Eva-Doreen Pfister

Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome

A primary immunodeficiency syndrome caused by loss-of-function mutations in the IL-21 receptor exhibits impaired B, T, and NK cell function.

Autophagy-enhancing drug carbamazepine diminishes hepatocellular death in fibrinogen storage disease

Fibrinogen storage disease (FSD) is a rare autosomal-dominant hereditary disorder characterized by hypofibrinogenemia and accumulation of fibrinogen aggregates within the hepatocellular endoplasmatic reticulum (ER). Some FSD patients present with elevated amino-transferases and fibrosis/cirrhosis similar to alpha-1-antitrypsin deficiency (ATD), also an ER storage disease. Pharmacological stimulation of autophagy has been shown to mediate clearance of protein aggregates and halt progression of liver fibrosis in in vivo models of ATD. Our aim was to evaluate the presence of autophagy and a possible response to autophagy-enhancing therapy in patients with FSD. Hepatic fibrosis was assessed by transient elastography in 2 newly identified FSD families with fibrinogen Aguadilla and Brescia mutations, encompassing 8 affected members. Available liver biopsies were assessed for autophagy. Two patients, who had had elevated alanine amino-transaminase levels (2-5 above upper limit of normal), were treated with the autophagy enhancer carbamazepine (CBZ). Transient elastography did not show evidence of significant fibrosis in any affected family members. Quantitative electron microscopy of one patient showed a 5.15-fold increase of late stage autophagocytic vacuoles compared to control livers. CBZ at low anticonvulsive treatment levels led to rapid normalization of alanine-aminotransferase and decrease of caspase-cleaved and uncleaved cytokeratin-18 fragments (M30 and M65). These effects reversed after discontinuation of treatment. Response to CBZ may be mediated by pharmacologically enhanced autophagy resulting in reduction of aggregate-related toxicity in FSD. These results suggest clinical applicability of pharmacological stimulation of autophagy in FSD, but potentially also in other related disorders.

Results of single‐center screening for chronic hepatitis E in children after liver transplantation and report on successful treatment with ribavirin

RNA screening for HEV in 22 liver‐transplanted children with chronic graft hepatitis out of a cohort of 267 liver‐transplanted children detected a single patient with chronic HEV infection. Although this patient remained viremic for 33 months, anti‐HEV‐IgG was not detectable with MP assay but with Wantai assay. We present the first case of successful ribavirin therapy in an immunosuppressed child with chronic HEV infection. In conclusion, chronic HEV infection in immunosuppressed children may not be detectable employing serological assays. Therefore, the most reliably screening method is screening for HEV‐RNA. Chronic HEV infection in children can successfully be treated with ribavirin.

Transsplenic Endovascular Therapy of Portal Vein Stenosis and Subsequent Complete Portal Vein Thrombosis in a 2-year-old Child

A complex catheter intervention for portal vein stenosis and subsequent complete thrombosis after split-liver transplantation was performed using transsplenic access to the portal vein circulation. The combination of intrahepatic, local thrombolysis and extrahepatic portal vein angioplasty performed twice on 2 consecutive days followed by anticoagulation with a high dose of heparin and clopidogrel completely resolved portal vein stenosis and thrombosis. Postinterventional angiographic and serial ultrasound examinations confirmed that the endovascular therapy was successful. In selected patients, percutaneous transsplenic access to the portal vein circulation may be used for diagnostic and therapeutic interventions even in early childhood.

Evaluation of living liver donors using contrast enhanced multidetector CT – The radiologists impact on donor selection

BackgroundLiving donor liver transplantation (LDLT) is a valuable and legitimate treatment for patients with end-stage liver disease. Computed tomography (CT) has proven to be an important tool in the process of donor evaluation. The purpose of this study was to evaluate the significance of CT in the donor selection process.MethodsBetween May 1999 and October 2010 170 candidate donors underwent biphasic CT. We retrospectively reviewed the results of the CT and liver volumetry, and assessed reasons for rejection.Results89 candidates underwent partial liver resection (52.4%). Based on the results of liver CT and volumetry 22 candidates were excluded as donors (31% of the cases). Reasons included fatty liver (n = 9), vascular anatomical variants (n = 4), incidental finding of hemangioma and focal nodular hyperplasia (n = 1) and small (n = 5) or large for size (n = 5) graft volume.ConclusionCT based imaging of the liver in combination with dedicated software plays a key role in the process of evaluation of candidates for LDLT. It may account for up to 1/3 of the contraindications for LDLT.

Estimation of glomerular filtration rate in liver‐transplanted children:Comparison of simplified procedures using 51Cr‐EDTA and endogenous markers with Sapirstein’s method as a reference standard

Berding G, Geisler S, Melter M, Marquardt P, Lühr A, Scheller F, Knoop BO, Pfister E‐D, Pape L, Bischoff L, Knapp WH, Ehrich JHH. Estimation of glomerular filtration rate in liver‐transplanted children: Comparison of simplified procedures using 51Cr‐EDTA and endogenous markers with Sapirstein’s method as a reference standard.
Pediatr Transplantation 2010: 14:786–795.

Predictive Factors for Survival in Children Receiving Liver Transplants for Wilson’s Disease: A Cohort Study Using European Liver Transplant Registry Data

Liver transplantation (LT) is a rescue therapy for life‐threatening complications of Wilson’s disease (WD). However, data on the outcome of WD patients after LT are scarce. The aim of our study was to analyze a large pediatric WD cohort with the aim of investigating the longterm outcome of pediatric WD patients after LT and to identify predictive factors for patient and transplant survival. This is a retrospective cohort study using data of all children (<18 years) transplanted for WD enrolled in the European Liver Transplant Registry from January 1968 until December 2013. In total, 338 patients (57.6% female) transplanted at 80 different European centers (1‐26 patients per center) were included in this study. The median age at transplantation was 14.0 years (interquartile range [IQR], 11.2‐16.1 years); patients were followed up for a median of 5.4 years (IQR, 1.0‐10.9 years) after LT. Overall patient survival rates were high with 87% (1‐year survival), 84% (5‐year survival), and 81% (10‐year survival); survival rates increased considerably with the calendar year (P < 0.001). Early age at LT, living donation, and histidine tryptophan ketoglutarate preservation liquid were identified as risk factors for poor patient survival in the multivariate analysis. LT is an excellent treatment option for pediatric patients with WD and associated end‐stage liver disease. Longterm outcome in these patients is similar to other pediatric causes for LT. Overall patient and graft survival rates improved considerably over the last decades. To improve future research in the field, the vast variability of allocation strategies should be harmonized and a generally accepted definition or discrimination of acute versus chronic WD needs to be found.

Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset

Genetic variants in the adenosine triphosphate‐binding cassette subfamily B member 4 (ABCB4) gene, which encodes hepatocanalicular phosphatidylcholine floppase, can lead to different phenotypes, such as progressive familial intrahepatic cholestasis (PFIC) type 3, low phospholipid‐associated cholelithiasis, and intrahepatic cholestasis of pregnancy. The aim of this multicenter project was to collect information on onset and progression of this entity in different age groups and to assess the relevance of this disease for the differential diagnosis of chronic liver disease. Clinical and laboratory data of 38 patients (17 males, 21 females, from 29 families) with homozygous or (compound) heterozygous ABCB4 mutations were retrospectively collected. For further analysis, patients were grouped according to the age at clinical diagnosis of ABCB4‐associated liver disease into younger age (<18 years) or adult age (≥18 years). All 26 patients diagnosed in childhood presented with pruritus (median age 1 year). Hepatomegaly and splenomegaly were present in 85% and 96% of these patients, respectively, followed by jaundice (62%) and portal hypertension (69%). Initial symptoms preceded diagnosis by 1 year, and 13 patients received a liver transplant (median age 6.9 years). Of note, 9 patients were misdiagnosed as biliary atresia, Alagille syndrome, or PFIC type 1. In the 12 patients with diagnosis in adulthood, the clinical phenotype was generally less severe, including intrahepatic cholestasis of pregnancy, low phospholipid‐associated cholelithiasis, or (non)cirrhotic PFIC3. Conclusion: ABCB4 deficiency with onset in younger patients caused a more severe PFIC type 3 phenotype with the need for liver transplantation in half the children. Patients with milder phenotypes are often not diagnosed before adulthood. One third of the children with PFIC type 3 were initially misdiagnosed, indicating the need for better diagnostic tools and medical education. (Hepatology Communications 2018;2:504‐514)

Side effects and efficacy of renal sparing immunosuppression in pediatric liver transplantation-A single center matched cohort study

Immunosuppressive combination therapy with MMF can reduce CNI associated nephrotoxicity. We investigated effectiveness and safety of de novo MMF‐tacrolimus based immunosuppression after pLTx. Patients after pLTx receiving immunosuppression with MMF/tacrolimus (MMF/TAC) were compared to retrospectively selected age‐ and diagnosis‐matched patients with tacrolimus monotherapy (TAC) and cyclosporine/prednisolone therapy (CSA) (19 patients each, n = 57). Effectiveness, renal function and side effects were analyzed for 1 year after pLTx. Tacrolimus reduction in combination therapy (0.7 μg/L over the year) was lower than aspired (2 μg/L).

Pediatric cirrhotic cardiomyopathy: Impact on liver transplant outcomes

In adults, cirrhotic cardiomyopathy (CCM) has a significant incidence and impact on liver transplantation. For pediatric liver transplantation (pLT), data on liver‐induced cardiac changes are scarce, and in particular, the comparison between cirrhotic and noncirrhotic liver disease has not been investigated. We retrospectively evaluated cardiac changes associated with CCM by echocardiography and 12‐lead electrocardiogram in 198 pLT‐candidates (median age 4.1 years) 4.2 before and 12 months after pLT. Results were correlated with the stage of liver fibrosis and cholestasis before transplantation. The left ventricular end‐diastolic diameter (LVIDd) z score, left ventricular mass z score, and left ventricular mass index were significantly higher in cirrhotic patients (‐0.10 versus 0.98, P < 0.001; ‐1.55 versus ‐0.42, P = 0.001; 78.99 versus 125.64 g/m2, P = 0.001, respectively) compared with children with noncirrhotic liver disease. Pathological z scores (>2SDS) for the LVIDd occurred more frequently in cirrhotic patients compared with patients with noncirrhotic liver disease (31/169 versus 1/29; P = 0.03) and were significantly associated with cholestasis. All observed cardiac changes were reversible 1 year after pLT. Pathological LVIDd z scores correlated highly with intensive care unit (ICU) stay (9.6 days versus 17.1 days, respectively, P = 0.002) but not with patient survival pre‐LT or post‐LT. In contrast to other studies, prolonged QTc time was not associated with liver cirrhosis in our patients. In conclusion, CCM‐associated cardiac changes in pLT candidates with cirrhotic liver disease are frequent, mild, and associated with cholestasis and reversible after pLT. They may impact peritransplant care and posttransplant hospitalization time. Further prospective evaluation is warranted. In particular, for QTc time prolongation etiological factors, possible protective effects of ursodeoxycholic acid treatment and the use as a screening parameter for CCM should be verified. Liver Transplantation 24 820–830 2018 AASLD.