Publications by authors named "Paloma Jara"

40 Publications

Effectiveness of immunosuppression minimisation, conversion or withdrawal strategies in paediatric solid organ and haematopoietic stem cell transplantation: a protocol of a systematic review and meta-analysis.

BMJ Open 2020 12 3;10(12):e037721. Epub 2020 Dec 3.

Clinical Pharmacology Department, Hospital Universitario La Paz, Madrid, Spain.

Introduction: Paediatric transplantation is the only curative therapeutic procedure for several end-stage rare diseases affecting different organs and body systems, causing altogether great impact in European children's health and quality of life. Transplanted children shift their primary disease to a chronic condition of immunosuppression to avoid rejection. Longer life expectancy in children poses a greater risk of prolonged and severe side effects related to long-term immunosuppressive (IS) disabilities and secondary cancer susceptibility. The goal remains to find the best combination of IS agents that optimises allograft survival by preventing acute rejection while limiting drug toxicities. This systematic review will aim to determine the optimal IS strategy within the so-called minimisation, conversion or withdrawal strategies.

Methods And Analysis: We will search the following databases with no language restrictions: Cochrane Central Register of Controlled Trials in the Cochrane Library, OvidSP Medline and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily; OvidSP Embase Classic+Embase; Ebsco CINAHL Plus, complete database; WHO International Clinical Trials Registry Platform search portal. We will include controlled and uncontrolled clinical trials along with any prospective or retrospective study that includes a universal cohort (all participants from a centre/region/city over a certain period). Cases series and cross-sectional studies are excluded. Two review authors will independently assess the trial eligibility, risk of bias and extract appropriate data points. The outcomes included in this review are: patient survival, acute graft rejection, chronic graft rejection, diabetes, graft function, graft loss, chronic graft versus host disease, acute graft versus host disease, surgical complications, infusion complications, post-transplant lymphoproliferative disease, liver function, renal function, cognition, depression, health-related quality of life, hospitalisation, high blood pressure, low blood pressure, cancer-other, cancer-skin, cardiovascular disease, bacterial infection, Epstein-Barr infection, cytomegalovirus infection, other viral infections and growth.
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http://dx.doi.org/10.1136/bmjopen-2020-037721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716658PMC
December 2020

Pediatric transplantation in Europe during the COVID-19 pandemic: Early impact on activity and healthcare.

Clin Transplant 2020 10 22;34(10):e14063. Epub 2020 Sep 22.

La Paz Institute of Biomedical Research - IdiPAZ, La Paz University Hospital, Madrid, Spain.

The current pandemic SARS-CoV-2 has required an unusual allocation of resources that can negatively impact chronically ill patients and high-complexity procedures. Across the European Reference Network on Pediatric Transplantation (ERN TransplantChild), we conducted a survey to investigate the impact of the COVID-19 outbreak on pediatric transplant activity and healthcare practices in both solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT). The replies of 30 professionals from 18 centers in Europe were collected. Twelve of 18 centers (67%) showed a reduction in their usual transplant activity. Additionally, outpatient visits have been modified and restricted to selected ones, and the use of telemedicine tools has increased. Additionally, a total of 14 COVID-19 pediatric transplanted patients were identified at the time of the survey, including eight transplant recipients and six candidates for transplantation. Only two moderate-severe cases were reported, both in HSCT setting. These survey results demonstrate the limitations in healthcare resources for pediatric transplantation patients during early stages of this pandemic. COVID-19 disease is a major worldwide challenge for the field of pediatric transplantation, where there will be a need for systematic data collection, encouraging regular discussions to address the long-term consequences for pediatric transplantation candidates, recipients, and their families.
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http://dx.doi.org/10.1111/ctr.14063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435500PMC
October 2020

Longitudinal evolution of vertically HIV/HCV-co-infected vs HCV-mono-infected children.

J Viral Hepat 2020 01 30;27(1):61-67. Epub 2019 Oct 30.

TRaslational Research Network in Pediatric Infectious Diseases (RITIP), Madrid, Spain.

HIV co-infection has been suggested to play a deleterious role on the pathogenesis of liver fibrosis among vertically HCV-infected children. The aim of this study was to describe the longitudinal evolution of vertically acquired HIV/HCV co-infection in youths, in comparison with HCV infection alone. This was a retrospective, multicentre study including vertically HIV/HCV-co-infected patients and age- and sex-matched vertically HCV-mono-infected patients. Progression to advanced liver fibrosis, defined as F3 or more by elastography or METAVIR biopsy staging, and response to treatment were compared by means of univariate and multivariate regression analyses and Cox regression models. Sixty-seven co-infected patients were compared with 67 matched HCV-mono-infected patients. No progression to advanced liver disease was observed during the first decade. At a median age of 20.0 [19.0, 22.0] years, 26.7% co-infected vs 20% mono-infected had progressed to advanced fibrosis (P = .617). Peg-IFN/RBV for HCV treatment was given to 37.9% vs 86.6% (P-value < .001). At treatment initiation, co-infected patients were older (16.9 ± 4.1 vs 11.7 ± 4.5 years, P < .001), and 47.1% vs 7.1% showed advanced fibrosis (P < .003), with no differences in hard-to-treat genotype distribution. Sustained viral response was comparable between groups (43.5% vs 44.0%, P = .122). In vertically HIV/HCV-co-infected patients, the progression to liver fibrosis was rare during childhood. At the end of adolescence, over 25% of patients displayed advanced liver disease. Response to Peg-IFN/RBV was poor and comparable in both groups, supporting the need for fast access to early treatment with direct-acting antivirals against HCV for vertically co-infected patients.
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http://dx.doi.org/10.1111/jvh.13206DOI Listing
January 2020

Erratum to "Multidisciplinary units in tertiary referral hospitals to improve management of Wilson disease" <[Gastroenterol Hepatol 39 (2016) 571-573]>.

Gastroenterol Hepatol 2017 05 30;40(5):377. Epub 2017 Mar 30.

Servicio de Hepatología, Hospital Clínic, Barcelona, España.

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http://dx.doi.org/10.1016/j.gastrohep.2017.02.005DOI Listing
May 2017

[Multidisciplinary units in tertiary referral hospitals to improve management of Wilson disease].

Gastroenterol Hepatol 2016 Nov 3;39(9):571-573. Epub 2016 Aug 3.

Servicio de Hepatología, Hospital Clínic, Barcelona, España.

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http://dx.doi.org/10.1016/j.gastrohep.2016.06.003DOI Listing
November 2016

Functional Rescue of Trafficking-Impaired ABCB4 Mutants by Chemical Chaperones.

PLoS One 2016 22;11(2):e0150098. Epub 2016 Feb 22.

La Paz University Hospital Health Research Institute-IdiPAZ, Madrid, Spain.

Multidrug resistance protein 3 (MDR3, ABCB4) is a hepatocellular membrane protein that mediates biliary secretion of phosphatidylcholine. Null mutations in ABCB4 gene give rise to severe early-onset cholestatic liver disease. We have previously shown that the disease-associated mutations p.G68R, p.G228R, p.D459H, and p.A934T resulted in retention of ABCB4 in the endoplasmic reticulum, thus failing to target the plasma membrane. In the present study, we tested the ability of two compounds with chaperone-like activity, 4-phenylbutyrate and curcumin, to rescue these ABCB4 mutants by assessing their effects on subcellular localization, protein maturation, and phospholipid efflux capability. Incubation of transfected cells at a reduced temperature (30°C) or exposure to pharmacological doses of either 4-PBA or curcumin restored cell surface expression of mutants G228R and A934T. The delivery of these mutants to the plasma membrane was accompanied by a switch in the ratio of mature to inmature protein forms, leading to a predominant expression of the mature protein. This effect was due to an improvement in the maturation rate and not to the stabilization of the mature forms. Both mutants were also functionally rescued, displaying bile salt-dependent phospholipid efflux activity after addition of 4-PBA or curcumin. Drug-induced rescue was mutant specific, given neither 4-PBA nor curcumin had an effect on the ABCB4 mutants G68R and A934T. Collectively, these data indicate that the functionality of selected trafficking-defective ABCB4 mutants can be recovered by chemical chaperones through restoration of membrane localization, suggesting a potential treatment for patients carrying such mutations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150098PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764328PMC
July 2016

Heterozygous ABCB4 mutations in children with cholestatic liver disease.

Liver Int 2016 Feb 3;36(2):258-67. Epub 2015 Aug 3.

La Paz University Hospital Health Research Institute-IdiPAZ, Madrid, Spain.

Background & Aims: Monoallelic defects in ABCB4, which encodes the canalicular floppase for phosphatidylcholine MDR3, have been encountered in association with a variety of hepatobiliary disorders, particularly in adult subjects. In this study, we examined the presence of heterozygous ABCB4 variants in a cohort of children with chronic cholestasis and assessed the pathogenicity of the missense changes identified.

Methods: Sixty-seven children with chronic liver dysfunction were studied by the sequencing of ABCB4 and multiplex ligation-dependent probe amplification analysis. The molecular defects arising from missense variants were analysed in MDCK-II and AD-293 cells.

Results: Defects in a single allele of ABCB4 were identified in nine subjects. They included one small insertion (p.I1242Nfs), one nonsense mutation (p.R144X) and six missense changes (p.T175A, p.G228R, p.A250T, p.S320F, p.P352L and p.A934T). In four children, these defects in ABCB4 co-existed with various medical conditions. In vitro phenotyping of the six missense variants revealed that four (T175A, G228R, S320F and A934T) led to reduced MDR3 protein levels. Two mutations (G228R and A934T) resulted in trapping of the protein in the endoplasmic reticulum. Phosphatidylcholine efflux activity was decreased to 56-18% of reference levels for MDR3 mutants T175A, A250T and S320F. The G228R, P352L and A934T mutants were found to be non-functional.

Conclusions: These results illustrate the varying effects of ABCB4 missense mutations and suggest that even a modest reduction in MDR3 activity may contribute or predispose to the onset of cholestatic liver disease in the paediatric age.
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http://dx.doi.org/10.1111/liv.12910DOI Listing
February 2016

Liver Transplant in a Patient under Methylphenidate Therapy: A Case Report and Review of the Literature.

Case Rep Pediatr 2015 22;2015:437298. Epub 2015 Jan 22.

Department of Clinical Pharmacology, Hospital Universitario La Paz, IdiPaz, School of Medicina, Universidad Autónoma de Madrid, Paseo de la Castellana 261, 28046 Madrid, Spain.

Background. Methylphenidate (MPH) is widely used in treating children with attention-deficit-hyperactivity disorder. Hepatotoxicity is a rare phenomenon; only few cases are described with no liver failure. Case. We report on the case of a 12-year-old boy who received MPH for attention-deficit-hyperactivity disorder. Two months later the patient presented with signs and symptoms of hepatitis and MPH was discontinued, showing progressive worsening and developing liver failure and a liver transplantation was required. Other causes of liver failure were ruled out and the liver biopsy was suggestive of drug toxicity. Discussion. One rare adverse reaction of MPH is hepatotoxicity. The review of the literature shows few cases of liver injury attributed to MPH; all of them recovered after withdrawing the treatment. The probable mechanism of liver injury was MPH direct toxicity to hepatocytes. In order to establish the diagnosis of MPH-induced liver injury, we used CIOMS/RUCAM scale that led to an assessment of "possible" relationship. This report provides the first published case of acute MPH-induced liver failure with successful hepatic transplantation. Conclusions. It is important to know that hepatotoxicity can occur in patients with MPH treatment and monitoring the liver's function is highly recommended.
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http://dx.doi.org/10.1155/2015/437298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320912PMC
February 2015

Liver transplantation for classical maple syrup urine disease: long-term follow-up.

J Pediatr Gastroenterol Nutr 2014 Nov;59(5):636-9

*Centro de Salud Puerta Bonita †Hepatology Department, Hospital Infantil La Paz ‡Pediatric Department, Hospital Ramón y Cajal §Pediatric Surgery Department, Hospital Infantil La Paz, Madrid, Spain.

Objectives: The aim of the study was to evaluate indications, results, and clinical and neurological evolution in children who have undergone liver transplantation for classical maple syrup urine disease (MSUD).

Methods: Descriptive study of liver transplantation for MSUD between 1991 and 2012. Eight patients were transplanted.

Results: Indications for transplant were poor metabolic control expressed as significant psychomotor disabilities (4 had psychomotor delays, 5 had spasticity, and 5 had epilepsy) and poor quality of life (mean number of acute metabolic decompensations and mean number of total hospitalizations before transplantation 5 and 12, respectively). Four required nasogastric tube, with a maximum 4 g/day protein-restricted diet in all of them. Seven sustained significant alterations in brain magnetic resonance imaging. Mean leucine and alloisoleucine levels were 608 (standard deviation [SD] 516) and 218 μmol/L (SD 216), respectively. All of the patients received transplants with deceased-donor livers, with ages between 1.5 and 2.5 years (mean 1.78 years). Mean posttransplantation follow-up period was 12.2 years (range 5-21 years). Final patient and graft survival was 87.5% and 75%, respectively. Following transplantation, none required hospitalization in the last 3 years nor did any have new acute metabolic decompensations following a normal diet. Five followed normal schooling, 2 had motor disabilities, and 2 had convulsive crises. Brain magnetic resonance imaging was taken in 4 patients, showing neuroimage improvement in 3 of them. Mean leucine levels were <350 μmol/L from the immediate posttransplantation period (mean 225 μmol/L, SD 78), with a maximum alloisoleucine level of 20 μmol/L.

Conclusions: Liver transplantation is an effective treatment for classical MSUD that arrests brain damage, although it does not reverse the process.
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http://dx.doi.org/10.1097/MPG.0000000000000469DOI Listing
November 2014

The impact of the prevention strategies on the indirect effects of CMV infection in solid organ transplant recipients.

Transplant Rev (Orlando) 2014 Apr 27;28(2):84-91. Epub 2014 Jan 27.

Hospital Puerta de Hierro, Madrid, Spain.

Transplant recipients receiving immunosuppressive therapy are at increased risk of active cytomegalovirus (CMV) infection and disease. Without appropriate prophylaxis, as many as 80% of solid organ transplant recipients may experience CMV infection. In addition to the direct effects of CMV, infection may be associated with a range of indirect effects, including an increase in risk of other infections, as well as a higher incidence of rejection, graft loss and death. The indirect effects of CMV infection can vary depending on the transplanted organ. For example, CMV-infected kidney transplant recipients may be at increased risk of cardiovascular disease and diabetes, while CMV infection in liver transplant recipients may potentiate hepatitis C infection and increase the risk of post-transplant lymphoproliferative disease. Indirect effects result from a number of pathological processes, including immune modulation and immunosuppression, generation of cytotoxic, pro-inflammatory responses, and smooth muscle proliferation. Prophylactic treatment with antiviral medication can reduce the risk of CMV disease, thereby improving graft survival and overall outcomes, particularly in kidney and heart transplant recipients. Antiviral prophylaxis should be considered for all patients at risk of CMV infection after solid organ transplantation. In this paper we review the main indirect effects of CMV infection in solid organ transplant recipients, and the impact of CMV prophylaxis on these effects.
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http://dx.doi.org/10.1016/j.trre.2014.01.001DOI Listing
April 2014

Functional analysis of ABCB4 mutations relates clinical outcomes of progressive familial intrahepatic cholestasis type 3 to the degree of MDR3 floppase activity.

Gut 2015 Jan 4;64(1):147-55. Epub 2014 Mar 4.

La Paz University Hospital Health Research Institute-IdiPAZ, Madrid, Spain.

Objective: Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a potentially lethal autosomal recessive liver disease associated with mutations in ABCB4, the gene encoding the canalicular translocator of phosphatidylcholine MDR3. While some affected children benefit from ursodeoxycholic acid (UDCA) therapy, others evolve to end-stage liver disease. We aimed to evaluate whether these different outcomes are related to the impact of ABCB4 mutations.

Design: Six children with PFIC3 were investigated by sequencing of ABCB4 exons and flanking intron-exon boundaries and by immunohistochemistry. ABCB4 missense mutations were phenotyped in vitro by assessing their effects on MDR3 expression, subcellular localisation, and phosphatidylcholine-translocating activity. The resulting data were contrasted with the clinical outcomes.

Results: Eight distinct ABCB4 mutations were identified: one nonsense, one splicing and six missense mutations, four of which (G68R, T201M, P479L, D459H) affected MDR3 expression level. G68R and D459H also led to retention of the protein in endoplasmic reticulum. Phosphatidylcholine efflux assays indicated that T201M, P479L, S978P and E1118K mutations impaired MDR3 activity to variable degrees. Three children with mutations that caused a total loss of MDR3 expression/function manifested progressive liver disease refractory to UDCA treatment. This was also the case in a patient carrying two different mutations that, in combination, resulted in a 90% reduction in total MDR3 activity. A favourable response to UDCA was achieved in two patients with estimated MDR3 activities of 50% and 33%, respectively.

Conclusions: These data provide experimental evidence of the correlation between the degree of MDR3 floppase activity and the clinical outcomes of PFIC3.
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http://dx.doi.org/10.1136/gutjnl-2014-306896DOI Listing
January 2015

Conversion from Prograf to Advagraf in adolescents with stable liver transplants: comparative pharmacokinetics and 1-year follow-up.

Liver Transpl 2013 Oct;19(10):1151-8

Clinical Pharmacology Service, La Paz University Hospital, Madrid, Spain; Department of Pharmacology, School of Medicine, Autonomous University of Madrid, Madrid, Spain.

The recommended dose of Advagraf for conversion from Prograf is considered to be 1:1 on a milligram basis. However, the long-term equivalence of Prograf and Advagraf has been questioned. The relative bioavailability of Advagraf and Prograf was evaluated in a single-center, open-label study of Prograf-to-Advagraf conversion in 20 patients, ranging in age from 12 to 18 years, who had a stable liver transplant and were receiving Prograf. After the supervised administration of Prograf for 7 days, the patients were converted to Advagraf. On days 7 and 14, serial blood samples were obtained for tacrolimus determinations. The pharmacokinetic parameters were calculated with a noncompartmental approach, and the relative bioavailability of both formulations was calculated according to standard statistical methods. Polymorphisms in cytochrome P450 3A5 (rs776746), adenosine triphosphate-binding cassette B1 (rs1045642), POR*28 (rs1057868), and POR (rs2868177) were determined with standard methods. The clinical and analytical data from a 1-year follow-up period were collected for all patients 30, 90, 180, and 360 days after conversion. The mean ratios for Cmax and AUC0-24 were 96.9 (90% confidence interval = 85.37-110.19) and 100.1 (90% confidence interval = 90.8-112.1), respectively. No relationship was found between the patients' genotypes and the pharmacokinetic tacrolimus values. During the follow-up, biochemical parameters (aspartate aminotransferase, alanine aminotransferase, bilirubin, cystatin C, and creatinine) did not change significantly; 3 patients presented with relevant clinical events, but no event was considered to be related to tacrolimus. A decrease in tacrolimus blood levels and an increase in dose/level ratios were observed 3 and 6 months after conversion, but they returned to basal levels by month 12. In conclusion, conversion from Prograf to Advagraf with a 1:1 dose equivalence is appropriate as an initial guideline. Our 1-year follow-up showed a transient decrease in tacrolimus levels, so closer monitoring of tacrolimus levels may be required after conversion.
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http://dx.doi.org/10.1002/lt.23711DOI Listing
October 2013

New concepts and best practices for management of pre- and post-transplantation cancer.

Transplant Rev (Orlando) 2012 Oct 15;26(4):261-79. Epub 2012 Aug 15.

Hospital Clínic, Barcelona, Spain.

Solid-organ transplant recipients are at increased risk of developing cancer compared with the general population. Tumours can arise de novo, as a recurrence of a preexisting malignancy, or from the donated organ. The ATOS (Aula sobre Trasplantes de Órganos Sólidos; the Solid-Organ Transplantation Working Group) group, integrated by Spanish transplant experts, meets annually to discuss current advances in the field. In 2011, the 11th edition covered a range of new topics on cancer and transplantation. In this review we have highlighted the new concepts and best practices for managing cancer in the pre-transplant and post-transplant settings that were presented at the ATOS meeting. Immunosuppression plays a major role in oncogenesis in the transplant recipient, both through impaired immunosurveillance and through direct oncogenic activity. It is possible to transplant organs obtained from donors with a history of cancer as long as an effective minimization of malignancy transmission strategy is followed. Tumour-specific wait-periods have been proposed for the increased number of transplantation candidates with a history of malignancy; however, the patient's individual risk of death from organ failure must be taken into consideration. It is important to actively prevent tumour recurrence, especially the recurrence of hepatocellular carcinoma in liver transplant recipients. To effectively manage post-transplant malignancies, it is essential to proactively monitor patients, with long-term intensive screening programs showing a reduced incidence of cancer post-transplantation. Proposed management strategies for post-transplantation malignancies include viral monitoring and prophylaxis to decrease infection-related cancer, immunosuppression modulation with lower doses of calcineurin inhibitors, and addition of or conversion to inhibitors of the mammalian target of rapamycin.
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http://dx.doi.org/10.1016/j.trre.2012.07.001DOI Listing
October 2012

NOTCH2 mutations in Alagille syndrome.

J Med Genet 2012 Feb 29;49(2):138-44. Epub 2011 Dec 29.

Division of Gastroenterology and Nutrition, Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Canada.

Background: Alagille syndrome (ALGS) is a dominant, multisystem disorder caused by mutations in the Jagged1 (JAG1) ligand in 94% of patients, and in the NOTCH2 receptor in <1%. There are only two NOTCH2 families reported to date. This study hypothesised that additional NOTCH2 mutations would be present in patients with clinical features of ALGS without a JAG1 mutation.

Methods: The study screened a cohort of JAG1-negative individuals with clinical features suggestive or diagnostic of ALGS for NOTCH2 mutations.

Results: Eight individuals with novel NOTCH2 mutations (six missense, one splicing, and one non-sense mutation) were identified. Three of these patients met classic criteria for ALGS and five patients only had a subset of features. The mutations were distributed across the extracellular (N=5) and intracellular domains (N=3) of the protein. Functional analysis of four missense, one nonsense, and one splicing mutation demonstrated decreased Notch signalling of these proteins. Subjects with NOTCH2 mutations demonstrated highly variable expressivity of the affected systems, as with JAG1 individuals. Liver involvement was universal in NOTCH2 probands and they had a similar prevalence of ophthalmologic and renal anomalies to JAG1 patients. There was a trend towards less cardiac involvement in the NOTCH2 group (60% vs 100% in JAG1). NOTCH2 (+) probands exhibited a significantly decreased penetrance of vertebral abnormalities (10%) and facial features (20%) when compared to the JAG1 (+) cohort.

Conclusions: This work confirms the importance of NOTCH2 as a second disease gene in ALGS and expands the repertoire of the NOTCH2 related disease phenotype.
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http://dx.doi.org/10.1136/jmedgenet-2011-100544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682659PMC
February 2012

High sustained virologic response rates in children with chronic hepatitis C receiving peginterferon alfa-2b plus ribavirin.

J Hepatol 2010 Apr 4;52(4):501-7. Epub 2010 Feb 4.

Children's Hospital, HELIOS Klinikum Wuppertal, Witten/Herdecke University, Heusnerstrasse 40, Wuppertal, Germany.

Background & Aims: Pegylated interferon (PEG-IFN) alfa-2b plus ribavirin (RBV) is the standard of care for adults with chronic hepatitis C but was not approved for the treatment of children at the time of this study. The aim of this study was to evaluate the efficacy and safety of PEG-IFN alfa-2b plus RBV in children.

Methods: Children and adolescents ages 3-17 years were treated with PEG-IFN alfa-2b (60microg/m(2)/week) plus RBV (15mg/kg/day). The duration of therapy was 24 weeks for genotype (G) 2 and G3 patients with low viral load (<600,000IU/ml) and 48 weeks for G1, G4, and G3 with high viral load (>or=600,000IU/ml). The primary end point was sustained virologic response (SVR), defined as undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of therapy.

Results: SVR was attained by 70 (65%) children. Genotype was the main predictor of response: G1, 53%; G2/3, 93%; G4, 80%. SVRs were similar in younger and older children. Baseline viral load was the main predictor of response in the G1 cohort. No new safety signals were identified, and adverse events (AEs) were generally mild or moderate in severity. Dose was modified because of AEs in 25% of children; 1 child discontinued because of an AE (thrombocytopenia). No serious AEs related to study drugs were reported.

Conclusion: Therapy with PEG-IFN alfa-2b plus RBV in children and adolescents with chronic hepatitis C offers favorable efficacy, reduced injection frequency, and an acceptable safety profile.
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http://dx.doi.org/10.1016/j.jhep.2010.01.016DOI Listing
April 2010

Treatment of hepatitis C in children.

Expert Rev Gastroenterol Hepatol 2010 Feb;4(1):51-61

Servicio de Hepatología, Hospital Infantil Universitario La Paz, Paseo Castellana 261, 28046 Madrid, Spain.

Hepatitis C affects 4-10% of children born to infected mothers, and 80% of them develop chronic infection. Most patients with chronic hepatitis C virus infection are asymptomatic, with persistent or intermittent biochemical abnormalities. Severe liver disease may develop 10 years after onset of infection, with a less than 2% overall risk during the pediatric age. Available therapies have no contraindication in children if otherwise healthy. The US FDA and EMEA have recently approved combined pegylated-IFN-alpha 2b plus ribavirin treatment for children, who should be over 3 years of age in order to avoid severe side effects. Experiences in pilot trials and international studies indicate a response rate of 50% in genotype 1 patients, and more than 90% in genotype 2 or 3 patients, indicating resolution of chronic disease.
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http://dx.doi.org/10.1586/egh.09.76DOI Listing
February 2010

[Childhood liver transplantation. Long-term results].

Gastroenterol Hepatol 2010 May 31;33(5):398-410. Epub 2010 Jan 31.

Servicio de Hepatología y Trasplante, Hospital Infantil Universitario La Paz, Madrid, España.

Liver transplantation allows long-term survival (10 years or more) in 75% of children receiving transplants before 2000. The risk of mortality after the first year is 4-10% in the next 10-20 years. Chronic rejection affects 6%. The need for late retransplantation is 3-5%. However, the follow-up of these patients involves the management of diverse problems in the graft (immunological, biliary, vascular) and others related to the use of immunosuppressants (renal dysfunction, lymphoproliferative syndrome). The transition from pediatric to adult care generates special needs. Adolescence and young adulthood are associated with a lack of compliance. Adult specialists should be aware of the special features of the original diagnosis and the surgical techniques used in childhood transplantation. Final quality of life is good overall but is lower than that in healthy young persons.
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http://dx.doi.org/10.1016/j.gastrohep.2009.11.004DOI Listing
May 2010

Liver histology damage in children with chronic hepatitis C.

Pediatr Infect Dis J 2010 Feb;29(2):189-90; author reply 190

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http://dx.doi.org/10.1097/INF.0b013e3181c11c27DOI Listing
February 2010

Chronic hepatitis C virus infection in children.

J Pediatr Gastroenterol Nutr 2010 Feb;50(2):123-31

Department of Pediatrics, Centre of Child Health, Sir Ganga Ram Hospital, New Delhi, India.

The importance of hepatitis C viral infection in the health care of children has grown in recent decades. More is now known about the epidemiology of this infection in children and the progression of disease in the pediatric age group, and the treatment options are increasing. In this review, we update readers on the state of our understanding of hepatitis C infection in children, provide the current recommendations for monitoring and treatment, and discuss emerging therapies.
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http://dx.doi.org/10.1097/MPG.0b013e3181c61995DOI Listing
February 2010

Recurrence of bile salt export pump deficiency after liver transplantation.

N Engl J Med 2009 Oct;361(14):1359-67

Pediatric Liver Service, La Paz University Hospital, Madrid, Spain.

Severe bile salt export pump (BSEP) deficiency is a hereditary cholestatic condition that starts in infancy and leads to end-stage liver disease. Three children who underwent orthotopic liver transplantation for severe BSEP deficiency had post-transplantation episodes of cholestatic dysfunction that mimicked the original disease. Remission of all episodes was achieved by intensifying the immunosuppressive regimen. The phenotypic recurrence of the disease correlated with the presence of circulating high-titer antibodies against BSEP that inhibit transport by BSEP in vitro. When administered to rats, these antibodies targeted the bile canaliculi and impaired bile acid secretion.
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http://dx.doi.org/10.1056/NEJMoa0901075DOI Listing
October 2009

Autoimmune hepatitis.

J Pediatr Gastroenterol Nutr 2009 Aug;49(2):158-64

King's College London School of Medicine at King's College Hospital, London, UK.

Autoimmune hepatitis is characterized by inflammatory liver histology, circulating nonorgan-specific autoantibodies, and increased levels of immunoglobulin G, in the absence of a known etiology. Two types of juvenile autoimmune hepatitis (AIH) are recognized according to seropositivity for smooth muscle and/or anti-nuclear antibody (AIH type 1) or liver kidney microsomal antibody (AIH type 2). There is a female predominance in both. AIH type 2 presents more acutely, at a younger age and commonly with immunoglobulin A deficiency, whereas duration of symptoms before diagnosis, clinical signs, family history of autoimmunity, presence of associated autoimmune disorders, response to treatment, and long-term prognosis are similar in the 2 groups. Immunosuppressive treatment with steroids and azathioprine, which should be instituted promptly to avoid progression to cirrhosis, induces remission in 80% of cases. Relapses are common, often due to nonadherence. Drugs effective in refractory cases include cyclosporine and mycophenolate mofetil. Long-term treatment is usually required, with only some 20% of AIH type 1 patients able to discontinue therapy successfully. In childhood, sclerosing cholangitis with strong autoimmune features, including interface hepatitis and serological features identical to AIH type 1, is as prevalent as AIH, but it affects boys and girls equally. Differential diagnosis relies on cholangiographic studies. In autoimmune sclerosing cholangitis liver parenchymal damage responds satisfactorily to immunosuppressive treatment, whereas bile duct disease tends to progress. In this article we review the state of the art of diagnosis, monitoring, and treatment for children with AIH.
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http://dx.doi.org/10.1097/MPG.0b013e3181a1c265DOI Listing
August 2009

Management of chronic hepatitis B in children.

J Pediatr Gastroenterol Nutr 2009 Apr;48(4):399-404

Harvard Medical School Dubai Center, Dubai Health Care City, Dubai, UAE.

Hepatitis B virus (HBV) infection is a worldwide problem and can cause acute liver failure, acute hepatitis, chronic hepatitis, liver cirrhosis, and liver cancer. In areas of high prevalence such as in Asia, Africa, southern Europe, and Latin America, the hepatitis B surface antigen positive rate ranges from 2% to 20%.In endemic areas, HBV infection occurs mainly during infancy and early childhood. Mother-to-infant transmission accounts for approximately half of the chronic HBV infections. In contrast to infection in adults, HBV infection during early childhood results in a much higher rate of persistent infection and long-term serious complications such as liver cirrhosis and HCC.Three phases of chronic hepatitis B have been identified: the immune-tolerant phase, the immune-active phase, and the inactive hepatitis B phase. These phases of infection are characterized by variations in viral replication, hepatic inflammation, spontaneous clearance, and response to antiviral therapy.The optimal goal of antiviral therapy for chronic HBV infection is to eradicate HBV and to prevent its related liver complications. However, due to the limited effect of available therapies in viral eradication, the goal of treatment is to reduce viral replication, to minimize liver injury, and to reduce infectivity. In this review the current recommendations for monitoring and treating chronic HBV infection in children are reviewed.
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http://dx.doi.org/10.1097/MPG.0b013e318197196eDOI Listing
April 2009

Knockdown of ATP8B1 expression leads to specific downregulation of the bile acid sensor FXR in HepG2 cells: effect of the FXR agonist GW4064.

Am J Physiol Gastrointest Liver Physiol 2009 May 19;296(5):G1119-29. Epub 2009 Feb 19.

Research Unit, La Paz University Hospital-Fundación para la Investigación Biomédica del Hospital Universitario La Paz (FIBHULP), Madrid, Spain.

Farnesoid X receptor (FXR) is a bile acid-sensing nuclear receptor that controls bile acid homeostasis. It has been suggested that downregulation of FXR contributes to the pathogenesis of an inherited disorder of bile secretion caused by mutations in ATP8B1. We have investigated the relationship between ATP8B1 knockdown and FXR downregulation in the human hepatoblastoma cell line HepG2. Transfection of HepG2 cells with ATP8B1 small interfering RNA (siRNA) duplexes led to a 60% reduction in the endogenous levels of ATP8B1 mRNA and protein and a concomitant decrease in FXR mRNA and protein content, as well as in FXR phosphorylation. This decrease was accompanied by a marked reduction in mRNA levels of a subset of FXR targets, such as bile salt export pump (ABCB11), small heterodimer partner, and uridine 5'-diphosphate-glucuronosyltransferase. ATP8B1 inhibition specifically targeted FXR since mRNA expression of other prominent nuclear receptors, such as pregnane X receptor and constitutive androstane receptor, or liver-enriched transcription factors, such as hepatocyte nuclear factor 1alpha (HNF-1alpha) and HNF-4alpha, was not altered. The expression of other key genes involved in bile acid synthesis, detoxification, and transport also remained unchanged upon ATP8B1 knockdown. Supporting the specificity of the effect, siRNA-mediated silencing of ABCB11, whose defect is associated with another inherited disorder of bile secretion, did not affect FXR expression. Treatment with the synthetic FXR agonist GW4064 was able to partially neutralize ATP8B1 siRNA-mediated FXR downregulation and fully counteract inhibition of FXR target genes. Collectively these findings indicate that ATP8B1 knockdown specifically downregulates FXR, and this action can be circumvented by treatment with FXR agonists.
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http://dx.doi.org/10.1152/ajpgi.90371.2008DOI Listing
May 2009

[Hepatitis B in pregnant women and children].

Enferm Infecc Microbiol Clin 2008 May;26 Suppl 7:66-70

Servicio de Hepatología y Trasplante Hepático, Hospital Infantil Universitario La Paz, Madrid, España.

In pregnant women and children, the hepatitis B virus can cause acute or chronic hepatitis or liver cirrhosis. Perinatally-acquired infection causes persistent infection in 90% of cases and can be avoided through administration of the hepatitis B vaccine and specific immunoglobulin in the first day of life. Prevention of mother-to-child transmission requires screening for hepatitis B surface antigen (HBsAg) in pregnant women to identify which newborns should be immunized. In some countries this strategy is substituted by universal vaccination of neonates. In infected children, inactivation of viral replication with conversion of HBeAG-positive to anti-HBe-positive status usually occurs. If this seroconversion does not take place and necroinflammatory activity persists in the liver, the use of antiviral agents such as interferon or nucleoside and nucleotide analogs is warranted.
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http://dx.doi.org/10.1016/s0213-005x(08)76521-2DOI Listing
May 2008

[Accreditation of processes in hepatology].

Gastroenterol Hepatol 2008 Aug-Sep;31(7):427-32

Asociación Española para el Estudio del Hígado, Escuela Andaluza de Salud Pública, Granada, España.

The Spanish Association for the Study of the Liver decided in 2006 to develop a project to assess the quality of the professionals, processes and medical units dealing with the management of patients with liver diseases in Spain. The current article reports the criteria proposed to assess the quality and the accreditation of the processes in hepatology. The processes considered include most patients with liver diseases and the accreditation system designed is highly specific. This document, together with a previous one published in gastroenterología y hepatología concerning the accreditation of the professionals and a third document dealing with the accreditation of liver units that will be published soon, form the basis of the quality assessment of hepatology in our country.
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http://dx.doi.org/10.1157/13125588DOI Listing
January 2009

Efficacy and safety of valganciclovir in liver-transplanted children infected with Epstein-Barr virus.

Liver Transpl 2008 Aug;14(8):1185-93

Pediatric Liver Service, Hospital Universitario La Paz, Madrid, Spain.

Epstein-Barr virus (EBV) infection after liver transplantation (LT) is associated with increased risk of posttransplant lymphoproliferative disorder (PTLD). Lowering immunosuppression is the current method to prevent PTLD in LT children with a high viral load. The aim of this study was to assess the efficacy and safety of valganciclovir (VGCV) in children with EBV infection after LT. Forty-seven children showing detectable EBV-DNA (72% asymptomatic) were treated with VGCV (520 mg/sqm twice daily) with no immunosuppression decrease (except in 4 cases). VGCV treatment started 17 months (median) after the onset of EBV infection. A 30-day treatment applied to 26 patients led to undetectable EBV-DNA in 11/32 courses (34.3%), with 82% relapsing. A long VGCV treatment (median: 8 months) achieved undetectable EBV-DNA in 20/42 (47.6%), 60% of whom maintained response off therapy. There were no new PTLD cases. Symptoms worsened in 1 (2.1%) in whom PTLD was suspected but not confirmed in liver and jejunum biopsies. Factors associated with achievement of undetectable EBV-DNA were a longer time from LT and a lower rate of intervening infections in comparison with nonresponders. The safety profile for VGCV was excellent. Graft rejection occurred in 6%. In conclusion, in 47 LT children with a sustained increased EBV load treated with VGCV and unchanged immunosuppression, PTLD was suspected in 1 child (2.1%). A viral load decrease could be achieved as EBV-DNA was undetectable in 47% of patients under prolonged treatment.
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http://dx.doi.org/10.1002/lt.21498DOI Listing
August 2008

Chronic hepatitis.

J Pediatr Gastroenterol Nutr 2008 Aug;47(2):225-33

Hepatobiliary Program, Seattle Children's Hospital and Regional Medical Center, Seattle, WA 98105, USA.

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http://dx.doi.org/10.1097/MPG.0b013e318181b08bDOI Listing
August 2008

[The Euro-Wilson project: a European project for the study of Wilson's disease].

Gastroenterol Hepatol 2008 Mar;31(3):117-9

Unidad de Enfermedades Digestivas, Corporació Sanitària Parc Taulí, Universitat Autònoma de Barcelona, Sabadell, Barcelona, Spain.

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http://dx.doi.org/10.1157/13116498DOI Listing
March 2008

[Molecular and clinical characteristics of a family with Alagille syndrome].

Med Clin (Barc) 2008 Jan;130(1):17-9

Servicio de Aparato Digestivo, Hospital Donostia, San Sebastián, Guipúzcoa, Spain.

Background And Objective: The Alagille syndrome (AS) is characterized by biliary ductopenia and abnormalities of heart, eyes, face, bones, kidneys and brain with a dominant inheritability. Mutations of Jagged 1 gene are observed in individuals with the full syndrome and/or relatives with little or no phenotypic features. Prognosis of patients depends on the hepatic and cardiovascular involvement.

Patients And Method: We present the cases of a woman and her 2 male nephews with AS. We performed a molecular study of the Jagged 1 gene in family members with and without the syndrome.

Results: The molecular study detected mutations in the position 2785+2 of TAAG (intron 19) of the Jagged 1 gene in 3 relatives with the full syndrome and in 2 other members with a partial syndrome. Other relatives, without mutation, have some of the phenotypic features of it.

Conclusions: We comment on the clinical forms of AS in this family and the detected mutation. Molecular diagnosis allows to make a genetic counsel.
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http://dx.doi.org/10.1157/13114539DOI Listing
January 2008