RESUMO
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
OBJECTIVE: Maralixibat, an ileal bile acid transporter inhibitor, is the first drug approved by the U.S. Food and Drug Administration for the treatment of cholestatic pruritus in patients aged ≥3 months with Alagille syndrome (ALGS). Approval was based on reductions in pruritus from the pivotal ICONIC trial, information from two additional trials (ITCH and IMAGO), and long-term extension studies. Although participants in these trials met strict inclusion and exclusion criteria, patients have received maralixibat under broader circumstances as part of an expanded access program or commercially. The expanded access and postapproval settings inform a real-world understanding of effectiveness and safety. The objective was to report on the use of maralixibat in the real-world setting in eight patients who otherwise would not have met entrance criteria for the clinical trials, providing unique insights into its effectiveness in the management of ALGS. METHODS: We reviewed records of patients with ALGS who received maralixibat but would have been excluded from trials due to surgical biliary diversion, reduction of antipruritic/cholestatic concomitant medications, administration of medication through a gastrostomy or nasogastric tube, or use in patients under consideration for transplantation. RESULTS: Maralixibat appeared to be effective with reductions in pruritus compared to baseline. Consistent with clinical trials, maralixibat was well tolerated without appreciable gastrointestinal complications. Liver enzyme elevations were observed but were interpreted as consistent with normal fluctuations observed in ALGS, with no increases in bilirubin. CONCLUSION: Maralixibat may be effective and well tolerated in patients with ALGS in broader clinical contexts than previously reported.
Assuntos
Síndrome de Alagille , Benzotiepinas , Colestase , Humanos , Síndrome de Alagille/complicações , Síndrome de Alagille/tratamento farmacológico , Síndrome de Alagille/cirurgia , Colestase/tratamento farmacológico , Colestase/complicações , Estudos Longitudinais , Prurido/tratamento farmacológico , Prurido/etiologia , Ensaios Clínicos como Assunto , LactenteRESUMO
BACKGROUND AND AIMS: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study. APPROACH AND RESULTS: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings. CONCLUSIONS: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS.
Assuntos
Síndrome de Alagille , Humanos , Síndrome de Alagille/complicações , Síndrome de Alagille/tratamento farmacológico , Feminino , Masculino , Estudos Retrospectivos , Criança , Lactente , Pré-Escolar , Intervalo Livre de Progressão , Adolescente , Proteínas de Transporte , Glicoproteínas de MembranaRESUMO
Children with Alagille syndrome and progressive familial intrahepatic cholestasis (PFIC) experience debilitating pruritus, for which there have been few effective treatment options. In the past 2 years, the ileal bile acid transporter (IBAT) inhibitors maralixibat and odevixibat have been approved for the management of cholestatic pruritus in these individuals, representing an important step forward in improving their quality of life. Emerging data suggest these drugs might also improve event-free survival, therefore potentially altering the typical disease course currently seen in these disorders. This Review will discuss how genetic advances have clarified the molecular basis of cholestatic disorders, facilitating the development of new therapeutic options that have only been evaluated in children. We focus specifically on the newly licensed IBAT inhibitors for patients with Alagille syndrome and PFIC and explore the next steps for these drugs in relation to other paediatric and adult cholestatic disorders, recognising that they have the potential to benefit a wider group of patients with gastrointestinal and liver disease.
Assuntos
Síndrome de Alagille , Colestase , Criança , Humanos , Síndrome de Alagille/tratamento farmacológico , Qualidade de Vida , Colestase/tratamento farmacológico , Prurido/tratamento farmacológicoRESUMO
BACKGROUND AND AIMS: Refractory pruritus and other complications of cholestasis are indications for liver transplantation (LT) in patients with Alagille syndrome (ALGS). We evaluated predictors of event-free survival and transplant-free survival in patients with ALGS treated with maralixibat (MRX), an ileal bile acid transporter inhibitor. APPROACH AND RESULTS: We assessed patients with ALGS from 3 clinical trials of MRX with up to 6 years of follow-up. Event-free survival was defined as the absence of LT, surgical biliary diversion, hepatic decompensation, or death; transplant-free survival was the absence of LT or death. Forty-three potential predictors were evaluated, including age, pruritus (ItchRO[Obs] 0-4 scale), biochemistries, platelets, and serum bile acids. Harrell's concordance statistic assessed goodness-of-fit, and then, Cox proportional hazard models confirmed the statistical significance of the predictors identified. A further analysis was performed to identify cutoffs using a grid search. Seventy-six individuals met the criteria of receiving MRX for ≥48 weeks with laboratory values available at week 48 (W48). The median duration of MRX was 4.7 years (IQR: 1.6-5.8); 16 had events (10 LT, 3 decompensation, 2 death, and 1 surgical biliary diversion). The 6-year event-free survival improved with a clinically meaningful >1-point ItchRO(Obs) reduction from baseline to W48 (88% vs. 57%; p = 0.005), W48 bilirubin < 6.5 mg/dL (90% vs. 43%; p < 0.0001), and W48 serum bile acid < 200 µmol/L (85% vs. 49%; p = 0.001). These parameters were also predictive of 6-year transplant-free survival. CONCLUSIONS: Improvement in pruritus by 48 weeks, and lower W48 bilirubin and serum bile acid levels were associated with fewer events. These data may help identify potential markers of disease progression for ALGS patients treated with MRX.
Assuntos
Síndrome de Alagille , Humanos , Síndrome de Alagille/tratamento farmacológico , Intervalo Livre de Progressão , Estudos Retrospectivos , Bilirrubina , Prurido/tratamento farmacológico , Prurido/etiologia , Ácidos e Sais BiliaresRESUMO
INTRODUÇÃO: El síndrome de Alagille es una enfermedad autosómica dominante con expresión variable ocasionada por defectos en la vía de señalización del receptor Notch debido a mutaciones en los genes JAGGED1 (95%) y NOTCH2 (2,5%). Se encuentra clasificada, y reconocida por el Ministerio de Salud de la Nación, como una enfermedad poco frecuente con una incidencia de aproximadamente 1 cada 30.000 recién nacidos vivos.13 Es considerada una enfermedad multisistémica cuyas principales manifestaciones son colestasis crónica, enfermedad cardíaca congénita, embriotoxón posterior, fenotipo facial característico y vértebras en alas de mariposa. Si bien las manifestaciones clínicas son muy variables, la predominante es la colestasis crónica neonata, donde habitualmente co-existen en diferentes grados de severidad: hepatoesplenomegalia, hiperbilirrubinemia conjugada, hipercolesterolemia, hipertrigliceridemia, y concentraciones elevadas de ácidos biliares y enzimas hepáticas. La colestasis suele intensificarse hasta la edad escolar y luego, en algunos niños, mejora o permanece estable. 2 Además, suelen presentar retraso del crecimiento, prurito y xantomas. El prurito se halla entre los más graves debidos a afecciones hepáticas, suele ser invalidante y se presenta a partir del segundo semestre de vida. 4 La evolución hacia una enfermedad hepática progresiva, cirrosis y fallo hepático, con indicación de trasplante hepático, acontece en el 21 a 31% de los casos. En niños menores de cinco años pueden considerarse como predictores de enfermedad hepática sostenida y grave, la presencia de concentraciones mayores de bilirrubina total de 6,5mg/dL, bilirrubina conjugada 4,5 mg/dl y colesterol 520 mg/dl. OBJETIVO: El objetivo del presente informe es evaluar rápidamente los parámetros de eficacia, seguridad, costos y recomendaciones disponibles acerca del empleo de maralixibat para el tratamiento de personas con síndrome de Alagille. MÉTODOS: Se realizó una búsqueda bibliográfica en las principales bases de datos tales como PUBMED, LILACS, BRISA, COCHRANE, SCIELO, EMBASE, TRIPDATABASE como así también en sociedades científicas, agencias reguladoras, financiadores de salud y agencias de evaluación de tecnologías sanitarias. Se priorizó la inclusión de revisiones sistemáticas, ensayos clínicos controlados aleatorizados, evaluación de tecnología sanitaria y guías de práctica clínica de alta calidad metodológica. En PubMed se utilizó la estrategia de búsqueda que se detalla en el Anexo I. La fecha de búsqueda de información fue hasta el 16 de enero de 2023. Para la búsqueda en Pubmed se utilizó la siguiente estrategia de búsqueda: (maralixibat [Supplementary Concept] OR maralixibat [tiab] OR livmarli [tiab]) AND ("Alagille Syndrome" [MESH] OR "Alagille Syndrome" [tiab] OR Arteriohepatic Dysplasia [tiab]). RECOMENDACIONES: No se hallaron recomendaciones referentes al uso de maralixibat en la indicación especificada por parte de las Sociedades Científicas y Agencias de evaluación de tecnologías sanitarias en Argentina y nivel mundial. Actualmente el Instituto Nacional de Salud y Cuidados de Excelencia del Reino Unido (NICE, su sigla del inglés National Institute for Health and Care Excellence) del Reino Unido se encuentra evaluándolo. CONCLUSIONES: La evidencia que sustenta la aprobación de comercialización de maralixibat para el tratamiento del prurito colestásico en personas mayores a 2 meses de edad con síndrome de Alagille, por parte de las agencias regulatorias relevadas, se basa en un ensayo clínico aleatorizado con un diseño de retirada y con un bajo número de pacientes. Este estudio mostraría que la utilización de este fármaco podría mejorar al mediano plazo, el prurito, los niveles de colesterol, de ácidos biliares y mejorar la calidad de vida reportada por los cuidadores respecto al estado basal. Otros estudios sostendrían que esos beneficios se podrían mantener al largo plazo. Si bien al mediano plazo no se observarían interrupciones del tratamiento debido a eventos adversos graves, al largo plazo se ha descripto interrupciones principalmente debido a la aparición de hipertransaminasemia. Su comercialización se encuentra recientemente autorizada en Estados Unidos y Europa para el tratamiento del prurito colestásico en personas mayores a 2 meses de edad con síndrome de Alagille. Las agencias han otorgado la designación de medicamento huérfano y han advertido sobre la estrecha monitorización del hígado, mediante exámenes de laboratorio hepáticos y de vitaminas liposolubles. No se hallaron guías de práctica clínica actualizadas en Argentina y en el Mundo que mencionen la tecnología en la indicación evaluada. No se hallaron evaluaciones económicas publicadas, aunque el costo mensual medio estimado al precio de adquisición de referencia es excesivamente elevado (USD 67.760).
Assuntos
Humanos , Ácidos e Sais Biliares/antagonistas & inibidores , Síndrome de Alagille/tratamento farmacológico , Argentina , Eficácia , Análise Custo-Benefício/economiaRESUMO
OBJECTIVE: The objective of this study was to assess the impact of treatment response to the ileal bile acid transporter inhibitor maralixibat on health-related quality of life (HRQoL) in children with Alagille syndrome. STUDY DESIGN: This analysis used data from the ICONIC trial, a phase 2 study with a 4-week double-blind, placebo-controlled, randomized drug withdrawal period in children with Alagille syndrome with moderate-to-severe pruritus. Clinically meaningful treatment response to maralixibat was defined a priori as a ≥1-point reduction in the Itch-Reported Outcome (Observer) score, from baseline to week 48. HRQoL was assessed using the Pediatric Quality of Life Inventory Generic Core, Family Impact, and Multidimensional Fatigue scale scores, which were collected via the caregiver. The minimal clinically important difference for HRQoL ranged from 4 to 5 points, depending on the scale. RESULTS: Twenty of the 27 patients (74%) included in this analysis achieved an Itch-Reported Outcome (Observer) treatment response at week 48. The mean (SD) change in Multidimensional Fatigue score was +25.8 (23.0) for responders vs -3.1 (19.8) for nonresponders (P = .03). Smaller and non-statistically significant mean changes were observed for the Pediatric Quality of Life Inventory Generic Core and Family Impact scores. Controlling for baseline Family Impact score, responders' Family Impact scores increased an average of 16.9 points over 48 weeks compared with non-responders (P = .05). Smaller and non-statistically significant point estimates were observed for the Pediatric Quality of Life Inventory Generic Core and Multidimensional Fatigue scores. CONCLUSION: The significant improvements in pruritus seen with maralixibat at week 48 of the ICONIC study are clinically meaningful and are associated with improved HRQoL. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02160782.
Assuntos
Síndrome de Alagille , Qualidade de Vida , Criança , Humanos , Síndrome de Alagille/tratamento farmacológico , Fadiga/tratamento farmacológico , Fadiga/etiologia , Prurido/tratamento farmacológico , Prurido/etiologiaRESUMO
Maralixibat (Livmarli™) is an orally-administered, small-molecule ileal bile acid transporter (IBAT) inhibitor being developed by Mirum Pharmaceuticals for the treatment of rare cholestatic liver diseases including Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC) and biliary atresia. Maralixibat received its first approval on 29 September 2021, in the USA, for use in the treatment of cholestatic pruritus in patients with ALGS 1 year of age and older. Maralixibat is also under regulatory review for ALGS in Europe, and clinical development for cholestatic liver disorders including ALGS in patients under 1 year of age, PFIC and biliary atresia is continuing in several other countries. This article summarises the milestones in the development of maralixibat leading to this first approval for ALGS.
Assuntos
Benzotiepinas , Proteínas de Transporte , Colestase Intra-Hepática , Glicoproteínas de Membrana , Humanos , Síndrome de Alagille/tratamento farmacológico , Atresia Biliar/tratamento farmacológico , Proteínas de Transporte/antagonistas & inibidores , Colestase Intra-Hepática/tratamento farmacológico , Ensaios Clínicos como Assunto , Aprovação de Drogas , Glicoproteínas de Membrana/antagonistas & inibidores , Estados Unidos , United States Food and Drug Administration , Benzotiepinas/administração & dosagem , Benzotiepinas/farmacologia , Benzotiepinas/uso terapêuticoRESUMO
BACKGROUND: Alagille syndrome is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical, sodium-dependent, bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in Alagille syndrome. METHODS: ICONIC was a placebo-controlled, randomised withdrawal period (RWD), phase 2b study with open-label extension in children (aged 1-18 years) with Alagille syndrome (NCT02160782). Eligible participants had more than three times the normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 µg/kg once per day, participants were randomly assigned (1:1) to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat until week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 µg/kg twice per day. The primary endpoint was the mean sBA change during the RWD in participants with at least 50% sBA reduction by week 18. Cholestastic pruritus was assessed using observer-rated, patient-rated, and clinician-rated 0-4 scales. The safety population was defined as all participants who had received at least one dose of maralixibat. This trial was registered with ClinicalTrials.gov, NCT02160782, and is closed to recruitment. FINDINGS: Between Oct 28, 2014, and Aug 14, 2015, 31 participants (mean age 5·4 years [SD 4·25]) were enrolled and 28 analysed at week 48. Of the 29 participants who entered the randomised drug withdrawal period, ten (34%) were female and 19 (66%) were male. In the RWD, participants switched to placebo had significant increases in sBA (94 µmol/L, 95% CI 23 to 164) and pruritus (1·7 points, 95% CI 1·2 to 2·2), whereas participants who continued maralixibat maintained treatment effect. This study met the primary endpoint (least square mean difference -117 µmol/L, 95% CI -232 to -2). From baseline to week 48, sBA (-96 µmol/L, -162 to -31) and pruritus (-1·6 pts, -2·1 to -1·1) improved. In participants who continued to week 204 (n=15) all improvements were maintained. Maralixibat was generally safe and well tolerated throughout. The most frequent adverse events were gastrointestinal related. Most adverse events were self-limiting in nature and mild-to-moderate in severity. INTERPRETATION: In children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome. FUNDING: Mirum Pharmaceuticals.
Assuntos
Síndrome de Alagille/tratamento farmacológico , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/uso terapêutico , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/uso terapêutico , Prurido/tratamento farmacológico , Adolescente , Proteínas de Transporte/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Glicoproteínas de Membrana/efeitos adversos , Resultado do TratamentoRESUMO
SIGNIFICANCE: Alagille syndrome is rare genetic disease, which affects liver and heart function. Cases are frequently diagnosed late, and a complete ocular examination aids in the diagnosis. Although ophthalmic manifestations are usually benign, occasionally, sight-threatening complications occur. PURPOSE: The case presented herein highlights a rare condition, which usually can be diagnosed by the ophthalmological findings. However, in this particular case report, the complication of angioid streaks and choroidal neovascularization is reported for the first time in Alagille syndrome. CASE REPORT: Α 32-year-old woman diagnosed with Alagille syndrome presented with diminution of vision in the left eye. The cause was choroidal neovascularization related to angioid streaks. She was treated with intravitreal injections of ranibizumab but developed an extensive macular scar. A few years later, she developed the same complication in the right eye and was treated similarly. CONCLUSIONS: Alagille syndrome has many ophthalmic manifestations, most of them benign with minimal threat to vision. Herein for the first time, we present a case of Alagille syndrome with angioid streak-related choroidal neovascularization, which resulted in severe vision loss.
Assuntos
Síndrome de Alagille/diagnóstico , Estrias Angioides/diagnóstico , Neovascularização de Coroide/diagnóstico , Adulto , Síndrome de Alagille/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Estrias Angioides/tratamento farmacológico , Neovascularização de Coroide/tratamento farmacológico , Feminino , Angiofluoresceinografia , Humanos , Injeções Intravítreas , Ranibizumab/uso terapêutico , Tomografia de Coerência Óptica , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
When encountered in children, xanthomas are most commonly associated with a group of disorders known as familial hyperlipidemias. Aside from cosmetic concerns, these xanthomas are typically asymptomatic, but when generalized pruritus is a prominent associated symptom, clinicians should consider a different set of diagnoses that includes cholestasis of the liver. In this article we present two illustrative cases of children with cholestatic disease, pruritus, and xanthomas and discuss other disorders that may include this triad.
Assuntos
Anormalidades Múltiplas/diagnóstico , Síndrome de Alagille/diagnóstico , Ataxia/diagnóstico , Encéfalo/anormalidades , Colestase/etiologia , Coloboma/diagnóstico , Dislipidemias/etiologia , Antagonistas dos Receptores Histamínicos/uso terapêutico , Hepatopatias/diagnóstico , Anormalidades Múltiplas/tratamento farmacológico , Síndrome de Alagille/tratamento farmacológico , Anestésicos Locais/administração & dosagem , Ataxia/tratamento farmacológico , Criança , Pré-Escolar , Colestase/diagnóstico , Colestase/tratamento farmacológico , Coloboma/tratamento farmacológico , Desonida/administração & dosagem , Diagnóstico Diferencial , Dislipidemias/diagnóstico , Feminino , Humanos , Hepatopatias/tratamento farmacológico , Morfolinas/administração & dosagem , Prurido/etiologia , Xantomatose/etiologiaRESUMO
Alagille syndrome (AGS) is a complex multisystem disorder that involves mainly the liver, heart, eyes, face, and skeleton. The main associated clinical features are chronic cholestasis due to a paucity of intrahepatic bile ducts, congenital heart disease primarily affecting pulmonary arteries, vertebral abnormalities, ocular embryotoxon, and peculiar facies. The manifestations generally become evident at a pediatric age. AGS is caused by defects in the Notch signaling pathway due to mutations in JAG1 or NOTCH2. It is inherited in an autosomal dominant pattern with a high degree of penetrance, but variable expressivity results in a wide range of clinical features. Here we report on a 31-year-old male patient who presented with elevated serum alkaline phosphatase and gamma-glutamyl transpeptidase, and was diagnosed with AGS associated with the JAG1 mutation after a comprehensive workup.
Assuntos
Síndrome de Alagille/diagnóstico , Colestase/diagnóstico , Adulto , Síndrome de Alagille/complicações , Síndrome de Alagille/tratamento farmacológico , Fosfatase Alcalina/sangue , Colestase/complicações , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Masculino , Tomografia Computadorizada por Raios X , Ultrassonografia , Ácido Ursodesoxicólico/uso terapêutico , gama-Glutamiltransferase/sangueRESUMO
The Notch signaling pathway is a fundamental signaling mechanism operating in most, if not all, multicellular organisms and in most cell types in the body. Like other "ivy league" pathways such as Wnt, PI3K, Sonic Hedgehog, Receptor Tyrosine Kinases (RTKs), and JAK/STAT signaling, the Notch pathway is a linear signaling mechanism, i.e., an extracellular ligand activates a receptor, which ultimately leads to transcriptional alterations in the cell nucleus, but Notch signaling is a strict cell-cell communication mechanism and lacks built-in amplification steps in the signaling pathway. Dysregulated Notch signaling, either by direct mutations in the pathway or by altered signaling output, is increasingly linked to disease, and Notch can act as an oncogene or tumor suppressor depending on the cellular context. This underscores that appropriate level of Notch signaling is important for differentiation and tissue homeostasis, a notion supported also by genetic data indicating that Notch signaling is very gene dosage-sensitive. Thus, too much or too little signaling can lead to disease and Notch can therefore be considered a Goldilocks signaling pathway. Given the emerging role of dysregulated Notch signaling in disease, there is increasing interest in developing therapeutic approaches to modulate Notch signaling. In this review we discuss recent findings on how signal transduction is tuned in the Notch pathway and how Notch signaling is dysregulated in disease. We also discuss different strategies to modulate Notch signaling for clinical use, for example by novel antibody-based tools and by taking advantage of the cross-talk between Notch and other signaling mechanisms.
Assuntos
Anticorpos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Síndrome de Alagille/tratamento farmacológico , Síndrome de Alagille/genética , Síndrome de Alagille/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Valva Aórtica/patologia , CADASIL/tratamento farmacológico , CADASIL/genética , CADASIL/metabolismo , Diferenciação Celular , Quimioterapia Combinada , Doenças das Valvas Cardíacas/tratamento farmacológico , Doenças das Valvas Cardíacas/genética , Doenças das Valvas Cardíacas/metabolismo , Humanos , Mutação , Neoplasias/genética , Fosfatidilinositol 3-Quinases , Receptores Notch/antagonistas & inibidores , Receptores Notch/efeitos dos fármacos , Receptores Notch/genética , Transdução de Sinais/genéticaRESUMO
Alagille syndrome, also known as arteriohepatic dysplasia, is a multisystem autosomal dominant disorder characterized by chronic cholestasis due to a paucity of intrahepatic bile ducts, peripheral pulmonary artery stenosis with associated vertebral, ocular, and renal anomalies, and characteristic facies. We report a case of Alagille syndrome in a 3-year-old boy with associated pruritus, follicular keratoses, palmar pits, and keratoderma-like changes over the dorsum of the hands. There have been single isolated case reports of phrynoderma and keratoderma. Palmar pits have not been reported in the literature.
Assuntos
Síndrome de Alagille/diagnóstico , Síndrome de Alagille/tratamento farmacológico , Síndrome de Alagille/patologia , Biópsia , Pré-Escolar , Diagnóstico Diferencial , Quimioterapia Combinada , Humanos , Ferro/uso terapêutico , Masculino , Ácido Ursodesoxicólico/administração & dosagem , Vitamina A/uso terapêutico , Vitamina D/uso terapêutico , Vitamina E/uso terapêuticoRESUMO
A case of a rare hereditary disease, Alagille-Watson syndrome, is reported. It most frequently affects liver and cardiovascular system which leads to biliary cirrhosis and cardiovascular catastrophe in young patients. Pathogenesis and clinical variants of the disease are described.
Assuntos
Síndrome de Alagille/patologia , Cirrose Hepática Biliar/etiologia , Adulto , Síndrome de Alagille/complicações , Síndrome de Alagille/tratamento farmacológico , Feminino , Humanos , Cirrose Hepática Biliar/tratamento farmacológico , Cirrose Hepática Biliar/patologia , Adulto JovemRESUMO
Neonatal conjugated jaundice is a common presentation of hereditary liver diseases, which, although rare, are important to recognize early. Developments in molecular genetic techniques have enabled the identification of causative genes, which has improved diagnostic accuracy for patients and has led to a greater understanding of the molecular pathways involved in liver biology and pathogenesis of liver diseases. This review provides an update of the current understanding of clinical and molecular features of the inherited liver diseases that cause neonatal conjugated jaundice.
Assuntos
Síndrome de Alagille/complicações , Colestase/etiologia , Síndrome de Alagille/diagnóstico , Síndrome de Alagille/tratamento farmacológico , Síndrome de Alagille/genética , Colestase/genética , Humanos , PrognósticoRESUMO
The authors describe two siblings, each with a different, rare genetic condition that affects liver function. The index case, the 18-year-old asymptomatic brother of a young man recently diagnosed with Wilson disease, presented for Wilson disease screening and was also found to have abnormal liver function suggestive of cholestasis. However, ceruloplasmin level, 24 h urine copper concentration and liver synthetic function were normal. Further hepatic investigations and genetic mutation analysis were performed, ultimately leading to a diagnosis of Alagille syndrome. He was treated with ursodiol, which resulted in normalization of his liver function tests. Subsequently, he was found to be a carrier for a mutation in the Wilson disease gene, ATP7B. In the present report, the potential implications of being a heterozygote for Wilson disease in the context of Alagille syndrome are discussed. Also stressed is that care must be exercised by the clinician when diagnosing family members who may present with two different disorders closely mimicking one another.
Assuntos
Adenosina Trifosfatases/genética , Síndrome de Alagille/diagnóstico , Síndrome de Alagille/genética , Proteínas de Transporte de Cátions/genética , Degeneração Hepatolenticular/diagnóstico , Degeneração Hepatolenticular/genética , Adolescente , Síndrome de Alagille/tratamento farmacológico , Colagogos e Coleréticos/uso terapêutico , ATPases Transportadoras de Cobre , Diagnóstico Diferencial , Degeneração Hepatolenticular/tratamento farmacológico , Humanos , Testes de Função Hepática , Masculino , Mutação , Linhagem , Irmãos , Ácido Ursodesoxicólico/uso terapêuticoRESUMO
OBJECTIVE: Fat-soluble vitamin (FSV) deficiencies are common complications in pediatric patients with chronic cholestasis. The aim of the present study was to evaluate the status of FSV deficiencies in patients under present practice and to test the effect of an oral, absorbable, fat-soluble vitamin formulation (OAFSV) in these patients. METHODS: We recruited a total of 23 pediatric patients receiving conventional FSV supplementation in a single medical center, with diagnosis of biliary atresia (10), progressive familial intrahepatic cholestasis (9), Alagille syndrome (2), and other conditions (2). Ten patients switched to OAFSV and continued for 3 months. Plasma levels of vitamins A, D, and E and an international normalized ratio (INR) for prothrombin time (PT), a surrogate marker for vitamin K deficiency, were measured. RESULTS: The proportion of patients with FSV A, D, E, and K deficiencies under conventional supplementation was 73.9%, 81.8%, 91.3%, and 20.0%, respectively. In patients with total bilirubin levels ≥3.0 âmg/dL, the proportion of at least 1 FSV deficiency was 100%; and the deficiency rates of vitamin A, D, E, and K were 78.6%, 100.0%, 100.0% and 21.4%, respectively. Of the 10 patients receiving standard daily dose of OAFSV for 3 months, no adverse events or overdose effects were found. The rates of vitamin A, D, and E deficiency in the patients receiving OAFSV decreased from 80.0%, 100%, and 100%, respectively, to 70.0%, 60.0%, and 60.0% after 3 months of oral supplementation. CONCLUSIONS: High rates of FSV deficiency were found in pediatric patients with chronic cholestasis under present follow-up. OAFSV supplementation is safe and potentially effective in pediatric patients with cholestasis.
Assuntos
Síndrome de Alagille/complicações , Deficiência de Vitaminas/tratamento farmacológico , Atresia Biliar/complicações , Colestase Intra-Hepática/complicações , Colestase/tratamento farmacológico , Suplementos Nutricionais , Vitaminas/uso terapêutico , Administração Oral , Adolescente , Síndrome de Alagille/sangue , Síndrome de Alagille/tratamento farmacológico , Deficiência de Vitaminas/sangue , Deficiência de Vitaminas/complicações , Deficiência de Vitaminas/epidemiologia , Atresia Biliar/sangue , Atresia Biliar/tratamento farmacológico , Bilirrubina/sangue , Criança , Pré-Escolar , Colestase/sangue , Colestase/etiologia , Colestase Intra-Hepática/sangue , Colestase Intra-Hepática/tratamento farmacológico , Feminino , Humanos , Lactente , Masculino , Solubilidade , Vitamina A/sangue , Vitamina A/uso terapêutico , Vitamina D/sangue , Vitamina D/uso terapêutico , Vitamina E/sangue , Vitamina E/uso terapêutico , Vitamina K/sangue , Vitamina K/uso terapêutico , Vitaminas/sangueRESUMO
El síndrome de Alagille es una enfermedad congénita y poco frecuente, se transmite de forma autosómica dominante, con expresividad variable. Se caracteriza por presentar colestasis, anomalías vertebrales y oculares, cardiopatía congénita y dismorfias faciales. El pronóstico de este síndrome es variable, depende fundamentalmente de la afectación hepática y los defectos cardiovasculares asociados. Se presentó el caso de una paciente con diagnóstico de síndrome de Alagille con evolución estable(AU)
The Alagilles syndrome is a few frequent congenital disease; it is transmitted in a dominant autosomal way, with variable expressivity. It characterizes for presenting cholestasis, vertebral and ocular anomalies, congenital cardiopathies and facial dysmorphias. The prognosis of this syndrome is variable, mainly depending of the hepatic injury and the associated cardiovascular defects. We presented the case of a patient with the diagnosis of Alagilles Syndrome and stable evolution(AU)