1

Update in Pediatric Liver Disease

• Pat McKiernan

• Children’s Hospital of Pittsburgh and University of Pittsburgh

2

• Conflicts to report

• Consultant for Albireo

Disclosures

3

Liver transplant for metabolic disease in US 1987-2017patient survival: children versus adults

3

0 2000 4000 6000 8000 10000

0.0

0.2

0.4

0.6

0.8

1.0

Time post transplant (Days)

Surv

ival R

ate Adults

Children

4

Summary of problem: 1. Death Rate per 100 Patient Years for Candidates Ever Waiting for Liver Alone Transplants during 2011-

2015 by Age

4

*Age is maximum of age at listing or age at beginning of the study cohort.

5

Placement of pediatric deceased donors whose livers were ultimately transplanted

UNOS 2010 -2105

J Ge et al Hepatology 2018,

From Cutting downTo splitting

+

7

Potential splittable livers UNOS 2010 to 2015

Perito et al Transplantation March 2019

8

Potential splittable livers and pediatric mortality and transplants UNOS 2010 to

2015

Perito et al Transplantation March 2019

9

Type of organ in DDLT recipient < 2 years

Fischler et al. JPGN May 2019

10

Percentage of DDLT and living donor liver transplantation in recipients < 2 years.

Fischler et al. JPGN May 2019

11

Waiting list mortality for children

12

11 11 127

2117 16

13

0

5

10

15

20

25

30

35

2016 2017 2018 2019 through Oct.

LIVING DONOR DECEASED DONOR

Donor type at CHP

13

Normal post transplant liver biopsy

14

Post transplant chronic hepatitis

15

Posttransplant perivenular inflammation

16

Fibrosis grade in children with chronic hepatitis at 1, 5 and 10 years post OLT

Time post OLT (years)

1051

Perc

enta

ge

of cases

50

40

30

20

10

0

Fibrosis

None

Mild

Moderate

Severe

Evans H et al; Hepatology 2006

17

Subclinical Damage in Long-term Pediatric Liver Transplant Allografts

• Screening for iWITH study

• 2909 recipients at 12 centres

• 584 met medical criterion

• 355 met medical criterion and logistics

• 276 approached

• 161 agreed

• 157 enrolled Feng et al. Gastroenterology 2018;155:1838–1851

18

Frequency of histological abnormalities

Feng et al. Gastroenterology 2018;155:1838–1851

19

Cluster analysis

20

3 distinct histological clusters

Feng et al. Gastroenterology 2018;155:1838–1851

21

Gene coexpression modules network analysis of the liver

transcriptome

Feng et al. Gastroenterology 2018;155:1838–1851

22

Differential gene expression between clusters.

Genes associated with T-cell rejection increased in cluster 1

Feng et al. Gastroenterology 2018;155:1838–1851

No increase in intragraft endothelial- or natural

killer cell–related gene signatures

23

Class II DSA MFI by cluster.

Feng et al. Gastroenterology 2018;155:1838–1851

24

Antigen-presenting foci localized primarilyto portal tracts in cluster 1

25 Haller et al IPTA 2019

Treatment cohorts at BCH

26

Demographics

Haller et al IPTA 2019

27

Protocol blood tests

Haller et al IPTA 2019

28

Histological diagnosis

P=0.001

P=0.001

n=125n=122 n=56 n=67

Other

IPTH

Normal/near normal

Mono(CNI only)

Combo(CNI-Pred)

5yr 5yrMono(CNI only)

10yrCombo(CNI-Pred)

10yr

Haller et al IPTA 2019

29

Allograft fibrosis

%

P=0.031 P=0.537

n=125 n=56 n=67n=122

Haller et al IPTA 2019

30

Increasing use of transient elastography to assess liver stiffness

Limited but increased experience in pediatrics

Preponderance in biliary atresia and cystic fibrosis

Mostly single center experiences

From Yu JH, Ultrasonography 2017;36:86-94Background

31

32

Study Aims

• To prospectively assess whether LSM are associated with clinical and laboratory features of portal hypertension and liver disease in children with biliary atresia (BA), Alagille syndrome (ALGS) and alpha-1 antitrypsin deficiency (A1AT)

• To confirm the feasibility of obtaining LSM in children with cholestatic liver diseases

NCT02922751

33

Clinically Evident Portal Hypertension

• Definite CEPH

– Spleen > 2cm BCM and Platelet < 150,000 or

– History of clinically evident ascites or

– Endoscopic esophageal or gastric varices

• Possible CEPH

– Spleen > 2cm BCM or platelet

34

Results - Enrollment

• Between Nov 2016 and August 2019

35

Results - Feasibility Feasibility 82.9%95% CI: 79.8-86.1%

36

Results – LSM v CEPH

37

Summary

• Longterm outlook post pediatric liver transplantation is excellent

• Current waiting list management does not give children sufficient priority

• The ideal very longterm immunosuppressant regimen not yet clear

• Elastography is valid in children with some modification

38

• Mention use of fibroscan elastography and use the shnedirer slides