RESUMO
AIMS: To study the effects of routine HLA screening and the policy of avoiding donor-dominant one-way HLA match to prevent graft-versus-host disease (GVHD) after living donor liver transplantation (LDLT). PATIENTS AND METHODS: The records of potential living liver donors and recipients who attended our center between 2007 and 2018 were reviewed retrospectively. RESULTS: Of the 149 patients who underwent LDLT and survived longer than 3 months, two developed GVHD despite our strict policy. The first patient presented with grade II GVHD limited to the skin. She was treated successfully by briefly discontinuing immunosuppression and switching to everolimus. In the second case, the policy had been relaxed due to the availability of a single donor for ABO-incompatible transplantation without any intervention to decrease anti-A antibody levels (special case: A2 to O). Nevertheless, the patient presented with grade I GVHD limited to skin and was treated successfully by adding oral methylprednisolone to tacrolimus and mycophenolate mofetil. To the best of our information, this is the second reported case who recovered from GVHD after LDLT from a donor, homozygous at HLA A, B and DR and a recipient, heterozygous for all. Sixteen potential donors (1.2% of all candidates) of 14 recipients were disqualified solely on the basis of the HLA results; five of these patients died due to unavailability of another donor. CONCLUSION: The results support the policy of avoiding HLA combinations that preclude immune recognition of graft lymphocytes as foreign to decrease the risk of GVHD after LDLT.
Assuntos
Doença Enxerto-Hospedeiro , Antígenos HLA , Teste de Histocompatibilidade , Transplante de Fígado , Doadores Vivos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Doença Enxerto-Hospedeiro/prevenção & controle , Antígenos HLA/imunologia , Antígenos HLA/genética , Imunossupressores/uso terapêutico , Estudos RetrospectivosRESUMO
BACKGROUND AND AIMS: Mutations in ATPase phospholipid transporting 8B1 (ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1. The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide insights by using the largest genetically defined cohort of patients with FIC1 deficiency to date. APPROACH AND RESULTS: This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication), FIC1-A (n = 67; no PPTMs), FIC1-B (n = 29; one PPTM), or FIC1-C (n = 34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years: 65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10 years, sBAs < 194 µmol/L: 49% vs. sBAs ≥ 194 µmol/L: 15%; P = 0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] µmol/L; P = 0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65 µmol/L (P = 0.05) tended to be associated with improved NLS. CONCLUSIONS: Less than half of patients with FIC1 deficiency reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.
Assuntos
Adenosina Trifosfatases/deficiência , Ácidos e Sais Biliares/sangue , Colestase Intra-Hepática/mortalidade , Adenosina Trifosfatases/genética , Adolescente , Ductos Biliares Intra-Hepáticos/cirurgia , Criança , Pré-Escolar , Colestase Intra-Hepática/sangue , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/cirurgia , Códon sem Sentido , Feminino , Seguimentos , Humanos , Lactente , Transplante de Fígado/estatística & dados numéricos , Masculino , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND & AIMS: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date. METHODS: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category. RESULTS: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27-0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 µmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001). CONCLUSIONS: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS. LAY SUMMARY: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease.
Assuntos
Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/deficiência , Ácidos e Sais Biliares , Procedimentos Cirúrgicos do Sistema Biliar/métodos , Carcinoma Hepatocelular , Colestase Intra-Hepática , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Ácidos e Sais Biliares/sangue , Ácidos e Sais Biliares/metabolismo , Procedimentos Cirúrgicos do Sistema Biliar/estatística & dados numéricos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/prevenção & controle , Pré-Escolar , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/fisiopatologia , Colestase Intra-Hepática/cirurgia , Feminino , Testes Genéticos/métodos , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/prevenção & controle , Masculino , Mutação , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de Sobrevida , TempoRESUMO
AIM: A high faecal calprotectin (FC) level is a non-invasive marker for inflammatory bowel disease. Nevertheless, healthy infants have elevated levels of FC with large variations. The aim of our study was to determine the levels of FC and associated factors in healthy infants aged 0-12 months. METHODS: Infants younger than 1 year of age were in the follow-up programme of the Well Child Unit. Data on the clinical characteristics, including birth, anthropometric measurements and feeding types of infants in the unit, were obtained from their personal health records. One fresh stool sample was collected from each infant. ELISA was used to measure FC. RESULTS: We included 84 infants younger than 1 year of age. The median FC value was 313 µg/g. The FC levels were greater in the youngest (0-30 days) group of infants than in the oldest (181-365 days) group (P < 0.001). The FC levels were higher in infants delivered by caesarean section than in those delivered vaginally (P = 0.016). The levels were also higher in infants who were solely breastfed than in those who received mixed feeding (breast milk and formula) during the first 6 months of life (P = 0.030). CONCLUSION: The FC levels in this group of infants were high, especially in the first month of life. Several birth and environmental factors influenced the FC values. Further studies with a larger cohort of infants and serial assessment of FC over time are required to better understand the patterns of this biomarker during infancy.
Assuntos
Cesárea , Complexo Antígeno L1 Leucocitário , Aleitamento Materno , Criança , Fezes , Feminino , Humanos , Lactente , Recém-Nascido , Leite Humano , GravidezRESUMO
OBJECTIVES: We aimed to investigate national allocation policies for pediatric liver transplantation (LT). METHOD: A survey was prepared by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Hepatology Committee in collaboration with the North American Studies of Pediatric Liver Transplantation consortium. The survey was sent to pediatric hepatologists and transplant surgeons worldwide. National data were obtained from centrally based registries. RESULTS: Replies were obtained from 15 countries from 5 of the world continents. Overall donation rate varied between 9 and 35 per million inhabitants. The number of pediatric LTs was 4 to 9 per million inhabitants younger than 18 years for 13 of the 15 respondents. In children younger than 2 years mortality on the waiting list (WL) varied between 0 and 20%. In the same age group, there were large differences in the ratio of living donor LT to deceased donor LT and in the ratio of split liver segments to whole liver. These differences were associated with possible discrepancies in WL mortality. CONCLUSIONS: Similarities but also differences between countries were detected. The described data may be of importance when trying to reduce WL mortality in the youngest children.
Assuntos
Gastroenterologia/legislação & jurisprudência , Política de Saúde , Transplante de Fígado/legislação & jurisprudência , Pediatria/legislação & jurisprudência , Obtenção de Tecidos e Órgãos/legislação & jurisprudência , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Listas de Espera/mortalidadeRESUMO
ABCD3 is one of three ATP-binding cassette (ABC) transporters present in the peroxisomal membrane catalyzing ATP-dependent transport of substrates for metabolic pathways localized in peroxisomes. So far, the precise function of ABCD3 is not known. Here, we report the identification of the first patient with a defect of ABCD3. The patient presented with hepatosplenomegaly and severe liver disease and showed a striking accumulation of peroxisomal C27-bile acid intermediates in plasma. Investigation of peroxisomal parameters in skin fibroblasts revealed a reduced number of enlarged import-competent peroxisomes. Peroxisomal beta-oxidation of C26:0 was normal, but beta-oxidation of pristanic acid was reduced. Genetic analysis revealed a homozygous deletion at the DNA level of 1758bp, predicted to result in a truncated ABCD3 protein lacking the C-terminal 24 amino acids (p.Y635NfsX1). Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation. To corroborate our findings in the patient, we studied a previously generated Abcd3 knockout mouse model. Abcd3-/- mice accumulated the branched chain fatty acid phytanic acid after phytol loading. In addition, analysis of bile acids revealed a reduction of C24 bile acids, whereas C27-bile acid intermediates were significantly increased in liver, bile and intestine of Abcd3-/- mice. Thus, both in the patient and in Abcd3-/- mice, there was evidence of a bile acid biosynthesis defect. In conclusion, our studies show that ABCD3 is involved in transport of branched-chain fatty acids and C27 bile acids into the peroxisome and that this is a crucial step in bile acid biosynthesis.
Assuntos
Transportadores de Cassetes de Ligação de ATP/deficiência , Transportadores de Cassetes de Ligação de ATP/metabolismo , Ácidos e Sais Biliares/biossíntese , Hepatopatias/metabolismo , Peroxissomos/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Ácidos Graxos/metabolismo , Feminino , Humanos , Hepatopatias/genética , Masculino , Camundongos , Camundongos Knockout , Peroxissomos/genéticaRESUMO
As pediatric liver transplantation comes of age, experts gathered to discuss current paradigms and define gaps in knowledge warranting research to further improve patient and graft outcomes. Identified areas ripe for collaborative research include understanding the molecular and cellular mechanisms of tolerance and the role of donor-specific antibodies, considering ways to expand donor pool, minimizing long-term side effects of immunosuppression, and fine-tuning surgical techniques to minimize biliary and vascular complications.
Assuntos
Transplante de Fígado , Criança , Esquema de Medicação , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Humanos , Imunossupressores/uso terapêutico , Avaliação de Resultados em Cuidados de Saúde , Pediatria , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/terapia , Qualidade de Vida , Obtenção de Tecidos e Órgãos/métodosRESUMO
Brucellosis is considered the most widespread zoonosis in the world. In endemic regions of brucellosis, childhood brucellosis includes up to one-third of all cases of human brucellosis. Brucellosis constitutes a public health problem in Turkey. A boy aged 12 yr who had PFIC2 had undergone deceased-donor liver transplantation in 2008 at the age of seven. The boy presented with fatigue, fever, and pain in the right leg and hip and was admitted to the hospital. Brucella melitensis grew in the blood culture, and the SAT was positive at a titer of 1:640. The patient was treated with oral doxycycline and rifampicin for eight wk. After treatment, the patient recovered and his blood cultures became negative. The patient's mother also had a high Brucella agglutination titer of 1:320 positive and was treated in the internal medicine department with spiramycin and doxycycline. Brucella infection should be suspected in liver transplant recipients with fever of unknown origin, especially in recipients who live in an endemic area.
Assuntos
Brucella melitensis/isolamento & purificação , Brucelose/diagnóstico , Colestase Intra-Hepática/cirurgia , Transplante de Fígado , Complicações Pós-Operatórias/diagnóstico , Brucelose/etiologia , Criança , Humanos , MasculinoRESUMO
BACKGROUND: Cirrhotic cardiomyopathy (CCMP) is a functional disorder characterized by electrophysiological disturbances, and diastolic and/or systolic dysfunction in patients with liver disease. This disorder is a well-defined entity in adults, but pediatric data are limited. The aim of the study was to determine the incidence, features, and risk factors of CCMP in children with portal hypertension (PHT). METHODS: This study included 50 children with cirrhotic PHT (40/50) and noncirrhotic PHT (10/50). Fifty healthy children were also selected for the control group. Electrocardiography and echocardiography were used to evaluate cardiac functions. Corrected QT (QTc)â≥â0.45 was accepted as prolonged on electrocardiography. The study group was divided into 3 groups: cirrhotic, noncirrhotic, and control. Then, the CCMP group was created according to the diagnostic criteria. Latent CCMP was diagnosed in the presence of prolonged-QTc along with a minor criterion (tachycardia). Manifest CCMP was diagnosed in the presence of at least 2 major criteria (prolonged-QTc along with abnormal echocardiographic findings). Moreover, in this study, the risk factors for CCMP were investigated. RESULTS: The CCMP group included 10 cases (20%). Nine of these cases had latent CCMP (18%), and the remaining one (2%) had manifest CCMP. All of the cases with CCMP had cirrhosis and ascites. None of the patients with CCMP had severe cardiac symptoms, but they were already using some cardioprotective drugs such as propanolol and spironolactone. As risk factors for CCMP, pediatric end-stage liver disease scores, Child-Pugh scores, and ascites grades were found to be significant for the determination of CCMP. The most important risk factor was ascites severity (Pâ=â0.001, odds ratio 9.4). CONCLUSIONS: Approximately 20% of children with PHT have CCMP. A detailed cardiac examination should be carried out periodically in children with cirrhotic PHT, especially in the presence of ascites and high Child-Pugh score.
Assuntos
Cardiomiopatias/etiologia , Hipertensão Portal/complicações , Cirrose Hepática/complicações , Adolescente , Anti-Hipertensivos/uso terapêutico , Ascite/etiologia , Pressão Sanguínea , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/epidemiologia , Cardiomiopatias/fisiopatologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Diuréticos/uso terapêutico , Ecocardiografia , Eletrocardiografia , Feminino , Frequência Cardíaca , Humanos , Hipertensão Portal/tratamento farmacológico , Incidência , Masculino , Propranolol/uso terapêutico , Fatores de Risco , Índice de Gravidade de Doença , Espironolactona/uso terapêutico , Taquicardia/etiologiaRESUMO
OBJECTIVES: Data regarding agreement on endoscopic features of oesophageal varices in children with portal hypertension (PH) are scant. The aim of this study was to evaluate endoscopic visualisation and classification of oesophageal varices in children by several European clinicians, to build a rational basis for future multicentre trials. METHODS: Endoscopic pictures of the distal oesophagus of 100 children with a clinical diagnosis of PH were distributed to 10 endoscopists. Observers were requested to classify variceal size according to a 3-degree scale (small, medium, and large, class A), a 2-degree scale (small and large, class B), and to recognise red wales (presence or absence, class Red). Overall agreement was considered fair if Fleiss and Cohen κ test was ≥0.30, good if ≥0.40, excellent if ≥0.60, and perfect if ≥0.80. RESULTS: Agreement between observers was fair with class A (κâ=â0.34) and class B (κâ=â0.38), and good with class Red (κâ=â0.49). The agreement was good on presence versus absence of varices (class Aâ=â0.53, class Bâ=â0.48). The agreement among the observers was good in class A when endoscopic features of severe PH (medium and large sizes, red marks) were grouped and compared with mild features (absent and small varices) (κâ=â0.58). CONCLUSIONS: Experts working in different centres show a fairly good agreement on endoscopic features of PH in children, although a better training of paediatric endoscopists may improve the agreement in grading severity of varices in this setting.
Assuntos
Endoscopia , Varizes Esofágicas e Gástricas/classificação , Varizes Esofágicas e Gástricas/patologia , Adolescente , Criança , Pré-Escolar , Endoscopia/educação , Endoscopia/estatística & dados numéricos , Varizes Esofágicas e Gástricas/complicações , Feminino , Humanos , Hipertensão Portal/complicações , Hipertensão Portal/patologia , Masculino , Variações Dependentes do Observador , Pediatria/educação , Pediatria/estatística & dados numéricos , Reprodutibilidade dos TestesRESUMO
Liver biopsy (LB) is still the criterion standard procedure for obtaining liver tissue for histopathological examination and a valuable tool in the diagnosis, prognosis, and management of many parenchymal liver diseases. The aim of this position paper is to summarise the present practice of paediatric LB and make recommendations about its performance. Although histological evaluation of the liver is important in assessing prognosis and exploring treatment, noninvasive techniques (ie, imaging, laboratory markers) may replace use of liver histology. The indications for LB are changing as present knowledge of aetiologies, pathomechanism, and therapeutic options in paediatric liver disease is evolving. Adult and paediatric literature was reviewed to assess the existing clinical practice of LB with focus on the technique, indications, risk of complications, and contraindications in paediatrics. This position paper presents types of LB, indications, complications, contraindications, and an essential checklist for paediatric LB.
Assuntos
Medicina Baseada em Evidências , Gastroenterologia/métodos , Hepatopatias/diagnóstico , Fígado/patologia , Ciências da Nutrição/métodos , Pediatria/métodos , Medicina de Precisão , Biópsia/efeitos adversos , Biópsia/normas , Criança , Pré-Escolar , Contraindicações , Europa (Continente) , Gastroenterologia/tendências , Humanos , Lactente , Recém-Nascido , Hepatopatias/patologia , Ciências da Nutrição/tendências , Pediatria/tendências , Prognóstico , Sociedades MédicasRESUMO
BACKGROUND: Essential micronutrients are important for maintenance of life. Deficiency of micronutrients is more likely to be encountered in children, and women studies are required to investigate the status of micronutrients in children and women. This study aimed to longitudinally evaluate changes in zinc, copper, and iron levels in breastfed infants and their mothers during the first year of life. METHODS: Serum and hair samples were obtained from 35 healthy breastfed infants (51% males, 49% females) and their mothers 2, 6, and 12 months after delivery. All of the samples were assessed using an atomic absorption spectrophotometer. Serum iron levels were determined by a Roche/Hitachi/Modular analyzer. Statistical analyses were performed using SPSS-PC (Version 21.00) software. RESULTS: Hair zinc (p < 0.05) and serum iron (p < 0.001) levels of infants were significantly decreased towards the end of the first year. Infants' serum copper levels were increased towards the end of the first year. Maternal serum and hair copper levels and serum iron levels were significantly decreased towards the end of the first year. There were no significant correlations between dietary zinc, copper, iron intake, and trace element levels of infants and their mothers. CONCLUSIONS: Infants' hair zinc levels, maternal and infants' hair copper levels, and infants' and maternal serum iron levels declined towards the end of the first year. Infants need more zinc after 6 months of age. Infants' and mothers' daily iron intake was less than the recommended intake.
Assuntos
Aleitamento Materno , Cobre/metabolismo , Cabelo/química , Ferro/metabolismo , Micronutrientes/metabolismo , Leite Humano/química , Zinco/metabolismo , Adulto , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Mães , Estudos Prospectivos , Espectrofotometria Atômica , Adulto JovemRESUMO
BACKGROUND: In patients with Alagille syndrome, cholestasis-associated clinical features can include high serum bile acids and severe pruritus that can necessitate liver transplantation. We aimed to evaluate the efficacy and safety of the ileal bile acid transporter inhibitor odevixibat versus placebo in patients with Alagille syndrome. METHODS: The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries (Belgium, France, Germany, Italy, Malaysia, the Netherlands, Poland, Türkiye, the UK, and the USA). Eligible patients had a genetically confirmed diagnosis of Alagille syndrome, a history of significant pruritus, and elevated serum bile acids. Patients were randomly assigned (2:1) to receive oral odevixibat 120 µg/kg per day or placebo for 24 weeks (in a block size of six and stratified by age: <10 years and ≥10 years to <18 years) via a web-based system. Patients, clinicians, study staff, and people analysing the data were masked to treatment allocation. The primary efficacy endpoint was change in caregiver-reported scratching score (on the PRUCISION instrument; range 0-4) from baseline to weeks 21-24. The prespecified key secondary efficacy endpoint was change in serum bile acid concentration from baseline to the average of weeks 20 and 24. Outcomes were analysed in patients who received at least one dose of study drug (the full analysis set for efficacy outcomes and the safety analysis set for safety outcomes). This trial is registered on ClinicalTrials.gov (NCT04674761) and EudraCT (2020-004011-28), and is completed. FINDINGS: Between Feb 26, 2021, and Sept 9, 2022, 52 patients were randomly assigned to receive odevixibat (n=35) or placebo (n=17), all of whom were included in the analysis sets. The median age was 5·5 years (IQR 3·2 to 8·9). 27 (52%) of 52 patients were male and 25 (48%) were female. The mean scratching score was elevated at baseline in both groups (2·8 [SD 0·5] for odevixibat vs 3·0 [0·6] for placebo). Mean scratching scores at weeks 21-24 were 1·1 (0·9) for odevixibat and 2·2 (1·0) for placebo, representing a least-squares (LS) mean change of -1·7 (95% CI -2·0 to -1·3) for odevixibat and -0·8 (-1·3 to -0·3) for placebo, which was significantly greater for odevixibat than for placebo (difference in LS mean change from baseline -0·9 [95% CI -1·4 to -0·3]; p=0·0024). Odevixibat also resulted in significantly greater reductions in mean serum bile acids from baseline versus placebo (237 µmol/L [SD 115] with odevixibat vs 246 µmol/L [121] with placebo) to the average of weeks 20 and 24 (149 µmol/L [102] vs 271 µmol/L [167]; LS mean change -90 µmol/L [95% CI -133 to -48] with odevixibat vs 22 µmol/L [-35 to 80] with placebo; difference in LS mean change -113 µmol/L [95% CI -179 to -47]; p=0·0012). The most common treatment-emergent adverse events were diarrhoea (ten [29%] of 35 patients in the odevixibat group vs one [6%] of 17 in the placebo group) and pyrexia (eight [23%] vs four [24%]). Seven patients had serious treatment-emergent adverse events during the treatment period: five (14%) in the odevixibat group and two (12%) in the placebo group. No patients discontinued treatment and there were no deaths. INTERPRETATION: Odevixibat could be an efficacious non-surgical intervention to improve pruritus, reduce serum bile acids, and enhance the standard of care in patients with Alagille syndrome. Longer-term safety and efficacy data of odevixibat in this population are awaited from the ongoing, open-label ASSERT-EXT study. FUNDING: Albireo Pharma, an Ipsen company.
Assuntos
Síndrome de Alagille , Prurido , Humanos , Método Duplo-Cego , Síndrome de Alagille/tratamento farmacológico , Síndrome de Alagille/complicações , Masculino , Feminino , Criança , Adolescente , Prurido/tratamento farmacológico , Prurido/etiologia , Resultado do Tratamento , Ácidos e Sais Biliares/sangue , Adulto , Pré-Escolar , Adulto Jovem , Proteínas de Transporte , Glicoproteínas de Membrana , Metilaminas , TiazepinasRESUMO
Hepatoportal sclerosis (HPS) is defined as sclerosis of portal areas in the absence of cirrhosis. There is little information about HPS in children in the literature. The aim of this study was to describe the clinical presentation, associated disorders, laboratory characteristics and outcome of children who were diagnosed as HPS. This study included 12 children diagnosed as HPS by the Pathology Department between 2005 and 2011. Data were collected from the gastroenterology clinic charts retrospectively, including demographics, presentation characteristics, laboratory data and recent status of patients. Twelve patients were enrolled (6 girls, 6 boys). The median age of patients was 13.5 yr. Median age at the time of biopsy was 11 yr. Four patients had splenomegaly, 3 had esophageal varices, one had hepatopulmonary syndrome and had been transplanted. Smooth muscle antibody was found positive in 4 patients, without autoimmune hepatitis findings in liver biopsy. One patient had celiac disease and another patient had positive celiac disease serology but pathology findings. Another patient had Turner's syndrome. Mean follow-up time was 39 months (3.3 yr) after biopsy. Hepatoportal sclerosis does not necessarily present with portal hypertension in children.
Assuntos
Hipertensão Portal/diagnóstico , Hepatopatias/diagnóstico , Esclerose/diagnóstico , Esclerose/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Gastroenterologia , Humanos , Hipertensão Portal/complicações , Hipertensão Portal/patologia , Fígado/patologia , Hepatopatias/complicações , Hepatopatias/patologia , Masculino , Veia Porta/patologia , Estudos RetrospectivosRESUMO
Transaldolase deficiency is a rare inborn autosomal recessive disorder caused by biallelic mutations in the TALDO1 gene. It is characterized by intrauterine growth restriction, dysmorphism, abnormal skin, cytopenia, hepatosplenomegaly, liver cirrhosis, endocrine problems, renal and cardiac abnormalities. We present two siblings of Turkish origin with early-onset form of transaldolase deficiency and hypergonadotropic hypogonadism in both sexes. The girl (index) was followed-up with cryptogenic cirrhosis, leukopenia and thrombocytopenia, skin abnormalities, congenital heart defects, hypercalciuria, nephrolithiasis, proteinuria, chronic kidney disease throughout childhood. She developed hypergonadotropic hypogonadism in adolescence period. Whole exome sequencing due to the multisystemic involvement revealed a previously described homozygous inframe deletion in TALDO1 gene. Her brother was born as a small for gestational age baby and was also followed-up with cryptogenic cirrhosis since his infancy, together with cytopenia, congenital heart defects, bilateral cryptorchidism, short stature, hypercalciuria, proteinuria and chronic kidney disease in childhood. He presented with testicular microlithiasis and hypergonadotropic hypogonadism in adolescence. Sanger sequencing of TALDO1 gene confirmed the presence of the same homozygous deletion with his sister. The mother was found to be a heterozygous carrier for this deletion. We describe two patients with multisystemic involvement since neonatal period who presented with an additional hypergonadotropic hypogonadism in adolescence. The diagnosis of transaldolase deficiency should be kept in mind for these patients, and they must be evaluated for gonadal functions especially during puberty.
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Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.
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Background & Aims: PEDFIC 2, an ongoing, open-label, 72-week study, evaluates odevixibat, an ileal bile acid transporter inhibitor, in patients with progressive familial intrahepatic cholestasis. Methods: PEDFIC 2 enrolled and dosed 69 patients across two cohorts; all received odevixibat 120 µg/kg per day. Cohort 1 comprised children from PEDFIC 1, and cohort 2 comprised new patients (any age). We report data through 15 July 2020, with Week 24 of PEDFIC 2 the main time point analysed. This represents up to 48 weeks of cumulative exposure for patients treated with odevixibat from the 24-week PEDFIC 1 study (cohort 1A) and up to 24 weeks of treatment for those who initiated odevixibat in PEDFIC 2 (patients who received placebo in PEDFIC 1 [cohort 1B] or cohort 2 patients). Primary endpoints for this prespecified interim analysis were change from baseline to Weeks 22-24 in serum bile acids (sBAs) and proportion of positive pruritus assessments (≥1-point drop from PEDFIC 2 baseline in pruritus on a 0-4 scale or score ≤1) over the 24-week period. Safety monitoring included evaluating treatment-emergent adverse events (TEAEs). Results: In cohort 1A, mean change from PEDFIC 1 baseline to Weeks 22-24 of PEDFIC 2 in sBAs was -201 µmol/L (p <0.0001). For cohort 1B and cohort 2, mean changes from odevixibat initiation to weeks 22-24 in sBAs were -144 and -104 µmol/L, respectively. The proportion of positive pruritus assessments in the first 24-week period of PEDFIC 2 was 33%, 56%, and 62% in cohorts 1A, 1B, and 2, respectively. Most TEAEs were mild or moderate. No drug-related serious TEAEs occurred. Conclusions: Odevixibat in patients with progressive familial intrahepatic cholestasis was generally well tolerated and associated with sustained reductions in sBAs and pruritus. Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT03659916). Impact and Implications: Disrupted bile flow is a hallmark feature of patients with progressive familial intrahepatic cholestasis and can result in build-up of bile constituents in the liver with spill over into the bloodstream; other effects that patients can experience include extremely itchy skin, and because not enough bile reaches the gut, patients can have problems digesting food, which may lead to poor growth. Odevixibat is an orally administered medication that shunts bile acids away from the liver. The current study, called PEDFIC 2, suggested that odevixibat can improve the problematic signs and symptoms of progressive familial intrahepatic cholestasis and was generally safe for patients.
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Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children and adolescents in the United States, and most probably also in the rest of the industrialized world.As the prevalence of NAFLD in childhood increases with the worldwide obesity epidemic, there is an urgent need for diagnostic standards that can be commonly used by pediatricians and hepatologists. To this end, we performed a PubMed search of the adult and pediatric literature on NAFLD diagnosis through May 2011 using Topics and/or relevant Authors as search words. According to the present literature, NAFLD is suspected based on the association of fatty liver combined with risk factors (mainly obesity), after the exclusion of other causes of liver disease. The reference but imperfect standard for confirming NAFLD is liver histology. The following surrogate markers are presently used to estimate degree of steatosis and liver fibrosis and risk of progression to end-stage liver disease: imaging by ultrasonography or magnetic resonance imaging, liver function tests, and serum markers of liver fibrosis.NAFLD should be suspected in all of the overweight or obese children and adolescents older than 3 years with increased waist circumference especially if there is a NAFLD history in relatives. The typical presentation, however, is in children ages 10 years and older. The first diagnostic step in these children should be abdominal ultrasound and liver function tests, followed by exclusion of other liver diseases. Overweight/obese children with normal ultrasonographic imaging and normal liver function tests should still be monitored due to the poor sensitivity of these tests at a single assessment.Indications for liver biopsy include the following: to rule out other treatable diseases, in cases of clinically suspected advanced liver disease, before pharmacological/surgical treatment, and as part of a structured intervention protocol or clinical research trial.
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Fígado Gorduroso/diagnóstico , Fígado Gorduroso/epidemiologia , Adolescente , Criança , Progressão da Doença , Fígado Gorduroso/complicações , Feminino , Gastroenterologia , Predisposição Genética para Doença , Humanos , Fígado/patologia , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Cirrose Hepática/fisiopatologia , Testes de Função Hepática , Masculino , Hepatopatia Gordurosa não Alcoólica , Obesidade/complicações , Obesidade/diagnóstico , Obesidade/epidemiologia , Prevalência , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of inherited paediatric liver diseases resulting from mutations in genes that impact bile secretion. We aimed to evaluate the effects of odevixibat, an ileal bile acid transporter inhibitor, versus placebo in children with PFIC. METHODS: Patients eligible for this 24-week, randomised, double-blind, completed, phase 3 study were paediatric outpatients diagnosed with PFIC1 or PFIC2 who had pruritus and elevated serum bile acids at screening. Patients were randomly assigned (1:1:1) using an interactive web-based system to once a day oral placebo, odevixibat 40 µg/kg, or odevixibat 120 µg/kg. Randomisation was done in a block size of six and stratified by PFIC type and patient age; patients, clinicians, and study staff were blinded to treatment allocation. Patients were enrolled at one of 33 global sites. Two primary endpoints were evaluated: proportion of positive pruritus assessments (PPAs; ie, scratching score of ≤1 or ≥1-point decrease as assessed by caregivers using the Albireo observer-reported outcome [ObsRO] PRUCISION instrument) over 24 weeks, and proportion of patients with serum bile acid response (ie, serum bile acids reduced by ≥70% from baseline or concentrations of ≤70 µmol/L) at week 24. Efficacy and safety were analysed in randomly allocated patients who received one or more doses of study drug. This study is registered with ClinicalTrials.gov, NCT03566238. FINDINGS: Between June 21, 2018, and Feb 10, 2020, 62 patients (median age 3·2 [range 0·5-15·9] years) were randomly allocated to placebo (n=20), odevixibat 40 µg/kg per day (n=23), or odevixibat 120 µg/kg per day (n=19). Model-adjusted (least squares) mean proportion of PPAs was significantly higher with odevixibat versus placebo (55% [SE 8] in the combined odevixibat group [58% in the 40 µg/kg per day group and 52% in the 120 µg/kg per day group] vs 30% [SE 9] in the placebo group; model-adjusted mean difference 25·0% [95% CI 8·5-41·5]; p=0·0038). The percentage of patients with serum bile acid response was also significantly higher with odevixibat versus placebo (14 [33%] of 42 patients in the combined odevixibat group [10 in the 40 µg/kg per day group and four in the 120 µg/kg per day group] vs none of 20 in the placebo group; adjusting for stratification factor [PFIC type], the proportion difference was 30·7% [95% CI 12·6-48·8; p=0·0030]). The most common treatment-emergent adverse events (TEAEs) were diarrhoea or frequent bowel movements (13 [31%] of 42 for odevixibat vs two [10%] of 20 for placebo) and fever (12 [29%] of 42 vs five [25%] of 20); serious TEAEs occurred in three (7%) of 42 odevixibat-treated patients and in five (25%) of 20 placebo-treated patients. INTERPRETATION: In children with PFIC, odevixibat effectively reduced pruritus and serum bile acids versus placebo and was generally well tolerated. Odevixibat, administered as once a day oral capsules, is a non-surgical, pharmacological option to interrupt the enterohepatic circulation in patients with PFIC. FUNDING: Albireo Pharma.