RESUMO
OBJECTIVES: Determining 24-hour urinary copper excretion (UCE) levels is useful for diagnosing Wilson's disease (WD) and for treatment monitoring. Exchangeable copper (ExC) is a novel potential marker, but its long-term changes have never been described in patients under chelation therapy. Our aim was to describe the long-term changes in ExC levels compared to UCE levels in symptomatic WD pediatric patients under chelation therapy. METHODS: A retrospective, descriptive, and analytical study including all patients under 18 years of age, diagnosed between 2006 and 2020, and treated with chelation therapy was conducted at the National Reference Center for WD in Lyon. Ceruloplasmin levels, serum copper, 24 h-UCE, ExC, and liver enzymes at diagnosis and during follow-up were analyzed. RESULTS: Our study included 36 patients, predominantly with hepatic form of WD (n = 31). The median [interquartile range (IQR)] age at diagnosis was 10.5 (8.4-13.1) years, and the median (IQR) follow-up duration was 6.3 (3.3-8.8) years. At diagnosis, the median (IQR) ExC value was 1.01 (0.60-1.52) µmol/L. There was a significant decrease during the first year of chelation treatment ( P = 0.0008), then a stabilization. The median (IQR) ExC values was 0.38 (0.22-0.63) µmol/L at 12-18 months and 0.43 (0.31-0.54) µmol/L at 5 years of chelation treatment ( P = 0.4057). Similarly, there was a significant decrease in 24-hour UCE ( P < 0.001) during the first year of chelation treatment, then a stabilization. CONCLUSIONS: Our study showed a significant decrease in ExC and 24-hour UCE levels during the first year of follow-up; The dynamics of both biomarkers were similar along the follow-up, demonstrating their usefulness in clinical practice for monitoring WD.
Assuntos
Degeneração Hepatolenticular , Adolescente , Biomarcadores , Ceruloplasmina/metabolismo , Quelantes/uso terapêutico , Terapia por Quelação , Criança , Cobre/metabolismo , Degeneração Hepatolenticular/diagnóstico , Degeneração Hepatolenticular/tratamento farmacológico , Humanos , Estudos RetrospectivosRESUMO
OBJECTIVES: To describe a cohort of Wilson disease (WD) pediatric cases, and to point out the diagnostic particularities of this age group and the long-term outcome. METHODS: Clinical data of 182 pediatric patients included in the French WD national registry from 01/03/1995 to 01/06/2019 were gathered. RESULTS: Diagnosis of WD was made at a mean age of 10.7â±â4.2âyears (range 1-18âyears). At diagnosis, 154 patients (84.6%) had hepatic manifestations, 19 (10.4%) had neurological manifestations, and 9 patients (4.9%) were asymptomatic. The p.His1069Gln mutation was the most frequently encountered (14% of patients).Neurological patients were diagnosed at least 1 year after they presented their first symptoms. At diagnosis, the median urinary copper excretion (UCE) was 4.2âµmol/24âhours (0.2-253). The first-line treatment was d-penicillamine (DP) for 131 (72%) patients, zinc salts for 24 (13%) patients, and Trientine for 17 (9%) patients. Liver transplantation was performed in 39 (21.4%) patients, for hepatic indications in 33 of 39 patients or for neurological deterioration in 6 of 39 patients, mean Unified Wilson's Disease Rating Scale of the latter went from 90â±â23.1 before liver transplantation (LT) to 26.8â±â14.1 (Pâ<â0.01) after a mean follow-up of 4.3â±â2.5âyears. Overall survival rate at 20âyears of follow-up was 98%, patient and transplant-free combined survival was 84% at 20âyears. CONCLUSION: Diagnosis of WD can be challenging in children, particularly at the early stages of liver disease and in case of neurological presentation; hence the support of clinical scores and genetic testing is essential. Diagnosis at early stages and proper treatment ensure excellent outcomes, subject to good long-term treatment compliance. LT is a valid option for end-stage liver disease not responding to treatment and can be discussed for selected cases of neurological deterioration.
Assuntos
Degeneração Hepatolenticular , Adolescente , Criança , Pré-Escolar , Cobre , França/epidemiologia , Degeneração Hepatolenticular/diagnóstico , Degeneração Hepatolenticular/genética , Degeneração Hepatolenticular/terapia , Humanos , Lactente , Penicilamina/uso terapêutico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Single daily dose (SDD) is a good way to improve adherence by simplifying treatment. Efficacy data concerning patients with Wilson disease (WD) taking an SDD are lacking. AIM: To report the effectiveness of the use of SDD for the treatment of WD. METHODS: This retrospective study included WD patients followed in the French National Network who received an SDD in maintenance phase. The treatment failure was defined as a composite criterion with the occurrence of at least one of the following criterion: death, transplantation, increase of transaminases >2xULN, hepatic decompensation, neurological aggravation, severe side effects related to treatment, and/or discontinuation of treatment. RESULTS: A total of 26 patients received an SDD (D-penicillamine=13, trientine=8, zinc=5) after a median interval of 152 months after diagnosis. After one year, two patients had treatment failure: transaminitis in one, continuation of neurological deterioration in the other related to a poor compliance. After a median duration of 41 months on SDD, 3 other patients had treatment failure (transaminitis=2, treatment discontinuation=1). There was no death, no liver transplantation, no hepatic decompensation, and no severe side effects related to treatment during the follow-up. Moreover, transaminases and serum exchangeable copper were not significantly different 1 year post-switch and at last follow-up compared to baseline. CONCLUSIONS: Maintenance therapy simplification through the use of an SDD could be considered in some WD patients. In this pilot study, SDD was effective in 21/26 patients (81%) without any concern regarding safety.
Assuntos
Degeneração Hepatolenticular , Humanos , Degeneração Hepatolenticular/tratamento farmacológico , Degeneração Hepatolenticular/diagnóstico , Estudos Retrospectivos , Estudos de Viabilidade , Projetos Piloto , Quelantes/efeitos adversos , Transaminases , CobreAssuntos
Duodenopatias/terapia , Duodeno/irrigação sanguínea , Hemorragia Gastrointestinal/terapia , Hemostase Endoscópica/métodos , Varizes/diagnóstico por imagem , Duodenopatias/etiologia , Endossonografia , Feminino , Hemorragia Gastrointestinal/etiologia , Hemostase Endoscópica/instrumentação , Humanos , Pessoa de Meia-Idade , Ruptura Espontânea/complicações , Ruptura Espontânea/diagnóstico por imagem , Varizes/complicaçõesRESUMO
BACKGROUND: Autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) are rare indications for liver transplantation (LT) in children. The aim of the present retrospective multicenter study was to evaluate long-term outcome after LT for autoimmune liver disease in childhood. METHODS: Retrospective data from 30 children who underwent a first LT from 1988 to 2018 were collected. RESULTS: The study population consisted of 18 girls and 12 boys, transplanted for AIH type 1 (n=14), AIH type 2 (n=7) or PSC (n=9). Mean age at LT was 11.8±5.2 years. The main indications for LT were acute (36.7%) or chronic end-stage liver failure (63.3%). Graft rejection occurred in 19 patients (63.3%); 6 pts required retransplantation for chronic rejection. Recurrence of initial disease was observed in 6 patients (20.0%), all of them with type 1 AIH, after a median time of 42 months, requiring retransplantation in 2 cases. Overall patient survival rates were 96.4%, 84.6%, 74.8%, 68.0%, 68.0%, 68.0% and 68.0% at 1, 5, 10, 15, 20, 25 and 30 years, respectively. Age at LT<1year (p<0.0001), LT for fulminant failure (p=0.023) and LT for type 2 AIH (p=0.049) were significant predictive factors of death. CONCLUSION: Long-term outcome after LT for pediatric autoimmune liver disease is impaired in patients with AIH because of consistent complications such as rejection and disease recurrence.
Assuntos
Colangite Esclerosante , Doença Hepática Terminal , Hepatite Autoimune , Transplante de Fígado , Criança , Feminino , Hepatite Autoimune/cirurgia , Humanos , Masculino , Estudos RetrospectivosRESUMO
BACKGROUND/AIM: The spectrum of ATP7B variants varies significantly according to geographic distribution, and there is insufficient data on the variants observed in the French population. METHODS: Clinical data of 113 children included in the French WD national registry were gathered from March 01, 1995 to July 01, 2020. Data included epidemiological, clinical, laboratory, genetics. RESULTS: Diagnosis was made at a mean age of 11.0 ± 4.1 years (range 1-18 years). At diagnosis, 91 patients (79.8 %) had hepatic manifestations, 18 (15.8 %) presented neurological manifestations, and 4 patients (3.5 %) were asymptomatic. Only 29 patients (25 %) were homozygous for a variant. We have found a total of 102 different variants including 14 novel variants. Recurrent variant p.His1069Gln was the most prevalent, n = 31 alleles (14,2%), with only seven homozygous; in contrast 55% of variants are identified in only one family. 45% were truncating variants. In respect of mutated exon, the three most prevalent were exon 14 (16.5%), exon 8 (13.8%), and exon 3 (11.5%). When considering patients with two Nonsense / Frameshift variants as a group and those with two Missense variants, we found significantly lower ceruloplasmin for the former: 2.8 ± 0.7 mg/dl vs 8.4 ± 5mg/dl (p<0.05). CONCLUSION: p.His1069Gln is the most frequent variant (14,2%) and exons 14, 8, and 2 of the ATP7B gene account for 41.7% of total variants. However, there is significant heterogeneity in the French population concerning the other ATP7B variants. Nonsense / Frameshift variants were associated with lower ceruloplasmin levels.
Assuntos
ATPases Transportadoras de Cobre/genética , Degeneração Hepatolenticular/genética , Fenótipo , Adolescente , Ceruloplasmina/análise , Criança , Pré-Escolar , Feminino , Frequência do Gene , Degeneração Hepatolenticular/sangue , Degeneração Hepatolenticular/patologia , Humanos , Masculino , MutaçãoRESUMO
INTRODUCTION: Liver transplantation (LT) is the therapeutic option for end-stage liver disease associated with alpha1 antitrypsin (A1AT) deficiency. The aim of the present retrospective study was to report on long-term outcomes following LT for A1AT deficiency. METHODS: The medical records of 90 pediatric and adult patients transplanted between 1982 and 2017 in France and Geneva (Switzerland) were reviewed. RESULTS: The study population consisted of 32 adults and 58 children; median age at transplant was 13.0 years (range: 0.2-65.1), and 65 were male (72.2%). Eighty-two patients (94.8% of children and 84.4% of adults) had the PI*ZZ genotype/phenotype and eight patients (8.9%) had the Pi*SZ genotype/phenotype. Eighty-four patients (93.3%) were transplanted for end-stage liver disease and six (all Pi*ZZ adults) for HCC. Median follow-up after LT was 13.6 years (0.1-31.7). The overall cumulative patient survival rates post-transplant were 97.8% at 1 year, and 95.5%, 95.5%, 92.0%, 89.1% at 5, 10, 15, 20 years respectively. The overall cumulative graft survival rates were 92.2% at 1 year, and 89.9%, 89.9%, 84.4%, 81.5% at 5, 10, 15 and 20 years, respectively. CONCLUSIONS: In a representative cohort of patients having presented with end-stage-liver disease or HCC secondary to A1AT, liver transplantation offered very good patient and graft survival rates.
Assuntos
Transplante de Fígado/mortalidade , Deficiência de alfa 1-Antitripsina/cirurgia , Adolescente , Adulto , Criança , Intervalo Livre de Doença , Feminino , Seguimentos , Sobrevivência de Enxerto/imunologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Deficiência de alfa 1-Antitripsina/complicaçõesRESUMO
BACKGROUND: Risk factors for the development of anti-HLA antibodies include blood transfusion, organ transplantation, and pregnancy. Humoral rejection, mediated by donor-specific anti-HLA antibodies (DSA), has been studied in all kind of solid organ transplantations, and several studies have suggested that post-liver transplantation (LT) DSA may play a role in acute and chronic rejection. OBJECTIVE: The aim of the present study was to assess the impact of pregnancy on the occurrence of DSA and the impact of DSA in a large population of young female LT recipients. METHODS: This single center retrospective study included all female patients who underwent a first LT between January 1990 and December 2010 and who were of childbearing age during post-LT follow-up (i.e. 18 to 40â¯years old). RESULTS: The study population consisted in 73 patients, and the mean age at LT was 20.9â¯years (0.6-39.9); 32 patients were transplanted during childhood. The global incidence of de novo DSA was 42.5% (31/73), after a median delay of 15.5â¯years (1-25) of follow-up after LT. Most de novo DSA were anti-class II alone (90.3%), and included anti-DQ for 80.6%. From the 73 patients, 33 presented at least one pregnancy after LT (45.2%) and before DSA screening. Multivariate analysis disclosed that history of pregnancy (ORâ¯=â¯6.37; 95%CI, 2.17-18.63, pâ¯=â¯0.001) and younger age at LT (ORâ¯=â¯0.96; 95%CI:0.92-0.99, pâ¯=â¯0.033) were significantly associated with de novo DSA. Among the 31 patients who had de novo DSA, the diagnosis of antibody-mediated rejection was made in 8 patients (25.8%), after a median delay of 74â¯months after LT; 6/8 (75.0%) had history of pregnancy. During follow-up, 3 of these 8 patients lost their liver graft and died. CONCLUSION: The results of the present study suggest that close monitoring of DSA in young women with history of pregnancy should be recommended regarding the risk of DSA-mediated rejection.
Assuntos
Rejeição de Enxerto/diagnóstico , Isoanticorpos/metabolismo , Transplante de Fígado , Complicações na Gravidez/diagnóstico , Gravidez/imunologia , Adolescente , Adulto , Fatores Etários , Feminino , Seguimentos , Rejeição de Enxerto/mortalidade , Antígenos HLA/imunologia , Humanos , Imunidade Humoral , Monitorização Fisiológica , Complicações na Gravidez/mortalidade , Estudos Retrospectivos , Risco , Análise de Sobrevida , Adulto JovemRESUMO
BACKGROUND: During the past decade, mTOR inhibitors (mTORi), everolimus and sirolimus, have been increasingly used after adult liver transplantation (LT). The aim of the present study was to describe the use of mTORi in pediatric LT recipients. METHODS: All pediatric LT recipients who received mTORi before December 2017 from 4 European pediatric LT centers were included and analyzed. RESULTS: The present retrospective study included 30 patients; 21 were male (70%), median age was 9.3 years (range: 1.2-17.1 years) at mTORi introduction. Main indications for mTORi introduction were pre-existing liver malignancy (43.3%), calcineurin inhibitor (CNI) nephrotoxicity (26.7%), or rejection (23.4%). At last follow-up, mTORi CNIs were withdrawn in 10 patients (10/29, 34.5%). The median dose of mTORi was 1.8 mg/day (range: 0.3-5.0) or 0.058 mg/kg/day (range: 0.01-0.26), and the median trough level was 5.1 µg/L (range: 1.0-15.5). After a median follow-up of 2.8 years (range: 0.2-10.0), 50.0% of the patients presented with at least one adverse event. The main adverse events included hyperlipidemia, proteinuria, dermatitis, and mucitis. Overall mTORi discontinuation rate was 23.3% (10.0% because of adverse event). Introduction of mTORi had no significant impact on renal function. CONCLUSION: Our results suggest that mTORi can be used in pediatric LT recipients in different clinical situations, both to reinforce immunosuppressive therapy, and to reduce CNI and related toxicity.
Assuntos
Everolimo/uso terapêutico , Imunossupressores/uso terapêutico , Fígado , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Transplantados , Adolescente , Criança , Pré-Escolar , Ciclosporina , Everolimo/administração & dosagem , Everolimo/efeitos adversos , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Lactente , Masculino , Estudos Retrospectivos , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Esteroides/uso terapêutico , Tacrolimo/uso terapêuticoRESUMO
BACKGROUND: The prevalence and clinical impact of anti-HLA donor-specific antibodies (DSA) after liver transplantation (LT) have not been extensively studied, especially in pediatric population. METHODS: The present cross-sectional study included 100 patients who underwent a first LT in childhood. Anti HLA immunization study was performed at a single time point during routine follow-up using Luminex® single antigen tests with classical anti-IgG conjugate and anti-C3d conjugate. RESULTS: The main indication for LT was biliary atresia (52%) and median age at LT was 4.6years. The median time between LT and DSA assessment was 7.8years (range 1-21years). DSA was identified in twenty-four patients (24%) after LT, with a prevalence of 8%, 28%, 33%, 50%, respectively 0-5years, 5-10years, 10-15years and >15years after LT. DSA were mainly class II (23/24) with a mean MFI of 9.731±5.489 and 18 (79.3%) were C3d-binding DSA. Multivariate analysis disclosed that time elapsed since LT (p<0.01) and history of fulminant hepatitis (p=0.04) were significantly associated with a higher rate of DSA. Liver function tests (at time of DSA assessment) were not different according to the presence or not of DSA (or C3d-binding DSA). Regarding histology, the DSA group had a higher rate of chronic rejection, cirrhosis and centrilobular fibrosis or cirrhosis. In addition, patients with C3d-binding DSA and high MFI (>10,000) had a significant poorer long-term graft survival (p=0.03). CONCLUSION: In our pediatric cohort of LT, prevalence of DSA was high and increased regularly with time. Presence of C3d positive-DSA with high MFI was associated with a higher rate of graft loss.