Liver transplant with controlled donors after circulatory death with normothermic regional perfusion and brain dead donors: A multicenter cohort study of transfusion, one-year graft survival and mortality.

BACKGROUND: Controlled donation after circulatory death (cDCD) has expanded the donor pool for liver transplantation (LT). However, transfusion requirements and perioperative outcomes should be elucidated. The aim of this multicenter study was to assess red blood cell (RBC) transfusions, one-year graft and patient survival after LT after cDCD with normothermic regional perfusion (NRP) compared with donors after brain death (DBD). METHODS: 591 LT carried out in ten centers during 2019 were reviewed. Thromboelastometry was used to manage coagulation and blood product transfusion in all centers. Normothermic regional perfusion was the standard technique for organ recovery. RESULTS: 447 patients received DBD and 144 cDCD with NRP. Baseline MCF Extem was lower in the cDCD group There were no differences in the percentage of patients (63% vs. 61% p = 0.69), nor in the number of RBC units transfused (4.7 (0.2) vs 5.5 (0.4) in DBD vs cDCD, p = 0.11. Twenty-six patients (6%) died during admission for LT in the DBD group compared with 3 patients (2%) in the cDCD group (p = 0.15). To overcome the bias due to a worse coagulation profile in cDCD recipients, matched samples were compared. No differences in baseline laboratory data, or in intraoperative use of RBC or one-year outcome data were observed between DBD and cDCD recipients. CONCLUSIONS: cDCD with NRP is not associated with increased RBC transfusion. No differences in graft and patient survival between cDCD and DBD were found. Donors after controlled circulatory death with NRP can increasingly be utilized with safety, improving the imbalance between organ donors and the ever-growing demand.

Diagnóstico genético de la epidermólisis bullosa: recomendaciones de un grupo español de expertos / Genetic diagnosis of epidermolysis bullosa: recommendations from an expert Spanish research group

La epidermólisis bullosa (EB), enfermedad genética de fragilidad mucocutánea rara y devastadora, es clínica y genéticamente heterogénea. Se caracteriza por la aparición de ampollas inducidas por contacto/fricción o de forma espontánea. La EB se clasifica en 4 tipos: simple, juntural, distrófica y síndrome de Kindler y en 30 subtipos. Esta genodermatosis está causada por defectos en proteínas implicadas en la adhesión dermoepidérmica, con al menos 19 genes caracterizados hasta el momento y más de 1.000 mutaciones identificadas, que explican la complejidad de su diagnóstico. El diagnóstico molecular de la EB es el último paso de un proceso laborioso que se inicia con la recogida de una historia clínica detallada y la toma de una biopsia cutánea, que incluya una zona de despegamiento entre la dermis y la epidermis inducida, en el momento de la recolección. Dicho despegamiento permite establecer el plano de rotura por mapeo antigénico y, en el mejor de los casos, un único gen candidato en el que realizar la búsqueda de las mutaciones patogénicas. Finalizado el diagnóstico molecular, se está en condiciones de ofrecer al paciente un asesoramiento genético adecuado (patrón de herencia, riesgo de recurrencia y opciones de diagnóstico prenatal y preimplantacional) y los consecuentes programas preventivos, así como un pronóstico clínico razonable que facilite su acceso a opciones terapéuticas y de rehabilitación específicas. Por último, el diagnóstico molecular es imprescindible para la participación de los pacientes en ensayos clínicos, de gran importancia en una enfermedad como la EB, que no tiene cura. El objetivo de la presente guía es difundir el procedimiento de diagnóstico de la EB tal y como se está llevando a cabo en nuestro laboratorio y, así, evitar diagnósticos clínicos subóptimos o incompletos. Las recomendaciones recogidas son fruto de nuestra experiencia de más de 10 años de diagnóstico molecular de EB en España

Epidermolysis bullosa (EB) is a rare genetic disease that causes mucocutaneous fragility. It comprises a clinically and genetically heterogeneous group of disorder characterized by spontaneous or contact/friction-induced blistering. EB is classified into 4 types-simplex, junctional, dystrophic, and Kindler syndrome-and 30 subtypes. The disease is caused by defects in proteins implicated in dermal-epidermal adhesion. At least 19 genes have been characterized and more than 1000 mutations identified, thus rendering diagnosis complex. Molecular diagnosis of EB is the last stage of a laborious process that starts with a detailed clinical history compilation and careful procurement of a skin fresh biopsy that includes an area where the epidermis detaches from the dermis. The detachment area makes it possible to establish the cleavage plane by antigen mapping and, in the best scenario, to identify a single candidate gene to search for pathogenic mutations. The results of the molecular diagnosis enable the physician to provide appropriate genetic counseling (inheritance pattern, risk of recurrence, and options for prenatal and preimplantation diagnosis) and implement subsequent preventive programs, as well as to establish a reasonable clinical prognosis facilitating access to specific therapy and rehabilitation. Lastly, molecular diagnosis is essential for the participation of patients in clinical trials, a critical issue given the current incurable status of EB. The present guidelines aim to disseminate the procedure for diagnosing EB in our laboratory and thus avoid suboptimal or incomplete clinical diagnoses. The recommendations we provide are the result of more than 10 years’ experience in the molecular diagnosis of EB in Spain

Genetic diagnosis of epidermolysis bullosa: recommendations from an expert Spanish research group. / Diagnóstico genético de la epidermólisis bullosa: recomendaciones de un grupo español de expertos.

Epidermolysis bullosa (EB) is a rare genetic disease that causes mucocutaneous fragility. It comprises a clinically and genetically heterogeneous group of disorder characterized by spontaneous or contact/friction-induced blistering. EB is classified into 4 types-simplex, junctional, dystrophic, and Kindler syndrome-and 30 subtypes. The disease is caused by defects in proteins implicated in dermal-epidermal adhesion. At least 19 genes have been characterized and more than 1000 mutations identified, thus rendering diagnosis complex. Molecular diagnosis of EB is the last stage of a laborious process that starts with a detailed clinical history compilation and careful procurement of a skin fresh biopsy that includes an area where the epidermis detaches from the dermis. The detachment area makes it possible to establish the cleavage plane by antigen mapping and, in the best scenario, to identify a single candidate gene to search for pathogenic mutations. The results of the molecular diagnosis enable the physician to provide appropriate genetic counseling (inheritance pattern, risk of recurrence, and options for prenatal and preimplantation diagnosis) and implement subsequent preventive programs, as well as to establish a reasonable clinical prognosis facilitating access to specific therapy and rehabilitation. Lastly, molecular diagnosis is essential for the participation of patients in clinical trials, a critical issue given the current incurable status of EB. The present guidelines aim to disseminate the procedure for diagnosing EB in our laboratory and thus avoid suboptimal or incomplete clinical diagnoses. The recommendations we provide are the result of more than 10 years' experience in the molecular diagnosis of EB in Spain.

Cardiac output monitoring with pulmonary versus transpulmonary thermodilution during liver transplantation: interchangeable methods?

BACKGROUND: Liver transplantation (LT) implies hemodynamic instability, making invasive monitoring of cardiac output (CO) mandatory. Intermittent thermodilution with pulmonary artery catheter (PAC) remains the clinical gold standard to measure CO. The agreement between PAC and new monitoring methods in LT needs to be further investigated. Our aim is to clarify whether cardiac index (CI) measurements with transpulmonary intermittent thermodilution, and continuous pulmonary thermodilution methods agree sufficiently with those performed intermittently with PAC to be considered interchangeable during LT. METHODS: We studied prospectively hemodynamic parameters of 72 consecutive patients undergoing LT. Each CI was obtained simultaneously with three different techniques: intermittent (PACi) and continuous (CCI) pulmonary artery thermodilution with PAC, and intermittent transpulmonary thermodilution (TPTD) with PiCCO2 in 8 time points of the procedure, obtaining 1350 paired measurements. Exclusion criteria was retransplantation. The statistical Bland Altman method for repeated measures was used to assess agreement, and polar plot methodology to evaluate trending ability. RESULTS: Analysis of agreement between PACi and TPTD measurements (N.=474 paired measurements) showed a bias of -0.42 L/min/m2, 95% limits of agreement (95%LoA) of ±1.5 L/min/m2 and percentage error of 45%. PACi-CCI comparisons (N.=431) showed bias of -0.02 L/min/m2, 95%LoA of ±1.96 L/min/m2, and percentage error of 64%. These results demonstrated questionable clinical agreement between PACi and TPTD, and no agreement between PACi and CCI. TPTD and CCI showed poor CO trending ability. CONCLUSION: Continuous pulmonary thermodilution with PAC is not an alternative monitoring method of CO. Transpulmonary thermodilution CO monitoring with PiCCO2 shows too questionable agreement with the clinical gold standard (PACi) being in the limit of acceptance to be considered interchangeable during liver transplantation.

Two novel recessive mutations in KRT14 identified in a cohort of 21 Spanish families with epidermolysis bullosa simplex.

BACKGROUND: Basal epidermolysis bullosa simplex (EBS) is a group of blistering genodermatoses mostly caused by mutations in the keratin genes, KRT5 and KRT14. Recessive mutations represent about 5% of all EBS mutations, being common and specific in populations with high consanguinity, where affected patients show severe phenotypes. OBJECTIVES: To accomplish the first mutational analysis in patients of Spanish origin with EBS and to delineate a comprehensive genotype-phenotype correlation. METHODS: Twenty-one EBS families were analysed. Immunofluorescence mapping at the dermoepidermal junction level was performed on skin biopsies from patients. Mutation screening of the entire coding sequences of KRT5 and KRT14 in genomic DNA was assessed by polymerase chain reaction and direct sequencing. RESULTS: KRT5 or KRT14 causative mutations were identified in 18 of the 21 EBS families. A total of 14 different mutations were disclosed, of which 12 were dominant missense mutations and two truncating recessive mutations. Five of the 14 mutations were novel including three dominant in KRT5 (p.V186E, p.T321P and p.A428T) and two recessive in KRT14 (p.K116X and p.K250RfsX8). The two patients with EBS carrying homozygous recessive mutations were affected by severe phenotypes and belonged to consanguineous families. All five families with the EBS Dowling-Meara subtype carried recurrent mutations affecting the highly conserved ends of the α-helical rod domain of K5 and K14. The seven mutations associated with the localized EBS subtype were widely distributed along the KRT5 and KRT14 genes. Two families with mottled pigmentation carried the P25L mutation in KRT5, commonly associated with this subtype. CONCLUSIONS: This study further confirms the genotype-phenotype correlation established for EBS in other ethnic groups, and is the first in a Mediterranean country (excluding Israel). This study adds two novel recessive mutations to the worldwide record to date, which includes a total of 14 mutations. As in previous reports, the recessive mutations resulted in a lack of keratin K14, giving rise to a generalized and severe presentation.

The first COL7A1 mutation survey in a large Spanish dystrophic epidermolysis bullosa cohort: c.6527insC disclosed as an unusually recurrent mutation.

BACKGROUND: Dystrophic epidermolysis bullosa (DEB) is a genodermatosis caused by mutations in COL7A1. The clinical manifestations are highly variable from nail dystrophy to life-threatening blistering, making early molecular diagnosis and prognosis of utmost importance for the affected families. Mutation identification is mandatory for prenatal testing. OBJECTIVES: To conduct the first mutational analysis of COL7A1 in a Spanish cohort, to assess mutation consequences at protein/mRNA level and to establish genotype-phenotype correlations. METHODS: Forty-nine Spanish patients with DEB were studied. Antigen mapping was performed on patient skin biopsies. COL7A1 mutation screening in genomic DNA was performed by polymerase chain reaction (PCR) and direct sequencing. Mutation consequences were determined by reverse transcriptase-PCR. RESULTS: Eight patients belonged to three unrelated families with dominant DEB. Forty-one were affected with recessive DEB (RDEB). Specifically, 27 displayed the severe generalized subtype, eight the other generalized subtype and six a localized phenotype (two pretibial, three acral and one inversa). Thirty-five mutations were identified, 20 of which are novel. The pathogenic mutation c.6527insC accounted for 46.3% of Spanish RDEB alleles. A consistent genotype-phenotype correlation was established. CONCLUSIONS: Although the COL7A1 database indicates that most DEB mutations are family specific, the pathogenic mutation c.6527insC was highly recurrent in our cohort. This level of recurrence for a single genetic defect has never previously been reported for COL7A1. Our findings are essential to the clinicians caring for patients with DEB in Spain and in the large population of Spanish descendants in Latin America. They also provide geneticists a molecular clue for a priority mutation screening strategy.

Cardiac electrophysiological effects of remifentanil: study in a closed-chest porcine model.

BACKGROUND: Remifentanil has been implicated as causing intraoperative bradyarrhythmias, but little information is available regarding its cardiac electrophysiological effects. Thus, we evaluated the cardiac electrophysiological properties before and after remifentanil in a closed-chest porcine model. METHODS: Eighteen Landrace-Large pigs were premedicated with ketamine and anaesthetized with propofol (4.5 mg kg(-1) bolus followed by 13 mg kg(-1) h(-1)). After instrumentation, an electrophysiological evaluation was performed under propofol and repeated after remifentanil (bolus of 1 microg kg(-1), followed by an infusion of 0.5 microg kg(-1) min(-1)). We evaluated sinus node function [sinus node recovery time (SNRT) and sinoatrial conduction time (SACT)], atrioventricular (AV) nodal function [AH intervals during sinus rhythm (SR) and atrial pacing, Wenckebach cycle length (WCL), and effective refractory periods (ERP)], atrial, His-Purkinje, and ventricular conduction and refractoriness. Significant changes between 'propofol protocol' and 'propofol+remifentanil protocol' were evaluated. RESULTS: Remifentanil caused a significant increase in sinus cycle length (21%, P=0.001) and a significant prolongation of SNRT (43%, P=0.001), corrected SNRT (136%, P=0.003), SACT (40%, P=0.005), AH interval during SR (17%, P=0.02), AH interval during atrial pacing (25%, P=0.01), and ventricular ERP (12%, P=0.004). There was a tendency towards a prolongation of WCL and AV nodal refractoriness. Similar significant changes were observed in a reference group of seven animals in which sevoflurane was used instead of propofol. No significant changes were observed in atrial parameters, His-Purkinje function, parameters of intraventricular conduction, and QT intervals. CONCLUSIONS: Remifentanil depresses sinus node function and most parameters of AV nodal function. This contributes to an explanation for clinical observations of remifentanil-related severe bradyarrhythmias.

Long-term follow-up of patients with small-bowel angiodysplasia on capsule endoscopy. Determinants of a higher clinical impact and rebleeding rate.

BACKGROUND: the clinical impact of small-bowel angiodysplasia has not been defined. We present a prospective study to determine the features of individuals with a higher risk of rebleeding or a worse clinical outcome. PATIENTS AND METHODS: thirty patients with angiodysplasia found on CE were included and followed for 12 months. Angiodysplasia were classified by their size as small ( 10 mm). We also studied angiodysplasia lesion numbers in each patient. Rebleeding was defined as a hemoglobin drop of more than 2 g/dl in the absence of melena or hematochezia in the case of occult GI bleeding, or with any or both manifestations. RESULTS: a therapeutic procedure was carried out in 13 patients (43.4%). Individuals with large angiodysplasia had higher transfusion requirements, a higher proportion of therapeutic procedure performed after CE, lower hemoglobin concentration, and a lower rebleeding rate. Patients with ten or more angiodysplasia lesions had also higher transfusion requirements and lower hemoglobin levels, but we found no differences in the number of therapeutic procedures or rebleeding rate between both groups. On follow up rebleeding was detected in 5 patients (16.7%), all of them with small angiodysplasias. Rebleeding was more frequent in patients who did not receive further interventions (23.53 vs. 7.69%; p = 0.037). CONCLUSIONS: angiodysplasia size >or= 10 mm determines a worse clinical impact and more possibilities of receiving a therapeutic procedure. Our findings support that patients with large lesions would benefit from therapeutic interventions with a reduction in rebleeding rate.

Long-term follow-up of patients with small bowel angiodysplasia on capsule endoscopy. Determinants of a higher clinical impact and rebleeding rate

Introducción: no se ha definido con exactitud el impacto clínicode las angiodisplasias del intestino delgado. Presentamos un estudioprospectivo para determinar las características de los individuos conmayor riesgo de recidiva hemorrágica o peor evolución clínica.Pacientes y métodos: en este estudio se incluyeron treintapacientes con angiodisplasias, halladas con la cápsula endoscópica,que fueron seguidos durante 12 meses. Las lesiones se clasificaronpor su tamaño en pequeñas (≤ 10 mm) o grandes (> 10mm). Estudiamos también el número de angiodisplasias en cadapaciente. La recidiva hemorrágica se definió como una caída enlas cifras de hemoglobina de 2 g/dl, en ausencia de melenas o hematoqueciapara la hemorragia de origen oscuro o en presenciade cualquiera de estas manifestaciones.Resultados: se realizaron procedimientos terapéuticos en 13pacientes (43,4%). Los pacientes con angiodisplasias grandes tuvieronmayores requerimientos transfusionales, un mayor númerode procedimientos diagnósticos realizados tras la cápsula endoscópica,cifras inferiores de hemoglobina y menor tasa de recidivahemorrágica. Los pacientes con diez o más angiodisplasias recibierontambién más transfusiones y presentaron cifras inferioresde hemoglobina, pero no hubo diferencias en los procedimientosterapéuticos o recidiva hemorrágica entre ambos grupos. En el seguimiento,la recidiva hemorrágica se detectó en 5 pacientes(16,7%), todos con angiodisplasias pequeñas. Esta fue más frecuenteen pacientes que no recibieron tratamiento (23,53 vs.7,69%; p = 0,037).Conclusiones: el tamaño >= 10 mm de las angiodisplasias determinaun mayor impacto clínico y más posibilidades de recibirtratamiento. Nuestros hallazgos indican que pacientes con lesionesde mayor tamaño se beneficiarían de procedimientos terapéuticoscon una reducción de la tasa de recidiva hemorrágica

Background: the clinical impact of small-bowel angiodysplasiahas not been defined. We present a prospective study to determinethe features of individuals with a higher risk of rebleeding ora worse clinical outcome.Patients and methods: thirty patients with angiodysplasiafound on CE were included and followed for 12 months. Angiodysplasiawere classified by their size as small (≤ 10 mm) orlarge (> 10 mm). We also studied angiodysplasia lesion numbersin each patient. Rebleeding was defined as a hemoglobin drop ofmore than 2 g/dl in the absence of melena or hematochezia inthe case of occult GI bleeding, or with any or both manifestations.Results: a therapeutic procedure was carried out in 13 patients(43.4%). Individuals with large angiodysplasia had highertransfusion requirements, a higher proportion of therapeutic procedureperformed after CE, lower hemoglobin concentration, anda lower rebleeding rate. Patients with ten or more angiodysplasialesions had also higher transfusion requirements and lower hemoglobinlevels, but we found no differences in the number of therapeuticprocedures or rebleeding rate between both groups. Onfollow up rebleeding was detected in 5 patients (16.7%), all ofthem with small angiodysplasias. Rebleeding was more frequent inpatients who did not receive further interventions (23.53 vs.7.69%; p = 0.037).Conclusions: angiodysplasia size >= 10 mm determines aworse clinical impact and more possibilities of receiving a therapeuticprocedure. Our findings support that patients with large lesionswould benefit from therapeutic interventions with a reductionin rebleeding rate

Distensión de la vesícula biliar por obstrucción tumoral coledociana (signo de Courvoisier) / Gallbladder distension caused by tumoral obstruction of the common bile duct (Courvoisier's sign)

No disponible

Diarrea crónica, hepatomegalia e hipertransaminemia: a propósito de un caso / No disponible

Comentamos el caso clínico de un niño de 2 años de edad con un déficit grave de alfa-1-antitripsina (A1AT), que presentaba diarrea, transaminasas elevadas y hepatomegalia sinotro tipo de manifestaciones clínicas acompañantes.Durante las dos primeras décadas de la vida, las alteraciones hepáticas son el principalproblema de salud de los individuos que padecen un déficit de A1AT, y las manifestacionespulmonares son más tardías. El déficit de A1AT es aproximadamente tan frecuente como lafibrosis quística y hoy día es prioritario identificar lo antes posible a los individuos afectadosdebido a la disponibilidad de terapias específicas contra la enfermedad. El diagnóstico deldéficit grave se confirma demostrando los niveles séricos por debajo de 80 mg/dL (11μmol/L) y llevando a cabo los estudios genéticos

We report a case of a 2-year-old girl with severe A1AT (alfa 1 antitrypsin deficiency),who developed diarrhea, elevated serum liver enzymes and hepatomegaly without anyother clinical conditions that may accompany A1AT deficiency.During the first two decades of life, liver dysfunction is the major threat to the health ofalpha-1-antitrypsin affected individuals, and pulmonary dysfunction is not a major concern.A1AT deficiency is approximately as common as cystic fibrosis, and today becomes imperativeto identify affected individuals due to the availability of specific therapy for A1ATdeficiency.The diagnosis of severe A1AT deficiency is confirmed by demonstrating a serum levelbelow 80 mg/dL (11 μmol/L) in combination with a severe deficient genotype

[Dual atrioventricular nodal conduction and arrhythmia with severe hemodynamic alterations during liver retransplantation]. / Arritmia por doble via intranodal con descompensación hemodinámica grave en un retrasplante hepático.

We report the case of a man who developed tachycardia caused by atrioventricular reentry related to dual nodal conduction during liver retransplantation. The hemodynamic alterations were severe. Arrhythmia and altered cardiac conduction are potential complications of liver transplantation. The development of tachyarrhythmias--atrial fibrillation as well as episodes of supraventricular and ventricular tachycardia and bradycardia--have been described. Such arrhythmias tend to occur particularly during reperfusion of the graft. Risk factors implicated are the severe ion imbalances, acid-base imbalance, and hypothermia that accompany the reperfusion of a new organ. A review of the possible pathogenic and etiological mechanisms that lead to arrhythmia in patients with end-stage liver disease is provided.

Arritmia por doble vía intranodal con descompensación hemodinámica grave en un retrasplante hepático / Dual atrioventricular nodal conduction and arrythmia with severe hemodynamic alterations during liver retransplantation

Presentamos el caso de un paciente que presentó una taquicardia por reentrada auriculo-ventricular, en relación con la presencia de una doble vía intranodal con importante repercusión hemodinámica durante un retrasplante hepático. Las alteraciones del ritmo y de la conducción cardiaca representan unas de las complicaciones potenciales durante el trasplante hepático. Así están descritas la aparición de taquiarritmias del tipo de fibrilación auricular, taquicardias supraventriculares, ventriculares y bradiarritmias. Estas arritmias ocurren especialmente durante la reperfusión del injerto. Los factores implicados se relacionan con la presencia de alteraciones iónicas graves, del equilibrio ácido base y de la hipotermia que acompañan a la reperfusión del nuevo órgano. Se revisan los posibles mecanismos etiopatogénicos implicados en la aparición de las alteraciones del ritmo en los pacientes con enfermedad hepática terminal

We report the case of a man who developed tachycardia caused by atrioventricular reentry related to dual nodal conduction during liver retransplantation. The hemodynamic alterations were severe. Arrhythmia and altered cardiac conduction are potential complications of liver transplantation. The development of tachyarrhythmias —atrial fibrillation as well as episodes of supraventricular and ventricular tachycardia and bradycardia— have been described. Such arrhythmias tend to occur particularly during reperfusion of the graft. Risk factors implicated are the severe ion imbalances, acidbase imbalance, and hypothermia that accompany the reperfusion of a new organ. A review of the possible pathogenic and etiological mechanisms that lead to arrhythmia in patients with end-stage liver disease is provided