity of fibrosis
• -1.675
• + 0.037 x age (yrs)
• + 0.094 x BMI (kg/m2)
• + 1.13 IFG / Diabetes
( yes=1, no = 0)
• + 0.99 x AST/ALT ratio
• - 0.013 x PLTs x109/L )
• – 0.66 x Albumin g/L
http://www.nafldscore.com/
Angula et al Hepatology 2007
Fibroscan with XL probe vs liver biopsy
Yoneda et al Dig Liv Dis 2008; 40: 371-8
Predicting Fibrosis: LSM
Angula et al Hepatology 2007
Accuracy of Fibroscan® in NAFLD• For advanced fibrosis (F3,4)
• AUC 0.8-0.9• Cut-offs between 9-10 kPa
• For cirrhosis (F4)• AUC 0.85-0.95• Cut-offs between 11-12 kPa
CASE
• 52 year old obese woman
• BMI 42 Kg/m2
• No alcohol use
• Chronically tired
• Blood pressure 145/95 mmHg
• ALT 90 IU/L
• LDL 160 mg/dL
• TGs 200 mg/dl
• HDL 30 mg/dl
• Fasting glucose 150 mg/dL
• HbA1C 7.0%
• HBsAg and anti-HCV negative
• Ferritin normal
• Ultrasound: increased liver
echogenicity, no focal lesions, no
gall stones, normal spleen
• Mother died of cirrhosis
• NAFLD fibrosis score: 2.0
• Fibroscan: 10.5 kPa
• Does she have NASH?
• Does she need a liver biopsy?
CASE: Questions
NAFLD Disease SpectrumNAFLD
• Increased risk of death compared to the general population
• CVS• Malignancy• Liver-related
• Worse prognosis with fibrosis~20%
NASH (20%-25%)
Isolated steatosis (70%-75%)
<5%
• No or very minimal progression to fibrosis
• No increased risk of death
Kleiner DE, et al Hepatology 2005
Item Definition Score
NAS
Steatosis
Low to medium power evaluation of steatosis<5% 05%-33% 1>33%-66% 2>66% 3
Lobular Inflammation
Overall assessment of inflammatory fociNo foci 0<2 foci/ x 200 field 12-4 foci / x200 field 2>4 foci / x 200 field 3
Hepatocyte Ballooning
None 0Few 1Many 2
Full score: 8
Fibrosis Stage
None 0
Perisinusoidal or periportal 1
Mild, zone 3 1A
Moderate, zone 3 1B
Portal / periportal 1C
Perisinusoidal and periportal 2
Bridging 3
Cirrhosis 4
DiagnosisNAFLD Activity Score (NAS Score)
Kleiner DE, et al Hepatology 2005
Fibrosis Stage
None 0
Perisinusoidal or periportal 1
Mild, zone 3 1A
Moderate, zone 3 1B
Portal / periportal 1C
Perisinusoidal and periportal 2
Bridging 3
Cirrhosis 4
DiagnosisNAFLD Activity Score (NAS Score)
• Making diagnosis of NASH
• (surrogates insufficient)
• Stage fibrosis
• If MRE, TE, or NAFLD
fibrosis score indeterminate
• Rule out concomitant liver
disease
• Autoimmune, Wilson’s,
Drug-induced injury
• Iron overload
DiagnosisThe Role of Liver Biopsy
• Liver biopsy: NASH with NAS score 7, stage 3 fibrosis
• Any effective therapy?
CASE
Management of NAFLD and NASH
• Weight reduction• Lifestyle interventions
• Bariatric surgery
• Pharmacologic therapy
• Pharmacologic Management
• Available products
• Products in the pipeline• PPAR agonists (ELA)
• FXR agonists (OCA, tropifexor)
• Anti-inflammatory - Anti-
fibrotics (Cenicriviroc)
• Acetyl-CoA-carboxylase
inhibitor
• PEG-FGF-21 (pegbelfermin
(BMS-986036))
• FGF-19 analogue (NGM282)
• Combinations
• There are no approved treatments for NASH
• Weight loss reduces hepatic steatosis (diet alone or with increased physical activity).
• Loss of 3–5% of body weight necessary to improve steatosis
• Weight loss of ~10% may be needed to improve necro-inflammation.
Lifestyle Interventions
Vilar-Gomez et al. Gastroenterology 2015
• Prospective study: 293 patients, histologically proven NASH, encouraged to change lifestyle to reduce weight over 52 weeks
• 261 had paired biopsies
• 88 (30%) lost >5% body weight
36
88
100
13
64
90
0
20
40
60
80
100
<7%n=239
7%-9.9%n=25
>10% n-29
<7%n=239
7%-9.9%n=25
>10%n-29
NAS improvement NASH Resolution
Perc
ent
wit
h e
nd
po
int
Lifestyle Interventions
Vilar-Gomez et al. Gastroenterology 2015, Promrat et al. Hepatology 2010, Harison et al Hepatology 2009, Wong et al, J Hepatol 203
• Prospective study: 293 patients, histologically proven NASH, encouraged to change lifestyle to reduce weight over 52 weeks
• 261 had paired biopsies
• 88 (30%) lost >5% body weight
Lifestyle Interventions
NAS 1; 18,30
NAS 2; 45,1
NAS 3; 14,6
NAS 4; 7,3
NAS 4; 7,3
NAS 5; 30,5
NAS 5; 7,3
NAS 6; 39
NAS 6; 6,1
NAS 7; 14,6
NAS 8; 8
0%
20%
40%
60%
80%
100%
Before After
Impact on histology (NAS Score) at 1 year
NAS 8
NAS 7
NAS 6
NAS 5
NAS 4
NAS 3
NAS 2
NAS 1
Lassailly M et al. Gastroenterology 2015
• At 1 year 82/109 had paired liver bx• NASH disappeared in 80% of cases • All histological features improved
Bariatric Surgery
Indications
Endoscopic Bariatric therapies
• Started diet and exercise program
• 6 months later:
• Losing weight but very slow progress
• ALT still elevated
• She is “scared of complications of bariatric surgery”
• Wants “medicine”
CASE
Pharmacologic Management for NASH
• There are no approved treatments for NASH
• Available products approved for other indications:
• Vitamin E
• Glitazones
• GLP-1 analogues (liraglutide, semaglutide)
PIVENS Study• Pioglitazone , Vitamin E,
placebo
• 96 weeks, adults with NASH,
• No DM, cirrhosis, Hep C, heart failure, limited alcohol
• Randomized trial:
• Pio: 80
• Vit E: 84
• Placebo: 83
Sanyal et al, NEJM 2010
Vit E vs placebo: p<0.05Pio vs placebo: NS
Pharmacologic therapy for NASH
43%
34%
19%
0%
10%
20%
30%
40%
50%
Vit E Pio Placebo
Improvement in NAS and Fibrosis
PIVENS Study
Pharmacologic therapy for NASH
Sanyal et al, NEJM 2010
PIVENS Study
Pharmacologic therapy for NASH
Differential treatment responseBaseline NAS score
Placebo not effective with NAS ≥ 6
Baseline BMI
Vit E not effective with BMI ≥ 40
Sanyal et al, NEJM 2010
Pioglitazone long-term
• 101 patients, 50 PIO 45 mg/d, 51 placebo
• 18 months, followed by 18-month open-label PIO.
Cusi et al, Ann Int Med, 2016
Vit. E and Pioglitazone AEs
• Vitamin E:
• 50% of patients do not respond
• Meta-analysis (136,000
participants) Vit E > 400 IU/day
→ higher risk of all cause mortality
• Increased risk of hemorrhagic
stroke
• Synthetic vitamin E → increased
risk of prostate cancer (risk 1.6 per
1000 person years)
Miller et al Ann Intern Med 2005
Klein, et al, JAMA 2011
• Pioglitazone
Ratziu V, Nat Revie Gastro Hepatol 2013
Linkoff AM, et al, JAMA 2007
Liraglutide (Victoza, Saxenda)
• Phase II randomized trial
• Overweight patients with and without DM
• Dose of 1.8 mg/day for 48 weeks.
• Approved for weight loss (Saxenda), and to reduce cardiovascular risk in type 2 DM.
Tølbøl KS et al, AASLD 2016, Pi-Sunyer X, et al. N Engl J Med 2015; 373: 11-22. Marso SP et al, NEJM, 2016, Mesquita F, et al; AASLD 2016
39%
9%9%
35%
0%10%20%30%40%50%
Reolustion of NASH Progression to Cirrhosis
LIR 1.8 mg/day vs Placebo
Liraglutide Placebo
• Long-acting human glucagon-like-peptide (GLP)-1 analogue
• Induces insulin secretion and reduces glucagon release.
• Reduces appetite and delays gastric emptying, resulting in weight loss.
• In phase IIb for treatment of NASH
• 1,824 Pts with elevated ALT and T2DM &/or obesity
• 52‐week in obese (SEM 0.05‐0.4 mg/day)
• 104‐wks in T2DM (SEM 0.5 or 1.0 mg/week)
GLP-1 Analogues: Semaglutide (Ozempic)
Newsome et al, AP&T 2019
• Long acting GLP-1 receptor agonist• Once weekly injection• Improves glycemic control, reduces body
weight, and cardiovascular disease risk in T2DM• FDA approved for DM
• Lubiprostone: type 2 chloride channel activator laxative
• Ameliorates increased intestinal permeability
Gut Permeability and NASH
Kessoku et al, EASL 2019
• NASH develops in two steps:
• Healthy liver become steatotic as
a consequence of insulin
resistance
• Additional insults, such as
bacterial LPS, induce oxidative
stress and production of
cytokines, particularly TNFa, that
sustain liver damage
Lubiprostone for NASH
• Efficacy, safety, and tolerability of
lubiprostone for the treatment of NASH
• 150 Patients
• NAFLD: ALT ≥ 40 IU/L, MRI-PDFF ≥ 5.2%,
MR elastgraphy < 6.7kPa
• RCT: 12 μg, 24 μg or placebo 12 weeks
Kessoku et al, EASL 2019
Management of NAFLD and NASH
• Products in the pipeline
• PPAR agonists (ELA)
• FXR agonists (OCA, tropifexor)
• Anti-inflammatory - Anti-fibrotics (Cenicriviroc)
• Acetyl-CoA-carboxylase inhibitor
• PEG-FGF-21 (pegbelfermin (BMS-986036))
• FGF-19 analogue (NGM282)
• Combinations
• Received liraglutide (Victoza) sc daily in addition to diet and exercise
• After 12 months: lost 10 kg
• BMI 36
• ALT 42
• Fibroscan: 10 kPa
CASE
Un-Answered Questions
• Effective upcoming therapies raise many questions:
• Should simple steatosis be treated?
• may be easily reversed
• is rarely progressive
• Who should be treated?
• Would treatment at initial stages ↓ disease
progression?
• NASH cirrhosis? No evidence that cirrhosis may be
reversed
• For how long? Indefinitely?
• NAFLD and NASH becoming the commonest liver disease
worldwide
• No approved treatments
• Few available products can be used off-label
• Several effective therapies in the pipeline?
• Lifestyle modification and weight loss essential
Conclusions
Thank You