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


• BMI 42 Kg/m2

• No alcohol use



• ALT 90 IU/L

• LDL 160 mg/dL

• TGs 200 mg/dl

• HDL 30 mg/dl


• HbA1C 7.0%


• Ferritin normal





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


• BMI 42 Kg/m2

• No alcohol use



• ALT 90 IU/L

• LDL 160 mg/dL

• TGs 200 mg/dl

• HDL 30 mg/dl


• HbA1C 7.0%


• Ferritin normal





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


MRI-PDFF


• 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


• BMI 42 Kg/m2

• No alcohol use



• ALT 90 IU/L

• LDL 160 mg/dL

• TGs 200 mg/dl

• HDL 30 mg/dl


• HbA1C 7.0%


• Ferritin normal





• 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


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


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



PIVENS Study


Differential treatment responseBaseline NAS score

Placebo not effective with NAS ≥ 6

Baseline BMI

Vit E not effective with BMI ≥ 40


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

NASH/NAFLD Management in Africa Clinical Case...

Documents

Transcript of NASH/NAFLD Management in Africa Clinical Case...