Descripción de polimorfismos genéticos en CYP3A5 y MDR-1 y su impacto en el rechazo agudo clínico de pacientes trasplantados de hígado del Hospital San Vicente Fundación Rionegro / Description of genetic polymorphisms in CYP3A5 and MDR-1 and their impact on clinical acute rejection in liver transplant patients at Hospital San Vicente Fundación Rionegro

Introducción. El tacrolimus es un medicamento inmunosupresor ampliamente usado en trasplante hepático, que presenta una gran variabilidad interindividual la cual se considera asociada a la frecuencia de polimorfismos de CYP3A5 y MDR-1. El objetivo de este estudio fue evaluar la frecuencia de los polimorfismos rs776746, rs2032582 y rs1045642 y su asociación con rechazo clínico y toxicidad farmacológica. Métodos. Se incluyeron pacientes inmunosuprimidos con tacrolimus a quienes se les realizó trasplante hepático en el Hospital San Vicente Fundación Rionegro entre 2020 y 2022, con supervivencia mayor a un mes. Se evaluaron las variables clínicas, rechazo agudo y toxicidad farmacológica. Se secuenciaron los genes de estudio mediante PCR, comparando la expresión o no en cada uno de los pacientes. Resultados. Se identificaron 17 pacientes. El 43 % de los pacientes se clasificaron como CYP3A5*1/*1 y CYP3A5*1/*3, entre los cuales se encontró asociación con aumento en la tasa de rechazo agudo clínico, al comparar con los pacientes no expresivos (100 % vs. 44 %, p=0,05); no hubo diferencias en cuanto a la toxicidad farmacológica u otros desenlaces. Se encontró el polimorfismo rs2032582 en un 50 % y el rs1045642 en un 23,5 % de los pacientes, sin embargo, no se identificó asociación con rechazo u otros eventos clínicos. Conclusiones. Se encontró una asociación entre el genotipo CYP3A5*1/*1 y CYP3A5*1/*3 y la tasa de rechazo clínico. Sin embargo, se requiere una muestra más amplia para validar estos datos y plantear modelos de medicina personalizada.

Introduction. Tacrolimus is an immunosuppressive drug widely used in liver transplantation, which presents great interindividual variability which is considered associated with the frequency of CYP3A5 and MDR-1 polymorphisms. The objective of this study was to evaluate the frequency of the rs776746, rs2032582 and rs1045642 polymorphisms and their association with clinical rejection and drug toxicity. Methods. Immunosuppressed patients with tacrolimus who underwent a liver transplant at the Hospital San Vicente Fundación Rionegro between 2020 and 2022 were included, with survival of more than one month. Clinical variables, acute rejection and pharmacological toxicity were evaluated. The study genes were sequenced by PCR, comparing their expression or not in each of the patients. Results. Seventeen patients were identified. 43% of the patients were classified as CYP3A5*1/*1 and CYP3A5*1/*3, among which an association was found with increased rates of clinical acute rejection when compared with non-expressive patients (100% vs. 44%, p=0.05). There were no differences in drug toxicity or other outcomes. The rs2032582 polymorphism was found in 50% and rs1045642 in 23.5% of patients; however, no association with rejection or other clinical events was identified. Conclusions. An association was found between the CYP3A5*1/*1 and CYP3A5*1/*3 genotype and the clinical rejection rate. However, a larger sample is required to validate these data and propose models of personalized medicine.

Aplicabilidad del índice de fragilidad hepática en pacientes cirróticos evaluados para trasplante / Applicability of the liver frailty index in cirrhotic patients evaluated for transplantation

Introducción. En las últimas décadas se han desarrollado diferentes scores y modelos para predecir el pronóstico en pacientes con enfermedad hepática crónica avanzada. Los más reconocidos y utilizados son el sistema de estadificación de Child-Pugh (CP) y el score de MELD, pero estos carecen de herramientas para evaluar objetivamente otros factores pronósticos. Por este motivo, se ha incorporado el concepto de fragilidad a la hepatología clínica. El objetivo de este artículo es examinar la aplicabilidad del índice de fragilidad hepática (IFH) en pacientes con cirrosis evaluados para trasplante hepático en Uruguay. Metodología. Estudio observacional, descriptivo y retrospectivo en el Servicio de Enfermedades Hepáticas del Hospital Central de las Fuerzas Armadas (HCFFAA) de enero de 2018 a diciembre de 2021. Resultados. Se evaluaron un total de 78 pacientes, excluyéndose 19 de estos, culminando con una muestra final de 59 pacientes. La edad media fue de 52 años, siendo el 66 % hombres. La principal etiología de la cirrosis fue la alcohólica, y la comorbilidad más frecuente fue el sobrepeso/obesidad (66 %). La media de IFH fue de 4,03 ± 0,45. El 90 % de los pacientes eran prefrágiles, el 10 % frágiles y ningún paciente fue clasificado como no frágil. El 76 % presentaba un estadio avanzado de la enfermedad al momento de la evaluación 42 % CP estadio B, 34 % CP C, 24 % CP A, con una media de MELD-Na de 17,8 ± 7,6. El 17 % tuvo complicaciones infecciosas. La mortalidad global (n=78) fue del 12 %, y la de los pacientes con IFH calculado fue del 22 %. Conclusiones. El cálculo del IFH es realizable en cirróticos como herramienta objetiva que brinda una mirada integral del paciente. A mayor severidad de la cirrosis, mayor es el IFH. Sin embargo, este índice no parece ser un predictor de la eventual realización del trasplante hepático, ni de muerte en lista de espera en nuestros pacientes.

Introduction. In recent decades, several scores and models have been proposed to predict prognosis in patients with advanced chronic liver disease. The most recognized and used are the Child-Pugh (CP) and the Model for End-stage Liver Disease (MELD) scores, but they lack tools to objectively evaluate other prognostic factors. For this reason, the concept of fragility has been incorporated into clinical hepatology. The objective of this study was to evaluate the applicability of the liver frailty index (LFI) in patients with cirrhosis evaluated for liver transplantation in Uruguay. Methodology. Observational, descriptive and retrospective study at the Hospital Central de las Fuerzas Armadas (HCFFAA) Liver Disease Service from January 2018 to December 2021. Results. A total of 78 patients were evaluated, 19 were excluded, culminating in a final sample of 59 patients. The mean age was 52 years, with 66% being men. The main etiology of cirrhosis was alcoholic and the most frequent comorbidity was overweight/obesity (66%). The mean LFI was 4.03 ± 0.45. 90% of patients were pre-fragile, 10% were fragile, and no patient was classified as non-fragile. 76% had an advanced stage of the disease at the time of evaluation: 42% CP stage B, 34% CP C, 24% CP A, with a mean MELD-Na of 17.8 ± 7.6. 17% had infectious complications. Overall mortality (n=78) was 12%, and that of patients with calculated LFI was 22%. Conclusions. The LFI can be calculated in cirrhotic patients, and it is an objective tool that provides a comprehensive view of the patient. LFI depends on the severity of the cirrhosis. However, this index is not a predictor of liver transplantation or death on the waiting list in our patients.

Caracterización clínico-epidemiológica de pacientes con enfermedad hepática esteatósica asociada a disfunción metabólica previa al trasplante en un hospital de cuarto nivel / Clinical-epidemiological characterization of patients with steatotic liver disease associated with metabolic dysfunction prior to transplantation in a fourth level hospital

Introducción. La enfermedad hepática esteatósica asociada a disfunción metabólica (MASLD) se ha convertido en la enfermedad hepática crónica más frecuente en los países occidentales, causando un aumento en los costos y en la ocupación hospitalaria. La caracterización integral previa al trasplante hepático en pacientes con MASLD es una gran interrogante, especialmente en nuestro medio. El objetivo del presente estudio fue realizar la caracterización clínico-epidemiológica de pacientes trasplantados por cirrosis hepática (CH) descompensada o carcinoma hepatocelular (CHC) asociado a MASLD. Metodología. Se desarrolló un estudio observacional retrospectivo, descriptivo, de corte transversal en el Servicio de Hepatología del Hospital Pablo Tobón Uribe en Medellín, Colombia. Se incluyeron pacientes mayores de 17 años, con diagnóstico de CH o de CHC asociado a MASLD que fueron trasplantados entre los años 2004 a 2017. Resultados. Se encontraron 84 pacientes que fueron trasplantados con esas características. La edad promedio de los pacientes fue de 59±10,5 con una mayor proporción significativa de hombres sobre mujeres, llegando casi al 70 %. Con relación a las comorbilidades, se encontró que el sobrepeso/obesidad, la hipertensión arterial y la diabetes mellitus tipo 2 fueron un hallazgo en el 44,1 %, 33,3 % y 33,3 %, respectivamente. Por otro lado, el 14,5 %, el 33,7 % y el 51,8 % presentaron un Child-Pugh A, B y C, respectivamente. La media del puntaje MELD fue de 18,9±6,26. Con respecto a las complicaciones de la cirrosis, el 77,4 % de los pacientes presentó ascitis, el 61,9 % encefalopatía hepática, el 36,9 % hemorragia del tracto digestivo superior y el 29,8 % peritonitis bacteriana espontánea. Conclusión. Los resultados expuestos mostraron nuestra experiencia en trasplante hepático en pacientes con CH y CHC asociado a MASLD. Se debe realizar una evaluación multidisciplinaria antes y después del trasplante en estos pacientes, haciendo especial énfasis en el manejo de la disfunción metabólica y sus componentes, entre los que se destacan la obesidad y la diabetes mellitus.

Introduction. Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most frequent chronic liver disease in Western countries, causing increased costs and hospital occupancy. The comprehensive pre-transplant characterization in patients with MASLD is a major question, especially in our setting. The aim of the present study was to perform the clinical-epidemiological characterization of transplanted patients with decompensated liver cirrhosis (LC) or hepatocellular carcinoma (HCC) associated with MASLD. Methodology. A retrospective, descriptive, cross-sectional observational study was carried out in the Hepatology Department of the Pablo Tobón Uribe Hospital in Medellin, Colombia. Patients over 17 years of age, with a diagnosis of LC or HCC associated with MASLD who were transplanted between 2004 and 2017 were included. Results. We found 84 patients who were transplanted with these characteristics. The mean age of the patients was 59±10.5 with a significantly higher proportion of men over women, reaching almost 70%. Regarding comorbidities, overweight/obesity, arterial hypertension, and type 2 diabetes mellitus were found in 44.1%, 33.3%, and 33.3%, respectively. On the other hand, 14.5%, 33.7%, and 51.8% had Child-Pugh A, B, and C, respectively. The mean MELD score was 18.9±6.26. Regarding complications of cirrhosis, 77.4% of patients developed ascites, 61.9% hepatic encephalopathy, 36.9% upper gastrointestinal tract hemorrhage, and 29.8% spontaneous bacterial peritonitis. Conclusion. The above results showed our experience of liver transplantation in patients with LC and HCC associated with MASLD. A multidisciplinary evaluation should be performed before and after transplantation in these patients, with special emphasis on the management of metabolic dysfunction and its components, including obesity and diabetes mellitus.

Evolution and innovation of preservation fluid for donor liver / 器官移植

Organ preservation fluid could mitigate cold ischemia injury and maintain normal function of the grafts. At present, how to reduce a series of injury caused by cold ischemia of donor liver and improve the preservation quality of grafts are the hot and challenging spots in this field. Currently, preservation fluid in clinical practice has not achieved ideal preservation effect, especially for the protection of marginal donor organs. In the context of severe donor shortage, the key solution is still to explore the optimal preservation protocol for donor liver to prevent grafts from cold ischemia injury. In this article, the mechanism of donor liver injury during cold ischemia, the classification and evolution of donor liver preservation fluid were summarized, the development direction and challenges of donor liver preservation fluid were discussed, aiming to provide novel ideas and references for the research and development of donor liver preservation fluid.

Analysis of three-dimensional visualization imaging of severe portal vein stenosis after liver transplantation and clinical efficacy of portal vein stent implantation / 器官移植

Objective To analyze three-dimensional imaging characteristics and advantages for severe portal vein stenosis after liver transplantation, and to evaluate clinical efficacy of portal vein stent implantation. Methods Clinical data of 10 patients who received portal vein stent implantation for severe portal vein stenosis after liver transplantation were retrospectively analyzed. Imaging characteristics of severe portal vein stenosis, and advantages of three-dimensional reconstruction imaging and interventional treatment efficacy for severe portal vein stenosis were analyzed. Results Among 10 patients, 3 cases were diagnosed with centripetal stenosis, tortuosity angulation-induced stenosis in 2 cases, compression-induced stenosis in 2 cases, long-segment stenosis and/or vascular occlusion in 3 cases. Three-dimensional reconstruction images possessed advantages in accurate identification of stenosis, identification of stenosis types and measurement of stenosis length. All patients were successfully implanted with portal vein stents. After stent implantation, the diameter of the minimum diameter of portal vein was increased [(6.2±0.9) mm vs. (2.6±1.7) mm, P<0.05], the flow velocity at anastomotic site was decreased [(57±19) cm/s vs. (128±27) cm/s, P<0.05], and the flow velocity at the portal vein adjacent to the liver was increased [(41±6) cm/s vs. (18±6) cm/s, P<0.05]. One patient suffered from intrahepatic hematoma caused by interventional puncture, which was mitigated after conservative observation and treatment. The remaining patients did not experience relevant complications. Conclusions Three-dimensional visualization technique may visually display the location, characteristics and severity of stenosis, which is beneficial for clinicians to make treatment decisions and assist interventional procedures. Timely implantation of portal vein stent may effectively reverse pathological process and improve portal vein blood flow.

Diagnosis and treatment of the portal vein complications for children undergoing spilt liver transplantation / 器官移植

Objective To investigate the diagnosis and treatment strategy of the portal vein complications in children undergoing split liver transplantation. Methods The clinical data of 88 pediatric recipients who underwent split liver transplantation were retrospectively analyzed. Intraoperative anastomosis at the bifurcating site of the portal vein or donor iliac vein bypass anastomosis was performed depending on the internal diameter and development of the recipient's portal vein. A normalized portal venous blood stream monitoring was performed during the perioperative stage. After operation, heparin sodium was used to bridge warfarin for anticoagulation therapy. After portal vein stenosis or thrombosis was identified with enhanced CT or portography, managements including embolectomy, systemic anticoagulation, interventional thrombus removal, balloon dilatation and/or stenting were performed. Results Among the 88 recipients, a total of 10 children were diagnosed with portal vein complications, of which 4 cases were diagnosed with portal vein stenosis at 1 d, 2 months, 8 months, and 11 months after surgery, and 6 cases were diagnosed with portal vein thrombosis at intraoperative, 2 d, 3 d (n=2), 6 d, and 11 months after surgery, respectively. One patient with portal vein stenosis and one patient with portal vein thrombosis died perioperatively. The fatality related to portal vein complications was 2% (2/88). Of the remaining 8 patients, 1 underwent systemic anticoagulation, 2 underwent portal venous embolectomy, 1 underwent interventional balloon dilatation, and 4 underwent interventional balloon dilatation plus stenting. No portal venous related symptoms were detected during postoperative long term follow up, and the retested portal venous blood stream parameters were normal. Conclusions The normalized intra- and post-operative portal venous blood stream monitoring is a useful tool for the early detection of portal vein complications, the early utilization of useful managements such as intraoperative portal venous embolectomy, interventional balloon dilatation and stenting may effectively treat the portal vein complications, thus minimizing the portal vein complication related graft loss and recipient death.

Strategies for ABO-incompatible liver transplantation / 器官移植

With rapid development of organ transplantation, the issue of global organ shortage has become increasingly prominent. At present, liver transplantation is the most effective treatment for end-stage liver disease. Nevertheless, the shortage of donors has been a key problem restricting the development of liver transplantation. China is a country with a larger number of hepatitis B, and the shortage of donor liver is particularly significant. Many critically ill patients often lose the best opportunity or even die because they cannot obtain a matched donor liver in time. As a strategy to expand the donor pool, ABO-incompatible (ABOi) liver transplantation offers new options for patients who are waiting for matched donors. However, ABOi liver transplantation is highly controversial due to higher risk of complications, such as severe infection, antibody-mediated rejection (AMR), biliary complications, thrombotic microangiopathy, and acute kidney injury, etc. In this article, research progress in preoperative, intraoperative and postoperative strategies of ABOi liver transplantation was reviewed, aiming to provide reference for clinical application and research of ABOi liver transplantation.

Research progress in perioperative management of portal vein thrombosis in liver transplantation / 器官移植

Portal vein thrombosis is one of the common complications of liver cirrhosis. The incidence of portal vein thrombosis is increased with the progression of diseases. The incidence and progression of portal vein thrombosis are associated with multiple factors. The indications of anticoagulant therapy remain to be investigated. At present, portal vein thrombosis is no longer considered as a contraindication for liver transplantation. Nevertheless, complicated portal vein thrombosis will increase perioperative risk of liver transplantation. How to restore the blood flow of portal vein system is a challenge for surgical decision-making in clinical practice. Rational preoperative typing, surgical planning and portal vein reconstruction are the keys to ensure favorable long-term prognosis of liver transplant recipients. In this article, epidemiological status, risk factors, typing and identification of portal vein thrombosis, preoperative and intraoperative management of portal vein thrombosis in liver transplantation, and the impact of portal vein thrombosis on the outcomes of liver transplantation were reviewed, aiming to provide reference for perioperative management of portal vein thrombosis throughout liver transplantation.

Sofosbuvir más glecaprevir/pibrentasvir como terapia de rescate postrasplante hepático en pacientes con exposición previa a inhibidores de NS5A. Serie de casos / Sofosbuvir plus glecaprevir/pibrentasvir as salvage therapy after liver transplantation in NS5A inhibitor-experienced patients. A case series

Resumen Antecedentes: El tratamiento de la infección crónica por el virus de la hepatitis C (VHC) con antivirales de acción directa logra tasas de respuesta virológica sostenida superiores a 95 %. Sin embargo, el manejo del fracaso virológico sigue siendo un desafío clínico y la evidencia sobre el retratamiento es limitada, especialmente en poblaciones como los receptores de trasplante hepático (TH). Objetivo: Este estudio evaluó el régimen de sofosbuvir más glecaprevir/pibrentasvir (GLE/PIB) en receptores de TH en quienes falló el régimen basado en inhibidores de la proteína no estructural 5A (NS5A). Material y métodos: Estudio retrospectivo de 111 pacientes trasplantados entre enero de 2018 y diciembre de 2020; 18 pacientes presentaron infección recurrente por VHC posterior al TH, tres de ellos tuvieron antecedentes de al menos un régimen basado en inhibidores de NS5A. Se inició terapia de rescate con sofosbuvir más GLE/PIB durante 12 semanas posterior al TH; se registraron las características basales de los pacientes y sus desenlaces. Resultados: En los tres pacientes se logró obtener una carga viral indetectable de VHC a las 12 semanas de finalizar el tratamiento. No se observaron eventos adversos graves. Conclusión: En nuestra serie, sofosbuvir más GLE/PIB durante 12 semanas demostró ser una terapia de rescate efectiva y segura posterior al TH en pacientes previamente tratados con inhibidores de NS5A.

Abstract Background: Treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals achieves a sustained virologic response rates higher than 95%. However, virologic failure remains a clinical challenge, and data on retreatment are limited, especially in special populations such as liver transplant (LT) recipients. Objective: This study evaluated the sofosbuvir plus glecaprevir-pibrentasvir (GLE/PIB) regimen in LT recipients who had failed to a nonstructural protein 5A (NS5A) inhibitor-based regimen. Material and methods: Retrospective study of 111 liver transplant recipients between January 2018 and December 2020; 18 patients presented with HCV recurrent infection after LT, out of whom three had a history of at least one NS5A inhibitor-based regimen. Salvage therapy with sofosbuvir plus GLE/PIB was started for 12 weeks; baseline characteristics and outcomes were recorded. Results: All three patients (100%) achieved an undetectable HCV viral load 12 weeks after treatment completion. No serious adverse events were observed. Conclusion: In our series, sofosbuvir plus GLE/PIB for 12 weeks is an effective and safe salvage therapy after LT in patients previously treated with NS5A inhibitors.

Trasplante hepático por hemangioendotelioma hepático difuso / Liver transplantation for diffuse epithelioid hemangioendothelioma

RESUMEN El hemangioendotelioma epiteloide hepático (HEH) es un tumor vascular, de etiología no aclarada, extraordinariamente infrecuente. La ausencia de características clínicas, analíticas y radiológicas especificas dificulta su correcto diagnóstico. El tratamiento del HEH depende del tamaño y localización tumoral, la extensión extrahepática y la condición médica del paciente. Entre las posibles opciones se encuentra el trasplante hepático, que obtiene unos buenos resultados clínicos, aunque el riesgo de recidiva no es despreciable. Presentamos un nuevo caso de HEH tratado mediante trasplante hepático.

ABSTRACT Hepatic epithelioid hemangioendothelioma (HEHE) is an extremely rare vascular tumor of unclear etiology. The diagnosis is difficult due to the absence of specific clinical characteristics, laboratory tests results and radiological findings. The management of HEHE depends on tumor size, location, extrahepatic extension, and patients' medical status. Liver transplantation is one of the possible options with good clinical results, although the risk of recurrence is not negligible. We present a new case of HEHE managed with liver transplantation.

Kasai Portoenterostomy at a Slightly Delayed Age and Native Liver Survival in Children With Biliary Atresia: Single Center Experience

Objectives: We studied the modifiable prognostic factors that extend native liver survival at 2 years after Kasai portoenterostomy (KPE). Methods: We reviewed hospital records of patients with neonatal cholestasis, with focus on infants diagnosed with biliary atresia in a tertiary care hospital between January, 2014 and May, 2021. We determined the association of outcome with clinical and laboratory variables. Results: Infants who underwent KPE at a median (IQR) age of 76 (72-79) days had best outcomes, with minimal severe post-KPE complications and 2- year survival rate of 84.6%, compared to other infants (younger and older age at KPE). The median (IQR) weight at KPE in this group was 4.66 (4.2, 5.0) kg. Conclusions: In contrast to traditional recommendations, babies with median age at KPE of 76 days had superior native liver survival (84.6%) and reduced post-KPE complications, as compared to earlier KPE age. Nutritional status and weight of infant at KPE could be associated with this survival difference. This observation needs confirmation through multicentric prospective studies in different settings.

Hepatitis B induced fulminant liver failure: A call for prevention

Acute fulminant hepatic failure is a condition in which a healthy liver deteriorates rapidly following an insult, resulting in the impairment of its synthetic functions. This condition is rare and is associated with high fatality rates. We report the case of a 19-year-old male who was brought to the emergency room in an unconscious state with jaundice and persistent fever for 2–3 weeks after recently commencing intravenous use of morphine. He was found to be hepatitis B surface antigen reactive, and his laboratory tests indicated severe liver dysfunction with elevated levels of serum bilirubin, aspartate transaminase, alanine transaminase, gamma-glutamyl transferase, and International normalized ratio. The patient was diagnosed with fulminant liver failure with coagulopathy and hepatic encephalopathy. The patient’s family was addressed and counseled regarding the urgent need for liver transplantation. However, due to a lack of funds and insurance, supportive treatment was the only option left. Despite all supportive measures, the patient expired within 48 h. This case highlights the importance of various socioeconomic issues involved with liver transplantation, as in a resource-limited setting, urgent transplantation seems nearly impossible. In addition, this case report raises certain ethical issues that need consideration, particularly in an injection drug use scenario. It also highlights the importance of addressing the rising issue of injection drug use among youth, particularly in the regions of Punjab.

Severe Acute Hepatitis: An Emerging Grave Illness in Children

Acute hepatitis of unknown origin in children has been recently described in the literature, and a case definition has also been proposed for this condition. The exact etiology is unknown and exclusion of infectious, metabolic, autoimmune and toxin mediated injuries is essential. Management for this condition is supportive, but some may require liver transplantation. Infection prevention and control practices are important as the etiology remains unidentified.

High versus low mean arterial pressure target in liver transplant patients. An open, controlled, single-center, randomized clinical trial - Protocol and methods (LIVER-PAM) / Alto versus baixo alvo de pressão arterial média em pacientes submetidos a transplante hepático. Um estudo clínico aberto, controlado, unicêntrico e randomizado -Protocolo e métodos (LIVER-PAM)

ABSTRACT Objective: To explain the rationale and protocol of the methods and analyses to be used in the LIVER-PAM randomized clinical trial, which seeks to understand whether a higher mean arterial pressure is capable of reducing the incidence of renal dysfunction postoperatively after liver transplantation. Methods: LIVER-PAM is an open-label, randomized, controlled, singlecenter clinical trial. Patients randomized to the intervention group will have a mean arterial pressure of 85 - 90mmHg in the initial 24 hours of postoperative management, while patients in the control group will have a mean arterial pressure of 65 - 70mmHg in the same period. A sample of 174 patients will be required to demonstrate a 20% reduction in the absolute incidence of renal dysfunction, with a power of 80% and an alpha of 0.05. Conclusion: If a 20% reduction in the absolute incidence of renal dysfunction in the postoperative period of liver transplantation is achieved with higher target mean arterial pressure in the first 24 hours, this would represent an inexpensive and simple therapy for improving current outcomes in the management of liver transplant patients. ClinicalTrials.gov Registry:NCT05068713

RESUMO Objetivo: Explicitar o racional e o protocolo de métodos e análises a serem utilizadas no ensaio clínico randomizado LIVER-PAM, que busca entender se um nível mais alto de pressão arterial média é capaz de reduzir a incidência de disfunção renal no pós-operatório de transplante hepático. Métodos: O LIVER-PAM é um estudo clínico randomizado, controlado, unicêntrico e aberto. Pacientes randomizados para o grupo intervenção terão como alvo de pressão arterial média 85 - 90mmHg nas 24 horas iniciais do manejo pós-operatório, enquanto pacientes do grupo controle terão como alvo de pressão arterial média 65 - 70mmHg no mesmo período. Uma amostra de 174 pacientes será necessária para demonstrar redução de 20% na incidência absoluta de disfunção renal, com poder de 80% e alfa de 0,05. Conclusão: Se a redução de 20% da incidência absoluta de disfunção renal no pós-operatório de transplante hepático for obtida com alvos maiores de pressão arterial média nas primeiras 24 horas, o manejo do paciente nesse cenário encontraria uma terapia barata e simples para a melhoria dos desfechos atuais. Registro Cliniclatrials.gov:NCT05068713

An experience on living donor liver transplantation for colorectal liver metastasis in south america: a new era in transplant oncology / Experiência de transplante de fígado para metástase colorretal na américa do sul: uma nova era em transplante oncológico

ABSTRACT BACKGROUND: Complete surgical resection is the treatment of choice for patients with liver metastases, but in some patients, it is not possible to obtain a complete R0 resection. Moreover, the recurrence rate is up to 75% after three years. After the experience of the Oslo group with cadaveric liver transplant, some centers are starting their experience with liver transplant for colorectal liver metastasis. AIMS: To present our initial experience with living donor liver transplant for colorectal liver metastasis. METHODS: From 2019 to 2022, four liver transplants were performed in patients with colorectal liver metastases according to the Oslo criteria. RESULTS: Four patients underwent living donor liver transplants, male/female ratio was 3:1, mean age 52.5 (42-68 years). All patients were included in Oslo criteria for liver transplant. Two patients had already been submitted to liver resection. The decision for liver transplant occurred after discussion with a multidisciplinary team. Three patients recurred after the procedure and the patient number 3 died after chemotherapy. CONCLUSIONS: Living donor liver transplant is a viable treatment option for colorectal liver metastasis in Brazil, due to a shortage of donors.

RESUMO RACIONAL: A ressecção cirúrgica completa é o tratamento de escolha para pacientes com metástases hepáticas, mas em alguns pacientes não é possível obter uma completa ressecção R0. Além disso, a taxa de recorrência é de até 75% após 3 anos. Após a experiência do grupo de Oslo com transplante hepático cadavérico, alguns centros estão iniciando sua experiência com transplante hepático para metástase hepática colorretal. OBJETIVOS: Apresentar a experiência inicial com transplante de fígado de doador vivo para metástase hepática colorretal. MÉTODOS: De 2019 a 2022, foram quatro transplantes hepáticos em pacientes com metástases hepáticas colorretais, de acordo com os critérios de Oslo. RESULTADOS: Quatro pacientes foram submetidos a transplante hepático de doador vivo, a relação homem/mulher de 3:1, a idade média foi de 52,5 (42-68 anos). Todos os pacientes foram incluídos nos critérios de Oslo para transplante de fígado. Dois pacientes já haviam sido submetidos à ressecção hepática. A decisão pelo transplante hepático ocorreu após discussão com equipe multidisciplinar. Três pacientes recidivaram após o procedimento e o paciente número 3 morreu após a quimioterapia. CONCLUSÕES: O transplante de fígado com doador vivo é uma opção viável de tratamento para metástase hepática colorretal no Brasil, devido à escassez de doadores.

Liver transplantation in patients with primary sclerosing cholangitis: a multicentric study / Transplante hepático em pacientes com colangite esclerosante primária: estudo multicêntrico

ABSTRACT BACKGROUND: The prevalence of primary sclerosing cholangitis (PSC) in the general population has not yet been clearly established. The management of PSC should focus on delaying the progression of the disease and restraining its complications. The only curative therapy for the disease remains liver transplantation (LT). PSC is currently the fifth most common indication for LT and corresponds to 5% of all LT indications in adults. AIMS: Our objective is to evaluate the indications and outcomes of PSC patients undergoing LT in three liver transplantation centers in southern Brazil - Hospital Santa Isabel in Blumenau, Santa Catarina state, and Hospital das Clínicas and Hospital Nossa Senhora das Graças, in Curitiba, Parana state). METHODS: This is a longitudinal observational study of patients with PSC who underwent LT in three major Brazilian medical centers. Electronic medical records and study protocols of all patients subjected to LT from January 2011 to December 2021 were retrospectively reviewed. RESULTS: Of the 1,362 transplants performed in the three medical centers, 37 were due to PSC. Recurrence of PSC occurred in three patients (8.1%) in 3.0±2.4 years (range, 1-4 years). The 1-year and 5-year survival rates after the first LT were 83.8 and 80.6%, respectively. The 1-year and 5-year graft survival rates were, respectively, 83.8 and 74.8%. CONCLUSIONS: Our experience with LT in patients with PSC demonstrated good patient and graft survival results. Most deaths were due to common factors in patients undergoing LT.

RESUMO RACIONAL: A prevalência de colangite esclerosante primária (CEP) na população em geral ainda não foi claramente estabelecida. O manejo da CEP deve se concentrar em retardar a progressão da doença e gerenciar suas complicações. A única terapia curativa para a doença continua sendo o transplante hepático (TH). A CEP é atualmente a 5ª indicação mais comum de TH e corresponde a 5% de todas as indicações de TH em adultos OBJETIVOS: O nosso objetivo é avaliar as indicações e os resultados do transplante de fígado em pacientes com CEP submetidos a TH em três centros de transplante de fígado no sul do Brasil (Hospital Santa Isabel, Blumenau, Santa Catarina; Hospital das Clínicas, Curitiba, Paraná; e Hospital Nossa Senhora das Graças, Curitiba, Paraná). MÉTODOS: Este é um estudo observacional longitudinal de pacientes com colangite esclerosante primária que foram submetidos a transplante hepático em três grandes centros médicos brasileiros. Os prontuários eletrônicos de todos os pacientes submetidos a TH de Janeiro de 2011 a Dezembro de 2021, foram avaliados retrospectivamente. RESULTADOS: De um total de 1.362 transplantes realizados nos três centros médicos, 37 eram devidos à CEP. A recorrência de CEP ocorreu em 3 pacientes (8,1%) em 3±2,4 anos (intervalo, 1-4 anos). A taxa de sobrevida de 1 ano e 5 anos após o 1° TH foi respectivamente de 83,8 e 80,6%. As taxas de sobrevida dos enxertos em 1 ano e 5 anos foram, respectivamente, 83,8 e 74,8%. CONCLUSÕES: A nossa experiência com TH em pacientes com CEP demonstrou bons resultados de sobrevida dos pacientes e dos enxertos. A maioria dos óbitos ocorreu devido a fatores comuns em pacientes submetidos a TH.

Liver transplant for metastatic neuroendocrine tumors: a single-center report / Transplante de fígado para tumores neuroendócrinos metastáticos: série de casos

ABSTRACT BACKGROUND: Neuroendocrine tumors are rare neoplasms of uncertain biological behavior. The liver is one of the most common sites of metastases, occurring in 50% of patients with metastatic disease. AIMS: To analyze a clinical series in liver transplant of patients with neuroendocrine tumors metastases. METHODS: A retrospective descriptive study, based on the review of medical records of patients undergoing liver transplants due to neuroendocrine tumor metastases in a single center in northeast Brazil, over a period of 20 years (January 2001 to December 2021). RESULTS: During the analyzed period, 2,000 liver transplants were performed, of which 11 were indicated for liver metastases caused by neuroendocrine tumors. The mean age at diagnosis was 45.09±14.36 years (26-66 years) and 72.7% of cases were females. The most common primary tumor site was in the gastrointestinal tract in 64% of cases. Even after detailed investigation, three patients had no primary tumor site identified (27%). Overall survival after transplantation at one month was 90%, at one year was 70%, and five year, 45.4%. Disease-free survival rate was 72.7% at one year and 36.3% at five years. CONCLUSIONS: Liver transplantation is a treatment modality with good overall survival and disease-free survival results in selected patients with unresectable liver metastases from neuroendocrine tumors. However, a rigorous selection of patients is necessary to obtain better results and the ideal time for transplant indication is still a controversial topic in the literature.

RESUMO RACIONAL: Os tumores neuroendócrinos são neoplasias raras de comportamento biológico incerto. O fígado é um local comum de metástase, ocorrendo em 50% dos pacientes com doença metastática. OBJETIVOS: Analisar casuística de transplante hepático por metástases de tumores neuroendócrinos. MÉTODOS: Estudo descritivo retrospectivo com revisão de prontuários de pacientes submetidos a transplante hepático por metástases de tumores neuroendócrinos em um único centro no Nordeste do Brasil durante 20 anos (janeiro de 2001 a dezembro de 2021). RESULTADOS: Durante o período analisado, foram realizados 2.000 transplantes hepático, sendo 11 indicados por metástases hepáticas de tumores neuroendócrinos. A média de idade ao diagnóstico foi de 45,09±14,36 anos (26-66 anos) e 72,7% dos casos eram do sexo feminino. O local do tumor primário mais comum foi o trato gastrointestinal (64% dos casos). Após detalhada investigação, três pacientes não tiveram o local do tumor primário identificado (27%). A sobrevida global um mês e após um ano do transplante foi de 90 e 70%, respectivamente. A sobrevida após 5 anos foi de 45,4%. A taxa de sobrevida livre de doença foi de 72,7% no primeiro ano e 36,3% em cinco anos. CONCLUSÕES: O transplante hepático é uma modalidade de tratamento com bons resultados de sobrevida global e sobrevida livre de doença, em pacientes selecionados com metástases hepáticas irressecáveis de tumores neuroendócrinos. No entanto, a seleção rigorosa dos pacientes é necessária para obter melhores resultados e o momento ideal para a indicação do transplante ainda é um tema controverso na literatura.

Prognostic factors of liver transplantation for acute-on-chronic liver failure / Fatores prognósticos de transplante hepático em "acute-on-chronic liver failure"

ABSTRACT BACKGROUND: Liver transplantation (LT) is the only treatment that can provide long-term survival for patients with acute-on-chronic liver failure (ACLF). Although several studies identify prognostic factors for patients in ACLF who do not undergo LT, there is scarce literature about prognostic factors after LT in this population. AIM: Evaluate outcomes of ACLF patients undergoing LT, studying prognostic factors related to 1-year and 90 days post-LT. METHODS: Patients with ACLF undergoing LT between January 2005 and April 2021 were included. Variables such as chronic liver failure consortium (CLIF-C) ACLF values and ACLF grades were compared with the outcomes. RESULTS: The ACLF survival of patients (n=25) post-LT at 90 days, 1, 3, 5 and 7 years, was 80, 76, 59.5, 54.1 and 54.1% versus 86.3, 79.4, 72.6, 66.5 and 61.2% for patients undergoing LT for other indications (n=344), (p=0.525). There was no statistical difference for mortality at 01 year and 90 days among patients with the three ACLF grades (ACLF-1 vs. ACLF-2 vs. ACLF-3) undergoing LT, as well as when compared to non-ACLF patients. CLIF-C ACLF score was not related to death outcomes. None of the other studied variables proved to be independent predictors of mortality at 90 days, 1 year, or overall. CONCLUSIONS: LT conferred long-term survival to most transplant patients. None of the studied variables proved to be a prognostic factor associated with post-LT survival outcomes for patients with ACLF. Additional studies are recommended to clarify the prognostic factors of post-LT survival in patients with ACLF.

RESUMO RACIONAL: O transplante hepático (TH) é o único tratamento a proporcionar sobrevida a longo prazo para pacientes com "acute-on-chronic liver failure" (ACLF). Vários estudos identificaram fatores prognósticos para pacientes em ACLF que não realizam TH, porém há poucos dados na literatura sobre fatores prognósticos nessa população transplantada. OBJETIVOS: Avaliar desfechos de pacientes ACLF submetidos a TH, e seus preditores de mortalidade. MÉTODOS: Foram avaliados pacientes em ACLF submetidos a TH entre janeiro de 2005 e abril de 2021. Variáveis como valores CLIF-C ACLF e pontuação no ACLF foram comparadas com os desfechos. RESULTADOS: A sobrevida de ACLF pós TH de pacientes (n=25) em 90 dias, 1, 3, 5 e 7 anos, foi de 80, 76, 59,5, 54,1 e 54,1% versus 86,3, 79,4, 72,6, 66,5 e 61,2% para pacientes submetidos a TH por outras indicações (n=344), (p=0,525). Não houve diferença estatística para mortalidade em 01 ano e 90 dias entre pacientes com os três graus de ACLF (ACLF-1 vs. ACLF-2 vs. ACLF-3), bem como quando comparados a pacientes não ACLF. O escore "chronic liver failure consortium" (CLIF-C) ACLF não se correlacionou com desfechos de óbito. Nenhuma das outras variáveis estudadas mostrou-se preditora independente de mortalidade em 90 dias, após um ano ou global. CONCLUSÕES: TH conferiu sobrevida em longo prazo à maioria dos pacientes transplantados, semelhante aos pacientes submetidos à TH por outras indicações. Nenhuma das variáveis estudadas mostrou-se fator prognóstico associado a desfechos de sobrevida pós-TH para pacientes com ACLF. Estudos adicionais são necessários para estabelecer fatores prognósticos pós-TH em pacientes com ACLF.

Pharmacokinetics and therapeutic target attainment of vancomycin in pediatric post-liver transplant patients

Abstract Introduction Vancomycin is widely prescribed to treat or prevent Gram-positive infections in pediatric liver transplant recipients. The objective of this prospective cohort study is to describe vancomycin pharmacokinetics and to evaluate the therapeutic target attainment after initial dose regimen. Materials and methods Patients with previous renal injury were excluded. Vancomycin therapy started with 40‒60 mg/kg/day. The pharmacokinetic parameters were assessed using two steady-state blood samples and the first-order kinetic equations. Therapeutic target was defined as vancomycin 24-hour Area Under the Curve/Minimum Inhibitory Concentration (AUC/MIC) ≥ 400 and < 600. Results Sixteen patients were included. The found vancomycin clearance, half-life, and volume of distribution were, respectively: 2.1 (1.3‒2.8) mL/kg/min, 3.3 (2.7‒4.4) hours, and 0.7 (0.5‒0.9) L/kg. With the initial dose, only 6 (37 %) patients reached the therapeutic target against Gram-positive pathogens with MIC 1 mg/L. After individual dose adjustments, all patients reached the target. The correlation between trough levels and AUC was low (R2= 0.5). Conclusions Pediatric patients with preserved renal function after liver transplantation have an increased volume of distribution for vancomycin, and most patients present subtherapeutic levels after the standard initial dosing regimen. With the vancomycin AUC-guided monitoring and dosing, it is possible to improve therapeutic target attainment.

Experience of patients undergoing liver transplantation during the covid-19 pandemic / Experiencia del patients sometido a trasplante hepático durante la pandemia de covid-19 / Vivência do paciente submetido ao transplante hepático durante a pandemia da covid-19

ABSTRACT Objective: to understand the experience of patients undergoing liver transplantation during the COVID-19 pandemic. Method: exploratory and qualitative research, developed in a reference hospital in liver transplantation, in the city of Florianópolis, Brazil. Participants were liver transplant patients between the years 2011 and 2021. Data collection conducted through a semi-structured script and data analysis performed according to content analysis. Results: from the participation of 23 patients, two categories of analysis emerged: "Perceptions about social isolation", with results related to coping and feelings related to social isolation; and "Actions and information: patients, support network and health services", revealing the meanings of strategies and changes developed in life activities of daily living as well as challenges faced with information and health services during the pandemic period. Conclusion: the study was able to understand liver transplant patients' experience in the face of the challenges they face during the pandemic. It allowed to visualize coping strategies, feelings and meanings based on recipients' perspective. As a contribution, it presents possibilities for achieving improvements in services and attention to weaknesses in health services, providing opportunities for reflections to improve this care and considering the specificities and complexities of the postoperative period of liver transplantation.

RESUMEN Objetivo: comprender la experiencia de los pacientes sometidos a trasplante hepático en la pandemia de COVID-19. Método: investigación exploratoria, con abordaje cualitativo, desarrollada en un hospital de referencia para trasplante hepático, en la ciudad de Florianópolis, Brasil. Los participantes fueron pacientes trasplantados de hígado entre los años 2011 y 2021. La recolección de datos se realizó a través de un guión semiestructurado y el análisis de datos se realizó de acuerdo con el análisis de contenido. Resultados: de la participación de 23 pacientes surgieron dos categorías de análisis: "Percepciones sobre el aislamiento social", con resultados relacionados al afrontamiento y sentimientos relacionados al aislamiento social; y "Acciones e información: paciente, red de apoyo y servicios de salud", revelando los significados de las estrategias y cambios desarrollados en las actividades de la vida diaria, así como los desafíos enfrentados con la información y los servicios de salud durante el período de la pandemia. Conclusión: el estudio logró comprender la experiencia de los pacientes trasplantados de hígado frente a los desafíos que enfrentan durante la pandemia. Permitido visualizar estrategias de afrontamiento, sentimientos y significados basados ​​en la propia perspectiva del receptor. Como aporte, presenta posibilidades para lograr mejoras en los servicios y atención a las debilidades de los servicios de salud, brindando espacios de reflexión para mejorar esa atención, considerando las especificidades y complejidades del postoperatorio del trasplante hepático.

RESUMO Objetivo: compreender a vivência do paciente submetido ao transplante hepático na pandemia da COVID-19. Método: pesquisa exploratória, de abordagem qualitativa desenvolvida em hospital de referência em transplante hepático, na cidade de Florianópolis, Brasil; os participantes foram pacientes transplantados hepáticos entre os anos de 2011 e 2021. Coleta de dados conduzida por meio de roteiro semiestruturado e análise dos dados realizada conforme análise de conteúdo. Resultados: da participação dos 23 pacientes, duas categorias de análise emergiram: "percepções acerca do isolamento social" com resultados relacionados aos enfrentamentos e sentimentos referentes ao isolamento social e "e "ações e informações: paciente, rede de apoio e serviços de saúde" desvelando os significados das estratégias e mudanças desenvolvidas nas atividades de vida diária bem como os desafios em face das informações e dos serviços de saúde durante o período da pandemia. Conclusão: o estudo foi capaz de compreender a vivência dos pacientes transplantados hepáticos ante os desafios enfrentados por eles durante a pandemia. Permitiu visualizar estratégias de enfrentamento, sentimentos e significados com base na perspectiva do próprio receptor. Como contribuição, apresenta possibilidades de alcance de melhorias nos serviços e de atenção às fragilidades dos serviços de saúde, oportunizando reflexões para a melhoria desse cuidado, considerando as especificidades e complexidades do pós-operatório do transplante hepático.