nash/nafld management in africa clinical case...

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