Conference on Liver Disease, Kairo, September 2019 Bildergebnis …regist2.virology-education.com/presentations/2019/COLDA/... · 2019. 9. 8. · Pioglitazone improves liver histology

TRANSPLANTATIONSZENTRUM

© Universitätsklinikum Leipzig

Thomas BergClinic and Polyclinic for Gastroenterology, Hepatology, Infectiology

and Pneumology

University Clinic Leipzig

New therapies in NAFLD/NASH

Conference on Liver Disease, Kairo, September 2019

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NAFLD/NASH: Epidemiology and definition

World-wide prevalence of non-alcoholic fatty liver disease

Younossi Z and Henry L. Gastroenterology 2016;150:1778Meta-analysis: NAFLD diagnosed by imaging (US, CT, MRI/SPECT; n=45 studies).Younossi. Hepatology. 2016;64:73.

Definitions of NAFLD, NAFL and NASH

*According to histological analysis or proton density fat fraction or >5.6% by proton MRS or quantitative fat/water-selective MRI;†Daily alcohol consumption of ≥30 g for men and ≥20 g for womenEASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

NAFLD•Excessive hepatic fat accumulation with IR•Steatosis in >5% of hepatocytes*•Exclusion of secondary causes and AFLD†

NASHNAFL

•Pure steatosis•Steatosis and mild lobular inflammation

CirrhoticF4 fibrosis

Fibrotic≥F2 to ≥F3 fibrosis

EarlyF0/F1 fibrosis

HCC

Definitive diagnosis of NASH requires a liver biopsy

EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

Definitions of NAFLD, NAFL and NASH

Nonalcoholic fatty liver disease (NAFLD)

a. Evidence of hepatic steatosis by imaging or histology

b. Lack of secondary causes of hepatic fat accumulation

Nonalcoholic fatty liver (NAFL)

≥5% hepatic steatosis without evidence of hepatocellular

injury in the form of hepatocyte ballooning

Nonalcoholic steatohepatitis(NASH)

≥5% hepatic steatosis and inflammation with hepatocyte injury (eg, ballooning), with or

without any fibrosis

The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance from AASLD_Accessed July 2017EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

Hepatocyte ballooning („ballooning injury“)

none „few“ „prominent“

inter-observer kappa 0.56

Histologic definition of NASH „Goldstandard: NAS Score“

Kleiner et al. Hepatology 2005NAS ≥ 5: NASH, NAS < 3: no NASH

Natural history of NAFLD over 8–13 years

de Alwis NMW, Day CP. J Hepatol 2008;48:S104–12Copyright © 2008 European Association for the Study of the Liver Terms and Conditions

Steatosis

NASH F1−F2fibrosis

HCC

Death/LTx Cirrhosis

AdvancedF3fibrosis

12−40%

5−10%

0−50%

8%

13%

25−50%

14%

25%

7%

http://www.elsevier.com/termsandconditions

NAFLD and NASH - a special concern regarding HCC?

Fan J-G et al. J Hepatol 2017; 67: 862

Multiple organs are likely to be involved in NAFLD

Nobili, V et al. J Hepatol 2013;58:1218−29 Copyright © 2013 European Association for the Study of the Liver Terms and Conditions

• Pathogenesis of NAFLD probably involves inter-organ crosstalk

– Adipose tissue, pancreas, gut, and liver

Visceral ectopic fat

http://www.elsevier.com/termsandconditions

Modified according to Slide credit: clinicaloptions.com

NAFLD as a Complex Disease Trait: Genetic and Environmental Modifiers

Genes

Environment

Normal

Steatosis

NASH

CirrhosisPNPLA3TM6SF2MBOAT…

http://www.clinicaloptions.com/oncology

Therapeutic strategies

Who is „at risk“?

Fibrosis Stage but not NASH Predicts Mortality and Time to Development of Severe Liver Disease

Ayonrinde OT et al., J Hepatol 2017; 67: 1265

Development of severe liver disease compared to matched controls

How to detect people at risk?

Tanaka N et al., World J Gastroenterol 2019

Non-invasive scores predicting ≥ 2 Fibrosis in NAFLD patients

Identification of patients at risk

Castera L et al., Gastroenterology 2019

Pre-test likelihood of NASH (with significant fibrosis)

Kornemann MA et al. J Hepatol 2017

Therapeutic strategies

How should we treat?

• The management of NAFLD should consist of treating liver disease as well as the associated metabolic comorbidities such as obesity, hyperlipidemia, insulin resistance, and T2DM.

• As patients with NAFLD without steatohepatitis or any fibrosis have excellent prognosis from a liver standpoint, pharmacological treatments aimed primarily at improving liver disease should generally be limited to those with biopsy-proven NASH and fibrosis.

AASLD GuidelineWho should be treated with pharmaceuticals

Chalasani N et al., Hepatology 2018

• Structured programmes aimed at lifestyle changes towards healthy diet and habitual physical activity are advisable in NAFLD

• Patient without NASH or fibrosis should receive counselling for healthy diet and physical activity but no pharmacotherapy

• In overweight/obese NAFLD, a 7-10 % weight loss is the target of most lifestyle interventions, and results in improvement of liver enzymes and histology

• Pharmacotherapy should be reserved for patients with NASH, particularly for those with significant fibrosis (stage F2 and higher). Patients with less severe disease, but at high risk of disease progression could also be candidates for treatment.

Therapy of NAFLD: EASL guidelines

EASL–EASD–EASO CPG NAFLD. J Hepatol 2016

Life style modifcations and weigth loss medications?

Romero-Gomez M et al., J Hepatol 2017; 67: 829

Therapy of NAFLD with diet and physical activity:Impact of weight loss

Pharmacotherapy for weight loss

Weight management medications are commonly underused

• Previous weight loss drugs had poor safety record (fenfluramine, sibutramine, rimonabant)

• Frequent follow-up needed for AE monitoring

• Need for long-term use (Goal ≥ 3% weight loss at 3 mos; ≥ 5% at 1 yr)

• Poor and inconsistent insurance coverage – often costly to patient

• Variable response among patients, including many nonresponders

Slide credit: clinicaloptions.com

http://www.clinicaloptions.com/

1. Garvey. Endocr Pract. 2016;(suppl 3):1. 2. Harrison. Hepatology. 2009;49:80 3. Wang. Biomed Rep. 2018;9:90. 4. Armstrong. Lancet. 2015;387:679.

Weight management medication

Mean efficacy criterion: significant difference in mean proportion achieving weight loss ≥ 5% drug vs placebo Categorical efficacy criterion: weight loss ≥ 5% in ≥ 35% of participants, with a significant and ≥ 2-fold difference in proportion achieving this in drug vs placebo groups

*Studied in NASH at 1.8-mg dose approved for diabetes, not 3-mg dose approved for weight loss.

Slide credit: clinicaloptions.com

http://www.clinicaloptions.com/

• Patients with NAFLD should not consume heavy amounts of alcohol

• There are insufficient data to make recommendations with regards to nonheavy consumption of alcohol by individuals with NAFLD

AASLD Guideline

Alcohol Use in Patients with NAFLD and NASH

Chalasani N et al., Hepatology 2018

Is any alcohol consumption strictly forbidden in NAFLD?

49Lee et al. Clin Gastroenterol Hepatol 2018;16:1404-1406

48

Does a (very) low alcohol intake safe lives in NAFLD?

N= 4.568 participants of the NHANES III-Survey (1998–2010) with NAFLD (Hepatic Steatosis Index)

Hajifathalian et al. Hepatology 2018;16:1511-1520

< 0.5 drinks/day

0.5-1.4 drinks/day

≥ 1.5 drinks/day

Therapy of NAFLD with coffee

Romero-Gomez M et al. J Hepatol 2017

Chen YP et al. Clin Nutr 2018

Dose-response relationship of coffee intake (cups per day) with the risk of occurrence of NAFLD

Therapy of NAFLD with coffee

Pharmacological treatment of NASH

EASL Clinical practical guideline:No drugs are approved for NASH

No specific therapy can be recommendedAny drug treatment is off label

EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

Weltweite Häufigkeit der Nicht-alkoholischen Fettleber (NAFLD)Pathopysiological processes in NAFLD as rationale for treatmentstrategies

Courtesy Dr. Q. Anstee

Fibrosis-stage based treatment algorithm for NAFLD/NASH

Sumida Y et al., J Gastroenterol 2018

Pioglitazone efficacy in NASH – Meta-analysis of RCT

42Musso et al. Hepatology 2017;65:1058-1061

• Pioglitazone improves liver histology in patients with and without T2DM with biopsy-proven NASH. Therefore, it may be used to treat these patients. Risks and benefits should be discussed with each patient before starting therapy.

• Until further data support its safety and efficacy, pioglitazone should not be used to treat NAFLD without biopsy-proven NASH.

• Vitamin E may improve steatosis, inflammation and ballooning and resolve NASH in some patients.

• The optimal duration of therapy is unknown; in patients with increased ALT at baseline, treatment should be stopped if there is no reduction in aminotransferases after 6 months of therapy.

Pioglitazone and Vitamin E: Current recommendations

EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402; Chalasani N et al. Hepatology 2018

Armstrong MJ et al., Lancet 2016

Weight (kg) ALT (U/L)

Targeting glucose metabolism: Liraglutide in NASH (LEAN trial)• Long-acting human GLP-1 analogue, t1/2 = 13 h, licensed for glycaemic control in type 2 diabetes• Biopsy-proven NASH, 48 weeks of treatment Liraglutide versus Placebo

Targeting glucose metabolism: Liraglutide in NASH (LEAN trial)• Long-acting human GLP-1 analogue, t1/2 = 13 h, licensed for glycaemic control in type 2 diabetes• Biopsy-proven NASH, 48 weeks of treatment Liraglutide versus Placebo

Armstrong MJ et al., Lancet 2016

Selected GLP-1-Analogues: Study data

Drug Mechanism of

Action

Effects on diabetes Effects on NASH Weight loss /

Specials

LiraglutideLong-acting

GLP-1-analogue

Licensed for glycaemiccontrol in overweight

diabeticians

Phase II: 39 % resolution of NASH vs. 9 % Placebo

(LEAN)

Weight loss at 56 wks: Liraglutide 1,8mg:

4,7 %1 ; Liraglutide 3,0 mg: 7,9

– 8,2 %2

SemaglutideLong-acting

GLP-1-analogue

Licensed for glycaemiccontrol in diabetes

mellitus (SUSTAIN trials, Phase IIIa3)

Phase I trial in NAFLD; Phase IIa trials in NASH with fibrosis (F1-F3) and cirrhosis (F4) launched

Oral formulation with similar effects on

lowering HbA1c and weight loss4

DulaglutideLong-acting

GLP-1-analogue

Licensed for glycaemiccontrol in diabetes

mellitus (AWARD trials, Phase III5)

Reduced transaminase activities, reduced liver

stiffness (n = 15)6

Greater weight reduction than

sitagliptin at 104 wks7

1: Mehta A et al., Obes Sci Pract 2017; 2: Pi-Sunyer X et al., NEJM 2015; 3: Aroda VR et al., Diabetes Metab 2019; 4: Bucheit J et al., Diabetes Technol Ther2019; 5: Jendle J et al., Diabetes Metab Res Rev 2016; 6: Seko Y et al., Hepatol Res 2017; 7: Weinstock RS et al., Diabetes Obes Metab 2015;

Statins• Confidently used to reduce LDL cholesterol and prevent cardiovascular risk• No benefits or harm to liver disease

n-3 polyunsaturated fatty acids• Reduction of both plasma and liver lipids• No data to support their use specifically for NASH

Ezetimibe• Conflicting results, no significant effects on steatosis, only some

improvement of hepatocyte ballooning

Use of lipid-lowering agents in NASH

EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402; Loomba R et al., Hepatology 2015; Nakade Y et al., Hepatol Res 2017

Should we stop statins in patients with cirrhosis?

Serper M et al. AASLD 2017; Abstract #2106

Adjusted overall survival for patients with cirrhosis

The „ideal NASH drug“

To qualify for an ideal drug candidate for the treatment of NASH, the drug should

1) positively regulate abnormal lipid metabolism to reduce steatosis, hepatic inflammation, and injury

2) improve underlying insulin resistance; and

3) induce antifibrotic responses

Cayman Currents, Issue 31, Fatty Liver Disease (NAFLD/NASH), Winter 2019

Targets for treatment based on fibrosis stage

Cayman Currents, Issue 31, Fatty Liver Disease (NAFLD/NASH), Winter 2019

NASH: Key targets for drugs in phase II and phase III clinical trials

Obeticholic acidElafibranor

Selonsertib Cenicriviroc

Connolly JJ et al., J Clin Transl Hepatol 2018

PPAR-α

β-oxidation Steatosis

▪ Clinical data in MetS▪ Clinical data in NASH

▪ Adverse events▪ ? Safety concerns

Less effective for NAFLD in humans

PPAR-γ PPAR-α/δ

Steatosis Insulin sensitivity Inflammation

β-oxidation Hepatic steatosis Insulin sensitivity Inflammation Fibrosis Dyslipidemia

Modified according to Slide credit: clinicaloptions.com

PPARs as Targets for NASH

Elafibranor and PPARα/∂/γ (IVA337)

Thiazolidinediones(i.e. pioglitazone)

Fibrates

Gross B, et al. Nat Rev Endocrinol 2016

http://www.clinicaloptions.com/oncology

Targeting lipid metabolism and inflammation:Elafibranor Phase II results in NASH after 1 year of tx

Ratziu V et al., Gastroenterol 2016

Histologic improvement of NASH• Elafibranor 120 mg: 19 %• Placebo: 12 %

• more pronounced differences in advanced NASH

• Phase III trial ongoing with NASH (F1-F3, NAS ≥ 4)

p = 0.045

Targeting lipid metabolism and inflammation:Elafibranor in NASH (RESOLVE-IT)

Pts with NASH, NAS ≥ 4 (individual

scores each ≥ 1), stage 1-3 fibrosis

(Planned N = 2000)

Elafibranor 120 mg PO QD

Placebo

Randomized 2:1

Wk 72: Interim analysis

Until accrual of predefined number of events (~ 4 yrs)

ClinicalTrials.gov. NCT02704403.

▪ Randomized, placebo-controlled, double-blind, multicenter phase III study in pts with NASH and fibrosis

Primary endpointsResolution of NASH w/o fibrosis worsening at Wk 72Composite of all-cause mortality, cirrhosis, liver-related clinical outcomes at ~ 4 years

Targeting inflammation: CCR2/CCR5-signalling pathway

Friedman S et al., Contemp Clin Trials 2016

Targeting inflammation: Cenicriviroc in NASH Phase II (CENTAUR)

• Cenicriviroc: CCR2/CCR5-Inhibitor, inhibition of monocyte and lymphocyte migration, anti-inflammatory and anti-fibrotic effects

• Phase II results after 1 year of treatment

Friedman S et al., Hepatology 2018• Phase III currently running with NASH and F2-F3 fibrosis

Targeting Inflammation and Fibrosis:Phase III STELLAR Program for Selonsertib in NASH

Phase 3

ClinicalTrials.gov.

Phase III Program for Selonsertib in NASH:STELLAR-3 (F3) and STELLAR-4 (F4)

• Week 48 Primary Endpoint

– ≥ 1 stage decrease in fibrosis, with no worsening of ballooning or inflammation

• Clinical Endpoint at Yr5

– Reduction in events of clinical decompensation, transplant, death (F3 and F4 study)

– Reduction in rates of progression to cirrhosis (F3 study)

Selonsertib 18 mg QD

Week 0 Week 48

Selonsertib 6 mg QD

Year 5

Liver biopsy

Histological Analysis Clinical Endpoint

Placebo QD

N=320

N=320

N=160

ClinicalTrials.gov

Negative Results of the STELLAR Program

Gilead Sciences, Inc., Press releases February 11 and April 25, 2019

Proportion of patients who achieved a ≥ 1-stage improvement in fibrosis without worsening of NASH

The primary endpoint of both studies was not met.

[%]

Placebo Selonsertib 6 mg Selonsertib 18 mg

p = 0.42

p = 0.93

n = 802

[%]

Placebo Selonsertib 6 mg Selonsertib 18 mg

p = 0.56

p = 1.00

n = 877

STELLAR-3 STELLAR-4

Hepatocyte Lipotoxicity

Combination therapies: Gilead NASH Program

ACC, acetyl CoA carboxylase; ASK1, apoptosis signal-regulating kinase 1; FXR, farnesoid X receptor

Inflammation

Fibrogenesis

ASK1(SEL; GS-4997)

ACC(GS-0976)

FXR(GS-9674)

Combinations of drugs are being evaluated for potential additional therapeutic benefit

Phase 2 trial investigating combination use of

Semaglutide (GLP-1 receptor agonist)

Cilofexor (FXR agonist)

Firsocostat (ACC inhibitor)

Possible treatment algorithm:

1) Combination of 2 or 3 drugs for 6 to 12 months (improvement in fibrosis, reduction of steatohepatitis)

2) Long-term maintenance therapy

Collaboration Novo Nordisk with Gilead Sciences: NASH project

Novo Nordisk NN9931-4492, Initiation Site 304; Younossi Z, Gastroenterol Hepatol (N Y) 2019

FXR Central to a Multitude of Key Pathways in Animal Models

↑ Cholesterol

↓ Bile acids

CYP7a1

↓ Fibrosis

↓ Hepatic triglycerides

↑ Glucose toleranceMultiple mechanisms

via ↓ SREPB-1C

RX

R

via ↑ β-oxidation

↓ stellate cell activation

via ↑ iNOS↓ Portal pressure

FXR agonist(eg, obeticholic acid)

1. Cariou B et al. ,Diabetes Metab. 2008;34:685-6912. Calkin AC et al., Nat Rev Mol Cell Biol. 2012;13:213-224

3. Verbeke L et al., Hepatology. 2014;59:2286-98

55Medical Education Purposes Only

REGENERATE Study Design

The interim analysis was conducted after 931 randomized patients with stage 2 or 3 liver fibrosis had or would have reached their actual/planned Month 18 visit (ITT population).EOS analysis of clinical outcomes to confirm clinical benefit.EOS, end of study; ITT, intent to treat; PBO, placebo; QD, once a day.Younossi Z, et al. Presented at EASL, 2019; Vienna, Austria. Oral (GS-06).

Study success was defined as achievement of one of these two primary endpoints

OCA 10 mg (QD)

OCA 25 mg (QD)

Placebo (QD)

Target ~2400 patients

Randomization 1:1:1

EOS0 18 48Months

Fibrosis Improvement by ≥1 Stage

with No Worsening of NASH

NASH Resolution

with No Worsening of FibrosisOR

Month 18 Interim Analysis

Primary Endpoints

BiopsiesEvent driven

Younossi Z et al., EASL 2019 Abstract GS-06, J Hepatol 2019


Fibrosis Improvement by ≥1 Stage with No Worsening of NASHPrimary Endpoint: ITT Population, N=931

Primary endpoint definition: fibrosis improvement by ≥1 stage (NASH CRN) with no worsening of NASH (defined as no worsening of hepatocellular ballooning, lobular inflammation or steatosis).Study success was defined as achievement of one of the two primary endpoints evaluated in the Month 18 interim analysis.*Statistically significant in accordance with the statistical analysis plan agreed with the FDA. All other p values are nominal.Younossi Z, et al. Presented at EASL, 2019; Vienna, Austria. Oral (GS-06).

Placebo OCA 10 mg OCA 25 mg0

10

20

30

40

% P

ati

en

ts

17.6%

23.1%

(n=311) (n=308)

*p=0.0002

11.9%

p=0.04

(n=312)



Fibrosis Improvement by ≥1 Stage with No Worsening of NASH Primary Endpoint: Per Protocol Population, N=668

Primary endpoint definition: fibrosis improvement by ≥1 stage (NASH CRN) with no worsening of NASH (defined as no worsening of hepatocellular ballooning, lobular inflammation or steatosis).Per protocol population defined as all patients from the ITT population who completed ≥15 months of treatment and had a Month 18/EOT biopsy, were on treatment for at least 30 days immediately preceding the biopsy, and did not have any major protocol deviation.P values are nominal.Younossi Z, et al. Presented at EASL, 2019; Vienna, Austria. Oral (GS-06).


10

20

30

40

% P

ati

en

ts

20.8%

27.5%

(n=224) (n=218)

p


Fibrosis Improvement by ≥2 StagesPer Protocol Population

P values are nominal.Per protocol population (N=668).Younossi Z, et al. Presented at EASL, 2019; Vienna, Austria. Oral (GS-06).


5

10

15

20

% P

ati

en

ts

7.1%

13.3%

(n=224) (n=218)

p=0.0008

4.5%

p=0.22

(n=226)



Placebo (n=220)

OCA 10 mg(n=223)

OCA 25 mg (n=213)

% Patients

30 20 10 0 10 20 30 40

38.0%

28.3%

23.2%

13.1%

16.6%

20.9%

Improved FibrosisWorsened Fibrosis

Regression or Progression of Fibrosis by ≥1 StagePer Protocol Population*

*Per protocol population with available fibrosis stage data at Month 18/EOT (n=656).Younossi Z, et al. Presented at EASL, 2019; Vienna, Austria. Oral (GS-06).



Changes in Liver Biochemistry Over TimePer Protocol Population

Per protocol population (N=668).SE, standard error.Younossi Z, et al. Presented at EASL, 2019; Vienna, Austria. Oral (GS-06).

0 3 6 9 12 15 1840

60

80

ALT (U/L)

Month

Mean

(S

E)

ULN

0 3 6 9 12 15 1820

40

60

AST (U/L)

Month

Mean

(S

E)

ULN

0 3 6 9 12 15 18

25

50

75

100

GGT (U/L)

Month

Mean

(S

E)

ULN

0 3 6 9 12 15 1860

80

100

120

140

ALP (U/L)

Month

Mean

(S

E)

ULN

Placebo (n=224)

OCA 10 mg (n=226)

OCA 25 mg (n=218)


FXR regulates bile acid metabolims through multiple levelsin the liver and intestine

Calkin and Tontonoz 2012

A new NASH player: Gut vascular barrier

Mouries J et al. J Hepatol 2019; epub

Mouries J et al., J Hepatol 2019

A new NASH player: Gut vascular barrier

• NASH is a growing and common cause of liver-related morbidity and mortality worldwide

• NASH is projected to soon become the leading indication for liver transplantation in the US

• Fibrosis stage is the strongest predictor of liver-related adverse clinical outcomes in patients with NASH

• There are currently no approved pharmacological therapies for NASH

NAFLD and NASH: a major unmet medical need

Angulo P, Gastroenterology 2015; Diehl AM, NEJM 2017; Dulai PS, Hepatology 2017

Summary I: New Therapies in NAFLD/NASH

• GLP1 analogs and SGLT2 inhibitors are likely to be hepatoprotective in NASH

• Pharmcological treatment of fatty liver should be reserved for patients withNASH, especially with advanced fibrosis

• Patients with advanced NASH should be referred to expertise centers to beevaluated for ongoing clinical studies

• The phase III data in patients with NASH and advanced fibrosis are

– promising for obeticholic acid

– disappointing for selonsertib

– and pending for several other drugs

41,43

Summary II: New Therapies in NAFLD/NASH

• Probably, bile acid/„enterohepatic“ drugs and anti-diabetic drugs arecompeting in a neck-to-neck race

• Combination therapies with several drugs might show additive effectswith more effective reduction in inflammation and/or fibrosis

• Bariatric surgery is a treatment option in obese individuals who failedlifestyle changes and pharmacotherapy

• Personalised and targeted treatment strategies for NASH arenot established yet

41,43

Conference on Liver Disease, Kairo, September 2019 Bildergebnis …regist2.virology-education.com/presentations/2019/COLDA/... · 2019. 9. 8. · Pioglitazone improves liver histology

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