Identification of a novel splice variant in SEC23B gene in a patient with concomitant presence of congenital dyserythropoietic anemia II and Gilbert's syndrome.

BACKGROUND: Congenital dyserythropoietic anemia Ⅱ (CDA Ⅱ) is a rare inherited disorder of defective erythropoiesis caused by SEC23B gene mutation. CDA Ⅱ is often misdiagnosed as a more common type of clinically related anemia, or it remains undiagnosed due to phenotypic variability caused by the coexistence of inherited liver diseases, including Gilbert's syndrome (GS) and hereditary hemochromatosis. METHODS: We describe the case of a boy with genetically undetermined severe hemolytic anemia, hepatosplenomegaly, and gallstones whose diagnosis was achieved by targeted next generation sequencing. RESULTS: Molecular analysis revealed a maternally inherited novel intronic variant and a paternally inherited missense variant, c.[994-3C > T];[1831C > T] in the SEC23B gene, confirming diagnosis of CDA Ⅱ. cDNA analysis verified that the splice acceptor site variant results in two mutant transcripts, one with an exon 9 skip and one in which exons 9 and 10 are deleted. SEC23B mRNA levels in the patient were lower than those in healthy controls. The patient was also homozygous for the UGT1A1*6 allele, consistent with GS. CONCLUSION: Identification of the novel splice variant in this study further expands the spectrum of known SEC23B gene mutations. Molecular genetic approaches can lead to accurate diagnosis and management of CDA Ⅱ patients, particularly for those with GS coexisting.

Unconjugated Hyperbilirubinemia in Acetaminophen-Related Acute Liver Failure.

BACKGROUND In the absence of liver transplantation, the natural history of acetaminophen-induced liver failure is characterized by a progressive increase of liver function tests, including bilirubin mainly as its conjugated form. The presence of high levels of unconjugated bilirubin is more unusual; its etiology is unclear and its prognostic factor has been poorly investigated. CASE REPORT A 52-year-old man with a history of chronic analgesics, alcohol, and illicit drug abuse developed acute liver failure in relationship with the ingestion of largely supra-therapeutic doses of acetaminophen over the days preceding admission. The patient received the classical N-acetylcysteine treatment regimen for acetaminophen overdose. Clinical course was characterized by a progressive worsening of the neurological condition, evolving to grade IV encephalopathy. Coagulation disorders persisted, with factor V level <10%. He fulfilled the criteria for liver transplantation, but this option was rejected after a careful psychiatric evaluation. Laboratory investigations revealed a progressive increase in serum unconjugated bilirubin until his death. As evidence for hemolysis was lacking, acquired deficit in bilirubin glucuronidation appeared likely and diagnosis of Gilbert's syndrome was excluded. CONCLUSIONS After the exclusion of other causes of high unconjugated bilirubin levels, the progressive increase in unconjugated bilirubin can reflect a persistent defect in bilirubin conjugation in relationship with liver centrilobular injury, but the relationship with acetaminophen-glucuronidation is not known and there are insufficient data to affirm that the ratio unconjugated/conjugated bilirubin could be used as a prognostic factor.

Prolonged Jaundice in a Premature Breastfed Infant With Gilbert's Syndrome.

INTRODUCTION: Neonatal jaundice and prematurity pose significant barriers to breastfeeding in the first days of life. There is limited literature exploring the relationship between prolonged jaundice in breastfed infants and Gilbert's (Meulengraght) syndrome. This case study describes the diagnostic and therapeutic challenges associated with Gilbert's syndrome in a late preterm breastfed infant born in Germany. MAIN ISSUE: In this case report, an infant born to a primipara woman presented at 3 weeks postpartum to an International Board Certified Lactation Consultant. The initial assessment revealed a late preterm infant with inadequate weight gain and jaundice. The dyad received breastfeeding support and eventually achieved adequate weight gain; however, the infant's jaundice persisted. MANAGEMENT: The consulting midwife suggested that the persistent jaundice was "breastmilk jaundice" and recommended temporarily interrupting breastfeeding. Due to a suspected family history of Gilbert's Syndrome, the dyad was referred, instead, to a pediatric gastroenterologist. Pathologic liver disease was excluded, and genetic testing confirmed Gilbert's Syndrome. At 6 months of age, the dyad was successfully breastfeeding and beginning complementary feeding. CONCLUSION: Genetic testing for Gilbert's Syndrome should be considered for infants with prolonged jaundice and positive family history. Interruption or cessation of breastfeeding are not evidence-based recommendations, and current guidelines do not support these practices. Lactation professionals play a critical role in the management of breastfeeding for preterm infants with prolonged jaundice and should refer to specialists to rule out pathologic etiologies.

Hiperbilirrubinemias hereditarias: un diagnóstico diferencial a considerar en ictericia / Hereditary hiperbilirrubinemias: a differential diagnosis to considerer in icterus

Las hiperbilirrubinemias hereditarias (HBH) son patologías originadas por defectos en las enzimas y proteínas que participan del metabolismo de la bilirrubina. El clearence de bilirrubina incluye captación y almacenamiento en hepatocitos, conjugación, excreción hacia la bilis y recaptura de su forma conjugada por hepatocitos. Las HBH varían de acuerdo a su patogenia, presentación clínica, niveles de bilirrubinemia y tratamientos disponibles. En general son poco frecuentes, a excepción del Síndrome de Gilbert. Están las que son de predominio indirecto, como el Síndrome de Gilbert y el de Crigler-Najjar, y las de predominio directo, como el Síndrome de Dubin-Johnson y el de Rotor. En general no requieren tratamiento específico y tienen curso benigno, a excepción del Síndrome de Crigler-Najjar para el cual existen medidas terapéuticas específicas a considerar, teniendo un pronóstico reservado para algunas de sus formas de presentación. Es importante el conocimiento de estos síndromes dado el alto índice de sospecha requerido para su diagnóstico y para su diferenciación de otras patologías hepatobiliares de mayor riesgo y severidad.

Hereditary hiperbilirrubinemias (HBH) are pathologies originated from the defect of the enzymes and proteins involved in the metabolism of bilirubin. The bilirubin clearance includes uptake and storage in hepatocytes, conjugation, excretion into bile and recapture of its conjugated form by hepatocytes. HBH vary according to their pathogenesis, clinical presentation, levels of bilirubin and available treatments. Generally they are infrequent, except for Gilbert Syndrome. There are those with indirect bilirubin predominance, such as Gilbert and Crigler-Najjar syndromes, and those with direct bilirubin predominance, including Dubin-Johnson and Rotor syndromes. In general, they do not require specific treatment and have a benign course, with the exception of the Crigler-Najjar Syndrome, for which there are specific therapeutic measures to consider, as well as a reserved prognosis for some of their forms of presentation. The knowledge of these syndromes is important 2 given the high index of suspicion required for its diagnosis and for its differentiation from other hepatobiliary pathologies of greater risk and severity.

Susceptibilidad genética del síndrome de Gilbert en población valenciana; eficiencia del test de ayuno / Genetic susceptibility to Gilbert's syndrome in a valencian population; efficacy of the fasting test

El estudio de la correlación entre el genotipo y el fenotipo: ¿éxito o fracaso? Objetivo. Describir la distribución poblacional de la variante UGT1A1*28 (código de variante genética rs8175347) localizada en el promotor del gen UGT1A1 y correlacionar sus genotipos con los resultados de la prueba de ayuno, así como su relación con la alteración bioquímica propia del síndrome de Gilbert (SG) en población valenciana. Pacientes y métodos. Estudiamos la prevalencia de los genotipos (TA)6/6 (TA)6/7 y (TA)7/7 de la variante deletérea rs8175347, en 144 pacientes con hiperbilirrubinemia, de los cuales 38 habían sido sometidos previamente a la prueba del ayuno para realizar el diagnóstico de SG, y en 150 individuos control. Analizando la región genómica de la caja TATA del promotor del gen UGT1A1 mediante secuenciación Sanger, se estableció la correlación de los genotipos rs8175347 con los resultados del test del ayuno y con las alteraciones bioquímicas de los pacientes. Resultados. La frecuencia de heterocigosidad del alelo (TA)7 en población control fue 32% y ascendió al 87,59% entre pacientes con sospecha de SG. La frecuencia del genotipo TA7/7 fue del 81,94% entre los pacientes, frente a un 11,33% en controles. La prueba de ayuno mostró un 15,79% de falsos negativos y un 5,26% de falsos positivos. Conclusiones. La elevada frecuencia del alelo (TA)7 entre individuos de población control valenciana, casi el doble del 5% descrito en individuos control europeos, corrobora la elevada frecuencia del SG descrita en población española, sin observarse diferencias significativas entre extremos geográficos del país. La eficacia y fiabilidad de la prueba del ayuno para el diagnóstico del SG es cuestionable (AU)

Ojective. To describe the populational distribution of the UGT1A1*28 variant (genetic variant code rs8175347) located in the promotor of the UGT gene and correlate its genotypes with the results of the fasting test, as well as its relationship with the biochemical disorder of Gilbert's syndrome (GS) in a Valencian population. Patients and methods. We studied the prevalence of the genotypes (TA)6/6 (TA)6/7 and (TA)7/7 of the deleterious variant rs8175347 in 144 patients with hyperbilirubinemia, 38 of whom had previously undergone the fasting test to diagnose GS, and in 150 control patients. By analysing the genomic region of the TATA box of the UGT1A1 gene promotor using Sanger sequencing, we established the correlation between the rs8175347 genotypes and the fasting test results and with the patients’ biochemical disorders. Results. The rate of heterozygosity of allele (TA)7 in the control population was 32% and increased to 87.59% among the patients with suspected GS. The rate of genotype TA7/7 was 81.94% among the patients with hyperbilirubinemia, compared with 11.33% in the control patients. The fasting test showed a 15.79% rate of false negatives and a 5.26% rate of false positives. Conclusions. The high frequency of allele (TA)7 among the Valencian control population, almost double the 5% reported for European control patients, confirms the high rate of GS reported in the Spanish population, without observing significant differences between the geographical ends of the country. The efficacy and reliability of the fasting test for the diagnosis of GS is questionable (AU)

Unusual presentation of Gilbert disease with high levels of unconjugated bilirubin. Report of two cases

Gilbert’s syndrome is a benign condition characterized by asymptomatic sporadic episodes of jaundice, due to a mild unconjugated hyperbilirubinemia caused by a deficiency in bilirubin glucoronidation. Under certain physiologic or pathologic events, bilirubin level rises but according to literature it does not reach out more than 3 mg/dl. We report 2 cases of Gilbert’s syndrome, genetically tested, which presented with bilirubin levels above 6 mg/dl without any trigger or coexisting condition. In conclusion, bilirubin levels higher than 6 mg/dl in Gilbert syndrome are rare, hemolytic and other metabolism diseases must be ruled out, and enetic testing may be necessary in some cases (AU)

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Fractura triplana de tobillo relacionada con fractura tibial homolateral en un adolescente. Caso clínico / Triplane fracture of the ankle associated with homolateral tibial fracture in a teenager. A case report

Introducción: las fracturas de la diáfisis tibial relacionadas con fracturas isolaterales triplanas son atípicas y son el resultado de fuerzas de torsión que producen fracturas espiroideas u oblicuas en la unión de los tercios medio y distal de la tibia. Caso clínico: niña de 13 años con síndrome de Gilbert que acudió a urgencias después de sufrir una caída cuando jugaba al baloncesto; se torció el tobillo cuando pisó el balón. Presentaba inflamación en el tercio distal de la pierna y el tobillo derechos, sin déficit neurovascular. En la radiografía simple se observó una fractura oblicua en la unión del tercio medio y distal de la tibia junto con una fractura triplana intraarticular del tobillo del mismo lado. Conclusiones: en nuestro caso fue necesario una reducción abierta de la fractura diafisaria debido a que era oblicua, desplazada e inestable, con el objetivo de obtener una reducción anatómica. Esto ayudó, a su vez, a obtener una reducción anatómica de la fractura triplana del tobillo que no precisó fijación interna (AU)

Introduction: Tibial shaft fractures associated with ipsilateral triplanar fractures are atypical and result from torque forces that cause spiral or oblique fractures at the junction between the mid and the distal tibia. Conclusion: sIn our case we had to perform an open reduction of the diaphyseal fracture since it was oblique, displaced and unstable; the purpose was to obtain an anatomical reduction. This also helped secure an anatomical reduction of the triplanar ankle fracture, which did not require internal fixation (AU)

Síndrome de Gilbert: estudio de 12 observaciones y revisión de la bibliografía médica / Gilbert’s syndrome: a study of 12 observations and review of the literature

El síndrome de Gilbert es el hallazgo de hiperbilirrubinemia indirecta leve-moderada con pruebas de función hepática normales y sin signos de hemólisis. Es un trastorno hereditario del metabolismo de la bilirrubina, benigno, con una prevalencia mundial cercana al 10%. Tiene un patrón de herencia variable, con polimorfismo genético. Se diagnostica mediante pruebas confirmatorias de provocación, como la prueba del ayuno, aunque el diagnóstico definitivo es genético. Su pronóstico es bueno y actualmente se discute sobre los diversos efectos de la hiperbilirrubinemia. En este artículo, se revisan los casos diagnosticados de síndrome de Gilbert en el servicio de pediatría de un hospital universitario en los últimos años, y se describen las principales características halladas

Gilbert’s syndrome is characterized by a mild or moderate elevation of unconjugated bilirubin, with normal liver function and no evidence of hemolysis. It is a benign inherited disorder of bilirubin metabolism, with a worldwide prevalence of nearly 10%. It has a variable pattern of inheritance, with genetic polymorphism. Diagnosis is based on a confirmatory provocation test, such as the fasting test, although the definitive diagnosis requires a genetic study. The prognosis is good and, at the present time, the varied effects of hyperbilirubinemia are a matter of debate. The cases of Gilbert’s syndrome diagnosed in the pediatric service of a university hospital in recent years were reviewed and the main characteristics are described

Un deportista de élite con Síndrome de Gilbert / An elite sportman with Gilbert´s syndrome

Presentamos el caso de un deportista de 24 años de edad perteneciente a la Selección Española Absoluta de Piragüismo, con hiperbilirrubinemia en presencia de antecedentes familiares de Síndrome de Gilbert. El objetivo de este estudio es intentar relacionar los niveles de bilirrubina total con la sensación de apatía que presenta tras la acumulación de cargas en los entrenamiento de resistencia

We analyzed the case of a 24 year old canoest from the Spanish National Team. He suffers from hiperbilirubinemia and some members of his family have been diagnosed with Gilbert´s syndrome. The goal of this estudy is to relate the levels of bilirubine with the feeling of apathy this athlete goes through after high intensity training sessions

Prueba breve (2 horas) con rifampicina: una herramienta útil en el síndrome de Gilbert / A shortened, 2-hour rifampin test: a useful tool in Gilbert's syndrome

OBJETIVO. Comparar la respuesta a las 2 y a las 4 horas de la administración oral de rifampicina en una serie de pacientes con enfermedad de Gilbert. INTRODUCCIÓN. El diagnóstico de la enfermedad de Gilbert conlleva, a menudo, la realización de pruebas innecesarias que incrementan la ansiedad del paciente. La prueba de la rifampicina puede apoyar el diagnóstico. Esta prueba ha sido descrita en grupos pequeños de pacientes y todavía carece de estandarización en lo relativo a la dosis, los momentos de obtención de las muestras de sangre, la presentación del resultado y su interpretación. PACIENTES Y MÉTODOS. En el estudio participaron 89 pacientes con enfermedad de Gilbert (incremento de la concentración de bilirrubina total sin hepatopatía ni hemólisis). Tras la obtención de una muestra inicial de sangre, se administraron 900 mg de rifampicina por vía oral y, posteriormente, a las 2 y a las 4 horas de esta administración, se volvieron a obtener muestras de sangre. En cada muestra se determinaron las concentraciones de bilirrubina total y de bilirrubina esterificada. También se determinó la concentración de haptoglobina. RESULTADOS. Mediante su expresión como el incremento relativo respecto a los valores basales, todas las variaciones observadas a las 2 horas de la administración de rifampicina fueron superiores al 15%. Se observó una correlación significativa (r = 0,902; p = 0,000) entre los incrementos relativos detectados a las 2 y a las 4 horas de la administración del medicamento. No se detectaron variaciones significativas en las concentraciones de haptoglobina. CONCLUSIÓN. La prueba de la rifampicina es útil para establecer el diagnóstico de la enfermedad de Gilbert, pero las variaciones en las concentraciones de bilirrubina total (basal y tras la administración de rifampicina) no permiten establecer un valor umbral absoluto. La correlación observada entre los incrementos relativos a las 2 y a las 4 horas indica que la versión breve de la prueba (2 horas) podría simplificar su aplicación

Introduction: Diagnosis of Gilbert's disease often involves unnecessary testing and patient anxiety. Rifampin test can support the diagnosis; it has been described in short series and lacks standardization in dose, collection times, result presentation and interpretation. Our objective was to compare the response to oral rifampin in a series of patients with Gilbert's disease, 2 and 4 h after drug administration. Patients and methods: Eighty-nine patients with Gilbert's disease (elevated total bilirubin with no hepatopathy or hemolysis) were recruited. After a basal blood collection, 900 mg rifampin were administered per os and new samples were drawn 2 and 4 h later. Total and esterified bilirubin were measured in every sample. Haptoglobin concentration was also analyzed. Results: When expressed as relative increase with respect to basal values, variations observed 2 h after rifampin intake were all above 15%. A significant correlation (r = 0.902; p = 0.000) was found between relative increases 2 and 4 h after drug administration. No significant variations were found in haptoglobin concentrations. Conclusion: Rifampin test is useful in diagnosing Gilbert's disease, but variations in total bilirubin concentrations (basal and post-rifampin) make that no absolute cut-off value can be used. Correlation between 2- and 4-h relative increases suggests that a shortened version could simplify the test

Síndrome de Gilbert / Gilbert's syndrome

Presentamos el caso de un paciente de 89 años con disnea e ictericia. Se procedió al estudio de esta última hasta llegar al diagnóstico final de síndrome de Gilbert. El objetivo era filiar el origen de la ictericia en un paciente anciano, descartando para ello todas las posibles causas. El diagnóstico se confirmó con la realización del test del ayuno y de la prueba de la rifampicina (AU)

Diagnóstico presuntivo de Síndrome de Gilbert en una comunidad agraria del centro-este de Argentina / Presumptive diagnosis of Gilbert's syndrome in an agrarian community from the middle-east of Argentina

Introducción.El síndrome de Gilbert es una hiperbilirrubinemia no conjugada,leve,crónica,intermitente,denaturaleza benigna,que ocurre en ausencia de hemólisis o enfermedad hepatocelular y que afecta al 1-5 por ciento

Diagnóstico presuntivo de Síndrome de Gilbert en una comunidad agraria del centro-este de Argentina / Presumptive diagnosis of Gilberts syndrome in an agrarian community from the middle-east of Argentina

Introducción.El síndrome de Gilbert es una hiperbilirrubinemia no conjugada,leve,crónica,intermitente,denaturaleza benigna,que ocurre en ausencia de hemólisis o enfermedad hepatocelular y que afecta al 1-5 por ciento

Síndrome de Gilbert estudo clínico e métodos de diagnóstico com apresentaçåo de seis casos observados pelo autor / Gilbert's syndrome

O autor apresenta as observaçÆes de seis pacientes portadores da Síndrome de Gilbert, diagnosticados e acompanhados em sua clínica particular, nos últimos dois anos, tecendo comentários sobre a conceituaçäo de referida síndrome, sua provável etiopatogenia, benignidade do quadro clínico presente e métodos semiológicos utilizados para seu diagnóstico, compreendendo anammese, exame físico, provas laboratoriais, biópsia hepática com exame histopatológico de fragmentos do fígado, dieta baixa em calorias, ou em lipídios, e testes de contra-prova através do uso oral do fenobarbital. Pôde comprovar, no estudo de seus casos, o aumento discreto ou moderado da bilirrubinemia às custas da fraçäo indireta ou näo conjugada; a normalidade das provas hepáticas realizadas; o aparecimento ou desaparecimento das crises de icterícia, pelo menos em alguns casos, após reduçäo do número de calorias e (ou) prática exagerada de exercícios físicos; a ausência de qualquer tipo de anormalidade no exame histopatológico de fragmentos de fígado, obtidos por biópsia hepática, no único caso em que foi utilizado; e, finalmente, a contraprova da baixa da bilirrubinemia mediante o emprego oral de fenobarbital