Background & Aims Homozygous loss of function mutations in interleukin-10 ( IL10 ) and interleukin-10 receptors ( IL10R ) cause severe infantile (very early onset) inflammatory bowel disease (IBD). ...Allogeneic hematopoietic stem cell transplantation (HSCT) was reported to induce sustained remission in 1 patient with IL-10R deficiency. We investigated heterogeneity among patients with very early onset IBD, its mechanisms, and the use of allogeneic HSCT to treat this disorder. Methods We analyzed 66 patients with early onset IBD (younger than 5 years of age) for mutations in the genes encoding IL-10, IL-10R1, and IL-10R2. IL-10R deficiency was confirmed by functional assays on patients' peripheral blood mononuclear cells (immunoblot and enzyme-linked immunosorbent assay analyses). We assessed the therapeutic effects of standardized allogeneic HSCT. Results Using a candidate gene sequencing approach, we identified 16 patients with IL-10 or IL-10R deficiency: 3 patients had mutations in IL-10, 5 had mutations in IL-10R1, and 8 had mutations in IL-10R2. Refractory colitis became manifest in all patients within the first 3 months of life and was associated with perianal disease (16 of 16 patients). Extraintestinal symptoms included folliculitis (11 of 16) and arthritis (4 of 16). Allogeneic HSCT was performed in 5 patients and induced sustained clinical remission with a median follow-up time of 2 years. In vitro experiments confirmed reconstitution of IL-10R−mediated signaling in all patients who received the transplant. Conclusions We identified loss of function mutations in IL-10 and IL-10R in patients with very early onset IBD. These findings indicate that infantile IBD patients with perianal disease should be screened for IL-10 and IL-10R deficiency and that allogeneic HSCT can induce remission in those with IL-10R deficiency.
This study aims to evaluate the long‐term efficacy and reintervention rate after primary percutaneous portal vein stent angioplasty for portal vein stenosis (PVS) in pediatric liver transplantation ...(LT) recipients. From 2004 to 2020, a total of 470 pediatric LTs were performed in our center. All cases were screened for interventional PVS treatment and analyzed retrospectively. We identified 44 patients with 46 percutaneous angioplasties for posttransplantation PVS. The median interval from LT to percutaneous catheter intervention was 5 months (16 days–104 months) with a median follow‐up (f/u) period after catheter intervention of 5.7 years (2–156 months). In 40 patients, an endovascular stent was placed as primary (n = 38) or secondary (n = 2) intervention. The median age at stent placement was 23 (6–179) months with a median weight of 10 kg (6–46 kg). Technical success and relief of PVS were achieved in all patients irrespective of age or weight. Adverse events occurred peri‐interventionally in two patients and were resolved with standard care. All primary portal vein (PV) stents remained patent until the end of f/u. Reinterventions have been successfully performed in 10 patients for suspected or proven restenosis, resulting in a primary patency rate of 75% and an assisted patency rate of 25%. The median time to reintervention was 6.2 years (range 1–10 years). The need for reintervention was independent of age or weight at both transplantation and initial angioplasty as well as of additional risk factors due to portal hypertension. Percutaneous transhepatic PV stent angioplasty in children is safe and effective in all age groups, with excellent long‐term patency. Primary stent angioplasty should be considered as first‐line treatment for PVS after pediatric LT.
Background and Aims
Progressive familial intrahepatic cholestasis (PFIC) is a collective term for a heterogenous group of rare, inherited cholestasis syndromes. The number of genes underlying the ...clinical PFIC phenotype is still increasing. While progressive liver disease and its sequelae such as portal hypertension, pruritus and hepatocellular carcinoma determine transplant‐free survival, extrahepatic manifestations may cause relevant morbidity.
Methods
We performed a literature search for extrahepatic manifestations of PFIC associated with pathogenic gene variants in ATP8B1, ABCB11, ABCB4, TJP2, NR1H4 and MYO5B. To illustrate the extrahepatic symptoms described in the literature, PFIC cases from our centres were revisited.
Results
Extrahepatic symptoms are common in PFIC subtypes, where the affected gene is expressed at high levels in other tissues. While most liver‐associated complications resolve after successful orthotopic liver transplantation (OLT), some extrahepatic symptoms show no response or even worsen after OLT.
Conclusion
The spectrum of extrahepatic manifestations in PFIC highlights essential, non‐redundant roles of the affected genes in other organs. Extrahepatic features contribute towards low health‐related quality of life (HRQOL) and morbidity in PFIC. While OLT is often the only remaining, curative treatment, potential extrahepatic manifestations need to be carefully monitored and addressed.
Wilson's disease is an autosomal recessive disorder resulting from copper excess. Some patients with clinical Wilson's disease symptoms exhibit no or only heterozygous pathogenic variants in the ...coding region of the disease‐causing ATP7B gene. Therefore, the ATP7B promoter region is of special interest. Metal‐responsive elements (MREs) located in the ATP7B promoter are promising motifs in modulating the ATP7B expression. We studied protein interaction of MREe, MREc, and MREd by electrophoretic mobility shift assays and revealed specific interactions for all MREs. We further narrowed down the specific binding site. Proteins potentially binding to the three MREs were identified by MatInspector analyses. Metal regulatory transcription factor 1 (MTF1) could be validated to bind to MREe by electrophoretic mobility shift assays. ATP7B promoter‐driven reporter gene expression was significantly increased because of this interaction. MTF1 is a strong candidate in regulating the ATP7B expression through MREe binding.
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.
Wilson's disease (WD, MIM#277900) is an autosomal recessive disorder resulting in copper excess caused by biallelic variants in the ATP7B gene (MIM#606882) encoding a copper transporting P‐type ...ATPase. ATP7B variants of unknown significance (VUS) are detected frequently, sometimes impeding a clear diagnosis. Functional analyses can help to classify these variants as benign or pathogenic. Additionally, variants already classified as (likely) pathogenic benefit from functional analyses to understand their pathomechanism, thus contribute to the development of personalized treatment approaches in the future. We described clinical features of six WD patients and functionally characterized five ATP7B missense variants (two VUS, three yet uncharacterized likely pathogenic variants), detected in these patients. We determined the protein level, copper export capacity, and cellular localization in an in vitro model and potential structural consequences using an ATP7B protein model based on AlphaFold. Our analyses give insight into the pathomechanism and allowed reclassification for the two VUS to likely pathogenic and for two of the three likely pathogenic variants to pathogenic.
We functionally characterized five ATP7B variants of interest detected in paediatric patients with clinical Wilson's disease using in vitro and in silico analyses. This allowed reclassification of the variants and provided deeper insights into their pathomechanism.
Neonatal sclerosing cholangitis (NSC) is associated with progressing biliary fibrosis that often requires liver transplantation in childhood. Several recent studies have identified variants in DCDC2, ...encoding doublecortin domain‐containing protein 2 (DCDC2), expressed in primary cilia, that accompany syndromic disease and NSC. We report four patients with hepatobiliary disease associated with two novel homozygous or compound heterozygous variants in DCDC2. Three patients with protein‐truncating variants in DCDC2, expressing no DCDC2, presented with the originally described severe hepatic phenotype in infancy. One patient with a novel homozygous DCDC2 missense variant shows a markedly milder phenotype only manifest in childhood and with retained DCDC2 expression. Concomitant nephronophthisis is present in three patients and learning disability in two. This report widens the phenotypic spectrum of DCDC2‐associated hepatobiliary disease. Testing for DCDC2 expression and DCDC2 variants should be included in the evaluation of cholangiopathy of unknown aetiology in childhood as well as in infancy.
Growth failure persists after pediatric liver transplantation and impairs pediatric development and quality of life. Steroid dose minimization attempts to prevent growth impairment, yet long‐term ...assessment in pediatric liver recipients is lacking. We identified risk factors for impaired linear growth after pediatric liver transplantation, with a special focus on low‐dose steroid therapy. This is a single‐center retrospective analysis of height development in pediatric liver recipients up to 5 years after transplantation. Risk factors for impaired linear growth (height Z‐scores≤‐2) at transplantation, after two (n = 347) and five years (n = 210) were identified by univariate and multivariate logistic regression. At transplantation, growth retardation was found in 52.2%, predominantly younger children. Height Z‐scores improved from −2.23 to −1.40 (SE 0.11; 95%CI 0.74–1.16; p < .001) two years and −1.19 (SE 0.07;0.08–0.34; p = .017) five years post‐transplant. Multivariate analysis showed previous growth impairment (OR=1.484; 95%‐CI=1.107–1.988; p = .004), graft loss (49.006;2.232–1076; p = .006), and prolonged cold ischemic time (1.034;1.007–1.061; p = .011) as main long‐term risk factors; steroid use was a significant predictor of 2‐year but not 5‐year growth impairment. In univariate analysis, impaired growth after 2 and 5 years was associated with continuous low‐dose (2.5 mg/m2BSA) steroid therapy (OR=3.323;1.578–6.996; p < .001/OR=8.352;1.089–64.07; p = .006)and graft loss (OR=2.513;1.395–4.525; p = .003/OR=3.378;1.815–7.576; p < .001). Furthermore, indication and era of transplantation affected growth. Our results show significant catch‐up growth after pediatric liver transplantation, yet growth failure strongly affects particularly young liver recipients. The main influenceable long‐term risk factor is pre‐existing growth failure, emphasizing the importance of early aggressive nutritional therapy. Moreover, low‐dose steroid therapy might impair growth and should therefore be critically questioned in long‐term immunosuppression.
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