PLRC - Weekly Update June 7, 2018

In this email:

P30 Grant submitted

Suggestions for upcoming Seminar Series

Recent Publications by PLRC Members

P30 grant application submitted - THANK YOU!!

It is our great pleasure to report that we met all deadlines and successfully submitted the P30 grant

application for the Pittsburgh Liver Research Center last Friday, June 1. Overall, the proposal looks

compelling, and we remain cautiously optimistic about it.

Please visit our website (www.livercenter.pitt.edu) for the most up-to-date information on the PLRC’s

organization. All of the Scientific Cores and the Clinical Component are established and are offering an

array of services, which are outlined on the website.

We remain indebted to the Institutional leadership at the University of Pittsburgh and UPMC for their

support that has enabled us to offer this rich variety of services. We are grateful to our Core and Program

directors for their invaluable time and efforts that allowed for the successful completion of the proposal.

Thanks to all the members of the PLRC and their administrative teams for submitting the required

documents and information in a timely manner. The PLRC has 80 full and associate members, and we are

extremely grateful to everyone for coming through for us!

Please look for information over the next few months regarding a PLRC mini-retreat at which we will

apprise you of the current state of the Center and the vision going forward.

Have a happy summer!

Seeking suggestions for 2018-19 PLRC seminar series

Over the next few weeks, we will begin planning the PLRC seminar series for Fall 2018 and Spring 2019.

If you have an idea for a liver-related speaker, please complete the attached form and return it by Friday,

June 22, to Ann Vinski (vinskiam@upmc.edu). Thank you!

Recent Publications by PLRC Members

1. Tassos Grammatikopoulos, Patrick James McKiernan, Anil Dhawan. Portal hypertension and its

management in children. Archives of Disease in Childhood 2018;103:186-191.

ABSTRACT: Portal hypertension (PHT), defined as raised intravascular pressure in the portal system, is a

complication of chronic liver disease or liver vascular occlusion. Advances in our ability to diagnose and

monitor the condition but also predict the risk of gastrointestinal bleeding have enabled us to optimise the

management of children with PHT either at a surveillance or at a postbleeding stage. A consensus among

paediatric centres in the classification of varices can be beneficial in streamlining future paediatric studies.

New invasive (endoscopic and surgical procedures) and non-invasive (pharmacotherapy) techniques are

currently used enabling clinicians to reduce mortality and morbidity in children with PHT.

For full text, please click here.

2. Lisa G.Sorensen, Katie Neighbors, Regina M. Hardison, Kathleen M. Loomes, James W. Varni, Vicky

L. Ng, Robert H. Squires, Estella M. Alonso. Health Related Quality of Life and Neurocognitive Outcomes

in the First Year after Pediatric Acute Liver Failure. The Journal of Pediatrics. Volume 196, May 2018,

Pages 129-138.e3.

ABSTRACT:

Objective: To determine health-related quality of life (HRQoL) and neurocognitive impairment in survivors

of pediatric acute liver failure (PALF).

Study design: A longitudinal prospective study was conducted. At 6 and 12 months after PALF

presentation, surveys of HRQoL were completed for 2- to 19-year-olds and executive functioning for ages

2-16 years. At 12 months, patients 3-16 years of age completed neurocognitive testing. HRQoL scores

were compared with a healthy, matched sample. Neurocognitive scores were compared with norms;

executive functioning scores were examined categorically.

Results: A total of 52 parent-report HRQoL surveys were completed at 6 months, 48 at 12 months; 25

patients completed neurocognitive testing. The median age at 6 months was 7.9 years (range 3.5-15.0),

and final diagnosis was indeterminate for 46.2% (n = 24). Self and parent-report on Pediatric Quality of

Life Inventory Generic and Multidimensional Fatigue scales fell below the healthy sample at 6 months and

12 months (almost all P < .001). Children reported lower mean scores on cognitive fatigue at 12 months

(60.91 ± 22.99) compared with 6 months (73.61 ± 27.49, P = .006) . The distribution of Behavior Rating

Inventory of Executive Function scores was shifted downward on parent-report (preschool) for all indices

at 6 months (n = 14, P ≤ .003); Global Executive Composite and Emergent Metacognition at 12 months

(n = 10, P = .03). Visual Motor Integration (VMI-6) Copying (mean = 90.3 ± 13.8, P = .0002) and VMI-6

Motor Coordination (mean = 85.1 ± 15.2 P = .0002) fell below norms, but full scale IQ (Wechsler Scales)

and Attention (Conners' Continuous Performance Test) did not.

Conclusions: Survivors of PALF appear to show deficits in motor skills, executive functioning, HRQoL, and

evidence for worsening cognitive fatigue from 6 to 12 months following PALF presentation.

For full text, please click here.

3. McKiernan P. (2017) Liver Transplantation for Hereditary Tyrosinaemia Type 1 in the United Kingdom.

In: Tanguay R. (eds) Hereditary Tyrosinemia. Advances in Experimental Medicine and Biology, vol 959.

Springer, Cham.

ABSTRACT: Fourteen children have undergone liver transplantation for hereditary tyrosinaemia type 1

(HT1) at Birmingham Children's hospital (BCH) since 1989; six were treated prior to the availability of

Nitisinone in 1993 and eight in the post Nitisinone era. Prior to 1993 essentially all children with HT1 were

referred for transplantation. In the Nitisinone era only those with unresponsive liver failure or suspected

malignancy were considered for transplantation. Those who were treated pre-emptively following newborn

screening have no evidence of liver disease and none have required transplantation.Absolute patient

survival is 86% for the whole group and 100% in the Nitisinone era. There has been a functional

correction of the metabolic defect in all cases allowing a normal diet. Persistent renal succinylacetone

production was universal but did not appear to have any clinical consequence. Renal function appeared

better, and hypertension less common in those treated in the Nitisinone era.Outcome was poorer for those

four children with established malignancy; one was unfit for transplantation and another developed a

pulmonary metastasis, which was successfully resected.

For full text, please click here.

4. Cindy L. Bryce, Chung Chou H. Chang, Yi Ren, Jonathan Yabes, Gabriel Zenarosa, Aditya Iyer,

Heather Tomko, Robert H. Squires, Mark S. Roberts. (2018) Using time-varying models to estimate post-

transplant survival in pediatric liver transplant recipients. PLoS ONE 13(5):

e0198132. https://doi.org/10.1371/journal.pone.0198132

ABSTRACT:

Purpose: To distinguish clinical factors that have time-varying (as opposed to constant) impact upon

patient and graft survival among pediatric liver transplant recipients.

Methods: Using national data from 2002 through 2013, we examined potential clinical and demographic

covariates using Gray’s piecewise constant time-varying coefficients (TVC) models. For both patient and

graft survival, we estimated univariable and multivariable Gray’s TVC, retaining significant covariates

based on backward selection. We then estimated the same specification using traditional Cox proportional

hazards (PH) models and compared our findings.

Results: For patient survival, covariates included recipient diagnosis, age, race/ethnicity, ventilator

support, encephalopathy, creatinine levels, use of living donor, and donor age. Only the effects of

recipient diagnosis and donor age were constant; effects of other covariates varied over time. We retained

identical covariates in the graft survival model but found several differences in their impact.

Conclusion: The flexibility afforded by Gray’s TVC estimation methods identify several covariates that do

not satisfy constant proportionality assumptions of the Cox PH model. Incorporating better survival

estimates is critical for improving risk prediction tools used by the transplant community to inform organ

allocation decisions.

For full text, please click here.

5. Carola Dröge, Michele Bonus, Ulrich Baumann, Caroline Klindt, Elke Lainka, Simone Kathemann,

Florian Brinkert, Enke Grabhorn, Eva-Doreen Pfister, Daniel Wenning, Alexander Fichtner, Daniel N.

Gotthardt, Karl Heinz Weiss, Patrick McKiernan, Ratna Dua Puri, I.C. Verma, Stefanie Kluge, Holger

Gohlke, Verena Keitel. Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with

cholestasis revealed a high number of different genetic variants. J Hepatol. 2017 Dec;67(6):1253-1264.

doi: 10.1016/j.jhep.2017.07.004. Epub 2017 Jul 19.

ABSTRACT:

Background & Aims: The bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3,

ABCB4) and the ATPase familial intrahepatic cholestasis 1 (FIC1, ATP8B1) mediate bile formation. This

study aimed to determine the contribution of mutations and common variants in the FIC1, BSEP and

MDR3 genes to cholestatic disorders of differing disease onset and severity.

Methods: Coding exons with flanking intron regions of ATP8B1, ABCB11, and ABCB4 were sequenced in

cholestatic patients with assumed genetic cause. The effects of new variants were evaluated by

bioinformatic tools and 3D protein modeling.

Results: In 427 patients with suspected inherited cholestasis, 149 patients carried at least one disease-

causing mutation in FIC1, BSEP or MDR3, respectively. Overall, 154 different mutations were identified, of

which 25 were novel. All 13 novel missense mutations were disease-causing according to bioinformatics

analyses and homology modeling. Eighty-two percent of patients with at least one disease-causing

mutation in either of the three genes were children. One or more common polymorphism(s) were found in

FIC1 in 35.3%, BSEP in 64.3% and MDR3 in 72.6% of patients without disease-causing mutations in the

respective gene. Minor allele frequencies of common polymorphisms in BSEP and MDR3 varied in our

cohort compared to the general population, as described by gnomAD. However, differences in ethnic

background may contribute to this effect.

Conclusions: In a large cohort of patients, 154 different variants were detected in FIC1, BSEP, and MDR3,

25 of which were novel. In our cohort, frequencies for risk alleles of BSEP (p.V444A) and MDR3 (p.I237I)

polymorphisms were significantly overrepresented in patients without disease-causing mutation in the

respective gene, indicating that these common variants can contribute to a cholestatic phenotype.

For full text, please click here.

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