Implementation of a re-linkage to care strategy in patients with chronic hepatitis C who were lost to follow-up in Latin America.

To achieve WHO's goal of eliminating hepatitis C virus (HCV), innovative strategies must be designed to diagnose and treat more patients. Therefore, we aimed to describe an implementation strategy to identify patients with HCV who were lost to follow-up (LTFU) and offer them re-linkage to HCV care. We conducted an implementation study utilizing a strategy to contact patients with HCV who were not under regular follow-up in 13 countries from Latin America. Patients with HCV were identified by the international classification of diseases (ICD-9/10) or equivalent. Medical records were then reviewed to confirm the diagnosis of chronic HCV infection defined by anti-HCV+ and detectable HCV-RNA. Identified patients who were not under follow-up by a liver specialist were contacted by telephone or email, and offered a medical reevaluation. A total of 10,364 patients were classified to have HCV. After reviewing their medical charts, 1349 (13%) had undetectable HCV-RNA or were wrongly coded. Overall, 9015 (86.9%) individuals were identified with chronic HCV infection. A total of 5096 (56.5%) patients were under routine HCV care and 3919 (43.5%) had been LTFU. We were able to contact 1617 (41.3%) of the 3919 patients who were LTFU at the primary medical institution, of which 427 (26.4%) were cured at a different institutions or were dead. Of the remaining patients, 906 (76.1%) were candidates for retrieval. In our cohort, about one out of four patients with chronic HCV who were LTFU were candidates to receive treatment. This strategy has the potential to be effective, accessible and significantly impacts on the HCV care cascade.

Implementación de una estrategia de revinculación a la atención en pacientes con infección crónica por el virus de la hepatitis C en el Hospital Central de las Fuerzas Armadas de Uruguay. Resultados preliminares

Resumen: Introducción: La infección crónica por el virus de la hepatitis C (VHC) es responsable de 400.000 muertes al año, asociadas fundamentalmente al desarrollo de cirrosis y carcinoma hepatocelular. El advenimiento de los nuevos antivirales de acción directa ha marcado un punto de inflexión en el tratamiento del VHC, llevando a casi 100% la curación de los pacientes tratados. En tal sentido, la OMS se ha fijado como objetivos para el año 2030, reducir un 90% las nuevas infecciones por el VHC y un 65% la mortalidad asociada a este virus, para lo cual es necesario el desarrollo de estrategias activas de diagnóstico y vinculación a la atención y tratamiento. El objetivo del trabajo es realizar un diagnóstico de situación de los pacientes infectados por el VHC en el Hospital Central de las Fuerzas Armadas (HCFFAA), e implementar y evaluar una estrategia secuencial de revinculación a la atención. Metodología: Se construyó la cascada de tratamiento mediante una estimación de los pacientes portadores de infección crónica por VHC basada en la prevalencia local y la revisión de historias clínicas de los pacientes asistidos en el servicio de Hepatología y Trasplante Hepático del HCFFAA. Se implementó una estrategia para contactar a los pacientes con infección por VHC de forma secuencial, buscando re-establecer el vínculo de estos con el servicio de salud, asegurando el acceso a la estadificación de la enfermedad hepática y al tratamiento antiviral. Resultados: La prevalencia global estimada de personas con infección crónica por VHC fue de 1.008 personas. De 135 pacientes con serología positiva, 113 tenían ARN confirmatorio, 76 habían recibido tratamiento y 70 habían alcanzado respuesta virológica sostenida. La implementación de la estrategia logró un aumento en la prescripción del tratamiento del 67% a 76% de los pacientes con infección crónica por VHC confirmada. Conclusiones: La implementación de la estrategia de revinculación fue exitosa, con un aumento de la prescripción del tratamiento antiviral en los pacientes candidatos a tratamiento. La búsqueda activa de los pacientes infectados no diagnosticados mediante el cribado es el siguiente paso para alcanzar los objetivos de erradicación.

Abstract: Introduction: Chronic infection by the hepatitis C virus (HCV) is responsible for 400,000 deaths per year, mainly associated with the development of cirrhosis and hepatocellular carcinoma. The advent of new direct-acting antivirals has marked a turning point in the treatment of HCV, leading to almost 100% cure of treated patients. In this sense, the WHO has set as objectives for the year 2030, to reduce new HCV infections by 90% and the mortality associated with this virus by 65%, for which it is necessary to develop active strategies for diagnosis and linkage to care and treatment. The objective of the work is to carry out a diagnosis of the situation of the patients infected by HCV in the Central Hospital of the Armed Forces (HCFFAA), and to implement and evaluate a sequential strategy of re-attachment to care. Methodology: The treatment cascade was constructed by estimating the number of patients with chronic HCV infection based on local prevalence and review of the medical records of patients seen in the Hepatology and Liver Transplant service of the HCFFAA. A strategy was implemented to contact patients with HCV infection sequentially, seeking to re-establish their link with the health service, ensuring access to liver disease staging and antiviral treatment. Results: The estimated global prevalence of people with chronic HCV infection was 1,008 people. Of 135 patients with positive serology, 113 had confirmatory RNA, 76 had received treatment, and 70 had achieved sustained virologic response. The implementation of the strategy achieved an increase in the prescription of treatment from 67% to 76% of patients with confirmed chronic HCV infection. Conclusions: The implementation of the rebinding strategy was successful, with an increase in the prescription of antiviral treatment in patients who are candidates for treatment. Active search for undiagnosed infected patients through screening is the next step to achieve eradication goals.

Resumo: Introdução: A infecção crônica pelo vírus da hepatite C (HCV) é responsável por 400.000 óbitos por ano, principalmente associada ao desenvolvimento de cirrose e carcinoma hepatocelular. O advento de novos antivirais de ação direta marcou um ponto de virada no tratamento do HCV, levando à cura de quase 100% dos pacientes tratados. Nesse sentido, a OMS estabeleceu como objetivos para o ano de 2030, reduzir em 90% as novas infecções por HCV e a mortalidade associada a este vírus em 65%, para o que é necessário desenvolver estratégias ativas de diagnóstico e vinculação aos cuidados e tratamento. O objetivo do trabalho é realizar um diagnóstico da situação dos pacientes infectados pelo HCV no Hospital Central das Forças Armadas (HCFFAA), e implementar e avaliar uma estratégia sequencial de reinserção aos cuidados. Metodologia: A cascata de tratamento foi construída estimando o número de pacientes com infecção crônica pelo HCV com base na prevalência local e revisão dos prontuários dos pacientes atendidos no serviço de Hepatologia e Transplante de Fígado do HCFFAA. Foi implantada uma estratégia de contato sequencial dos pacientes com infecção pelo HCV, buscando restabelecer o vínculo com o serviço de saúde, garantindo o acesso ao estadiamento da doença hepática e ao tratamento antiviral. Resultados: A prevalência global estimada de pessoas com infecção crônica pelo HCV foi de 1.008 pessoas. Dos 135 pacientes com sorologia positiva, 113 tiveram RNA confirmatório, 76 receberam tratamento e 70 alcançaram resposta virológica sustentada. A implementação da estratégia conseguiu um aumento na prescrição de tratamento de 67% para 76% dos pacientes com infecção crônica pelo HCV confirmada. Conclusões: A implementação da estratégia de religação foi bem sucedida, com aumento da prescrição do tratamento antiviral em pacientes candidatos ao tratamento. A busca ativa de pacientes infectados não diagnosticados por meio de triagem é o próximo passo para atingir as metas de erradicação.

Infecciones bacterianas no espontáneas en pacientes cirróticos hospitalizados, Hospital Central de las Fuerzas Armadas, marzo 2018-diciembre 2020

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Abstract: Introduction: Bacterial infections in cirrhotic patients are a frequent complication, which occurs mainly in advanced stages of the disease. Non-spontaneous infections or infections not related to portal hypertension include mainly those of the urinary tract, acute pneumonia, and skin and soft tissue infections. They generate a significant impact on the evolution of the disease, since they increase morbidity and mortality, and are also the most common precipitating factor of acute over chronic liver failure, a serious condition with high short-term mortality. The objective of this work is to know the incidence, and describe the clinical, epidemiological, microbiological, and evolutionary characteristics of non-spontaneous bacterial infections, in patients with liver cirrhosis, admitted to the Military Hospital, in the period between March 2018 and December 2020. Methodology: A cross-sectional, descriptive and single-center study was carried out, which included hospitalized patients, diagnosed with liver cirrhosis, who presented a bacterial infection not related to portal hypertension on admission or during hospital stay. Data were analyzed using frequency distribution and summary measures for the different variables. The incidence of non-spontaneous bacterial infections was calculated based on the total population of cirrhotic patients admitted during that period. Results: Of the total number of cirrhotic patients admitted, 17.5% had a bacterial infection not linked to portal hypertension, with a mean age of 61 years, 70% being men. The main etiology of cirrhosis was alcoholic. The vast majority of patients (95%) presented an advanced stage of liver disease (60% Child-Pugh stage B and 35% stage C), with a mean MELD-Na of 21. The most frequent infection was that of the urinary tract (50%), followed by acute pneumonia (20%), skin and soft tissue infections (10%) and acute cholangitis (10%). The most prevalent microorganisms were gram negative bacilli such as Klebsiella pneumoniae and Escherichia coli. 40% of the patients presented acute-on-chronic liver failure at the time of admission and an additional 5% developed it during evolution. Of this group of patients, 20% died during hospitalization. Conclusions: The present study constitutes an approximation to the knowledge of non-spontaneous infections in cirrhotic patients, being necessary the development of studies with a greater number of patients in order to establish a statistically significant association between the presence of bacterial infection and the development of acute on chronic liver failure, and from this with short-term mortality.

Resumo: Introdução: Infecções bacterianas em pacientes cirróticos são uma complicação frequente, que ocorre principalmente em estágios avançados da doença. Infecções não espontâneas ou infecções não relacionadas à hipertensão portal incluem principalmente aquelas do trato urinário, pneumonia aguda e infecções de pele e tecidos moles. Geram um impacto significativo na evolução da doença, pois aumentam a morbidade e a mortalidade, sendo também o fator precipitante mais comum da insuficiência hepática aguda sobre a crônica, uma condição grave com alta mortalidade em curto prazo. O objetivo deste trabalho é conhecer a incidência e descrever as características clínicas, epidemiológicas, microbiológicas e evolutivas das infecções bacterianas não espontâneas, em pacientes com cirrose hepática, internados no Hospital Militar, no período entre Março de 2018 e dezembro de 2020. Metodologia: Foi realizado um estudo transversal, descritivo e unicêntrico, que incluiu pacientes internados, com diagnóstico de cirrose hepática, que apresentavam infecção bacteriana não vinculada à hipertensão portal na admissão ou durante a internação. Os dados foram analisados ​​por meio de distribuição de frequência e medidas de resumo para as diferentes variáveis. A incidência de infecções bacterianas não espontâneas foi calculada com base na população total de pacientes cirróticos admitidos nesse período. Do total de cirróticos admitidos, 17,5% apresentavam infecção bacteriana não ligada à hipertensão portal, com média de idade de 61 anos, sendo 70% homens. A principal etiologia da cirrose foi alcoólica. A grande maioria dos pacientes (95%) apresentava doença hepática em estágio avançado (60% Child-Pugh estágio B e 35% estágio C), com média de MELD-Na de 21. A infecção mais frequente foi a do trato urinário (50%), seguida de pneumonia aguda (20%), infecções de pele e tecidos moles (10%) e colangite aguda (10%). Os microrganismos mais prevalentes foram bacilos gram negativos como Klebsiella pneumoniae e Escherichia coli. 40% dos pacientes apresentavam insuficiência hepática aguda-crônica no momento da admissão e outros 5% a desenvolveram durante a evolução. Desse grupo de pacientes, 20% morreram durante a internação. Conclusões: O presente estudo constitui uma aproximação ao conhecimento das infecções não espontâneas em pacientes cirróticos, sendo necessário o desenvolvimento de estudos com maior número de pacientes a fim de estabelecer uma associação estatisticamente significativa entre a presença de infecção bacteriana e o desenvolvimento de quadro agudo de insuficiência hepática crônica, e a partir disso com mortalidade a curto prazo.

Predictive Cardiometabolic Risk Profiling of Patients Using Vascular Age in Liver Transplantation.

Liver transplantation is the last therapeutic option in patients with end-stage liver diseases. The adequate clinical management of transplant-patients impacts their vital prognosis and decisions on many occasions are made from the interaction of multiple variables involved in the process. This work is based on the National Liver Transplantation Program in Uruguay. We performed predictive analysis of cardiometabolic diseases on the transplanted cohort between 2014 and 2019, considering vascular age as a key factor. This aims at classification of the cohort based on the vascular age of the evaluated patients before transplantation for risk-profiling. Predicted high-risk group of the patients showed substantial deterioration of post-transplant health-conditions, including higher mortality rate. In our knowledge, this is the first study in Latin America incorporating vascular age toward predictive analysis of cardiometabolic risk factors in liver transplantations. Predictive risk-modeling using vascular age in a pre-transplantation scenario provides significant opportunity for early prediction of post-transplant risk factors, leading to efficient treatment with anticipation.

Complete Genome Sequence of Hepatitis E Virus Genotype 3 Obtained from a Chronically Infected Individual in Uruguay.

Hepatitis E virus (HEV) is a leading cause of acute viral hepatitis worldwide. We report the full-length genome sequence of an HEV-3 strain obtained from a chronically infected patient from Uruguay. This strain shared only 86% nucleotide sequence identity with the most closely related reference strain belonging to subtype 3m.

Infecciones espontáneas en el paciente cirrótico: características clínicas y microbiológicas en una cohorte bi-institucional del Uruguay / Spontaneous infections in cirrhotic patients: clinical and microbiological characteristics in a bi-institutional cohort from Uruguay / Infecções espontâneas em pacientes cirróticos: características clínicas e microbiológicas em uma coorte biinstitucional do Uruguai

Resumen: Los pacientes cirróticos hospitalizados presentan una alta prevalencia de infecciones bacterianas. Entre ellas, las denominadas infecciones espontáneas del cirrótico, que incluyen la peritonitis bacteriana espontánea, la bacteriemia espontánea y el empiema bacteriano espontáneo, constituyen un grupo particular, con un elevado riesgo de complicaciones y mortalidad. El presente trabajo tiene como objetivo describir y caracterizar las infecciones espontáneas en el cirrótico, la microbiología prevalente y su perfil de resistencia antibiótica, en 2 centros asistenciales de Montevideo-Uruguay. Se realizó un estudio transversal, descriptivo y multicéntrico, que incluyó pacientes con cirrosis hepática hospitalizados, en el periodo marzo 2018-marzo 2019. Del total de pacientes ingresados con cirrosis (156), 25 (16%) desarrollaron una infección espontánea del cirrótico. En 24 de estos pacientes (96%) la cirrosis se encontraba en estadios avanzados (Child-Pugh B-C, MELD＞15). La forma de presentación más frecuente fue la peritonitis bacteriana espontánea (52%), seguida de la bacteriemia espontánea (40%) y del empiema bacteriano espontáneo (8%). El aislamiento microbiológico fue posible en 17 casos (68%). En 12 de ellos (70%) se aislaron bacilos Gram negativos, en 4 (24%) bacilos Gram positivos, y Candida en 1 solo caso. Se identificaron 3 cepas productoras de BLEE (2 K. pneumoniae y 1 E. coli), y 4 microorganismos con otros perfiles de resistencia antibiótica (2 E. faecalis, 1 K. oxytoca, 1 E. cloacae). La prevalencia de microorganismos multirresistentes fue del 41%, siendo todos los casos en el grupo de adquisición nosocomial. La realización de otros estudios en esta área podría aproximarnos al conocimiento de la epidemiología local, para la optimización de los tratamientos empíricos dirigidos a los microorganismos más prevalentes, con el objetivo de mejorar el abordaje de las infecciones en los pacientes con cirrosis.

Abstract: Hospitalized cirrhotic patients present with a high prevalence of bacterial infections. Among them, spontaneous cirrhotic infections include spontaneous bacterial peritonitis, spontaneous bacteremia and spontaneous bacterial empyema, which constitute a particular group, with a high risk of complications and mortality. The work above aims to describe and characterize the spontaneous infections in the cirrhotic, the prevalent microbiology and its resistance profile, in 2 healthcare centers in Montevideo-Uruguay. A multicenter, descriptive, cross-sectional study was held, including hospitalized patients with liver cirrhosis, between March 2018 - March 2019. 25 (16%) of the 156 patients admitted with cirrhosis developed a spontaneous cirrhotic infection. 24 (96%) of these patients were in an advanced stage of their disease, (Child-Pugh B-C, MELD＞15). The most frequent presentation was the spontaneous bacterial peritonitis (52%), followed by the spontaneous bacteremia (40%) and the spontaneous bacterial empyema (8%). Microbiological isolation was possible in 17 cases (68%), of which 12 (70%) developed gram negative bacilli, 4 (24%) gram positive bacilli and 1 case Candida. 3 ESBL producing strains were identified, (2 K. pneumoniae and 1 E. coli), and other 4 microorganisms with different antibiotic resistance profile (2 E. faecalis, 1 K. oxytoca, 1 E. cloacae). The prevalence of multiresistant microorganisms was 41%, all of nosocomial acquisition. Research on this topic may provide more knowledge about the local epidemiology, improving the empiric treatments, targeting the most prevalent microorganisms, in order to better approach the infections in cirrhotic patients.

Resumo: Pacientes cirróticos hospitalizados presentam alta prevalência de infecções bacterianas. Dentre elas, as chamadas infecções cirróticas espontâneas, que incluem a peritonite bacteriana espontânea, a bacteremia espontânea e o empiema bacteriano espontâneo, constituem um grupo particular, com alto risco de complicações e mortalidade. O presente trabalho tem como objetivo descrever e caracterizar as infecções espontâneas em pacientes cirróticos, a microbiologia prevalente e seu perfil de resistência aos antibióticos, em 2 centros de saúde em Montevidéu-Uruguai. Foi realizado um estudo transversal, descritivo e multicêntrico, que incluiu pacientes hospitalizados com cirrose hepática, no período de março de 2018 a março de 2019. Do total de pacientes internados com cirrose (156), 25 (16%) desenvolveram infecção cirrótica espontânea. A cirrose estava em estágios avançados, em 24 desses pacientes (96%) (Child-Pugh B-C, MELD ＞ 15). A forma de apresentação mais frequente foi peritonite bacteriana espontânea (52%), seguida de bacteremia espontânea (40%) e empiema bacteriano espontâneo (8%). O isolamento microbiológico foi possível em 17 casos (68%). Em 12 deles (70%) foram isolados bacilos Gram negativos, em 4 (24%) bacilos Gram positivos e Candida em apenas 1 caso. Foram identificadas 3 cepas produtoras de ESBL (2 K. pneumoniae e 1 E. coli) e 4 microrganismos com outros perfis de resistência a antibióticos (2 E. faecalis, 1 K. oxytoca, 1 E. cloacae). A prevalência de microrganismos multirresistentes foi de 41%, todos no grupo de aquisição nosocomial. A realização de outros estudos nesta área poderá nos aproximar do conhecimento da epidemiologia local, para a otimização de tratamentos empíricos direcionados aos microrganismos mais prevalentes, com o objetivo de melhorar o manejo de infecções em pacientes com cirrose.

Resultados del Programa Nacional de Trasplante Hepático del Uruguay a 10 años de su inicio / Results of the National Program of Liver Transplantation in Uruguay 10 years after it was initiated / Resultados do Programa Nacional de Transplante de Fígado do Uruguai 10 anos após seu início

Resumen: Introducción: el trasplante hepático (TH) constituye el tratamiento de elección en pacientes con enfermedades hepáticas severas e irreversibles, sin opción de tratamientos alternativos eficaces. La medición de indicadores de calidad permite detectar problemáticas susceptibles de ser mejoradas a fin de optimizar los resultados. Objetivo: presentar los resultados del Programa Nacional de Trasplante Hepático (PNTH) del Uruguay a 10 años de su implementación y compararlos con los estándares de calidad internacionales. Material y método: estudio retrospectivo de los TH realizados del 14/7/2009 al 14/7/2019. Resultados: N: 190 TH. Edad promedio: 45 años. Sexo: 60% hombres. MELD promedio al TH: 21. Principales indicaciones: cirrosis (59%) y hepatocarcinoma (21%). Mortalidad posoperatoria: 7,4% y perioperatoria: 2,1% (estándares <10% y 1%). Tasa de retrasplante: precoz 3,7% y tardío 4,2% (estándares <5% y 8%). Tasa de reintervención: 13,1% (estándar <10%) y de no función primaria: 2,6% (estándar <2%). Sobrevida: 86,6% al año, 81,8% a 3, 77,4% a 5 y 63,2% a 10 años (estándares >80, 75, 70 y 60%). Pacientes evaluados en menos de 30 días: 47% (estándar >75%). Tasa de hígados no implantados sin causa objetiva: 0,5% (estándar <1%). El 86% de los usuarios expresaron satisfacción (estándar >80%). Mortalidad en lista: 19% (estándar <15%). Mortalidad precoz con hígado funcionante: 1% (estándar <1%). Conclusiones: el PNTH del Uruguay cumple con la mayoría de los indicadores de calidad, presentando resultados en sobrevida por encima de los estándares internacionales.

Summary: Introduction: liver transplantation constitutes the first therapy chosen by patients with severe and irreversible liver conditions, when no effective alternative options are available. Measurement of quality indicators allow for the detection of problems that may be solved in order to optimize results. Objective: to present the results obtained in the National Program of Liver Transplantation in Uruguay, 10 years after its implementation and to compare them to international quality standards. Method: retrospective study of liver transplantations performed from July 14, 2009 through July 14, 2019. Results: N: 190 Liver transplantations (LT). Average age: 45 years old. Gender: 60% male. MELD average MELD (Model for End-stage Liver Disease) upon LT: 21. Main indications: cirrhosis he(59%) y hepatocarcinoma (21%). Post-surgery mortality: 7.4% and peri-operative mortality 2.1% (standards <10 and 1%). Re-transplantation rate: early 3.7% and late 4.2% (standards <5% and 8%). Reoperation rate: 13.1% (standard <10%) and of non-primary function: 2.6% (standard <2%). Survival: 86.6% per year, 81.8% after 3 years, 77.4% after 5 and 63.2% after 10 years (standards >80, 75, 70 and 60%). Patients assessed in less than 30 days: 47% (standard >75%). Non-implanted livers with no objective cause rate: 0.5% (standard <1%). 86% of users stated they were satisfied (standard >80%). Mortality in the waiting list: 19% (standard <15%). Early mortality with functioning liver: 1% (standard <1%). Conclusions: national Program of Liver Transplantation in Uruguay meets most quality indicators standards, evidencing survival results that are above international standards.

Resumo: Introdução: o transplante de fígado (TH) é o tratamento de escolha em pacientes com doenças hepáticas graves e irreversíveis, sem a opção de tratamentos alternativos eficazes. A medição de indicadores de qualidade permite detectar problemas que podem ser melhorados para otimizar os resultados. Objetivo: apresentar os resultados do Programa Nacional de Transplante de Fígado (PNTH) do Uruguai 10 anos após sua implantação e compará-los com os padrões internacionais de qualidade. Materiais e métodos: estudo retrospectivo do HT realizado de 14/07/2009 a 14/07/2019. Resultados: N: 190 TH. Idade média: 45 anos. Sexo: 60% homens. Escala MELD média no TH: 21. Principais indicações: cirrose (59%) e hepatocarcinoma (21%). Mortalidade pós-operatória: 7,4% e peri-operatória 2,1% (padrões <10 e 1%). Taxa de retransplante: 3,7% inicial e 4,2% tardio (padrão <5% e 8%). Taxa de reintervenção: 13,1% (padrão <10%) e não função primária: 2,6% (padrão <2%). Sobrevivência: 86,6% em 1 ano, 81,8% em 3, 77,4% em 5 e 63,2% em 10 anos (padrões> 80, 75, 70 e 60%). Pacientes avaliados em menos de 30 dias: 47% (padrão> 75%). Taxa de fígados não implantados sem causa objetiva: 0,5% (padrão <1%). 86% dos usuários expressaram satisfação (padrão> 80%). Mortalidade em lista de espera: 19% (padrão <15%). Mortalidade precoce com fígado funcionante: 1% (padrão <1%). Conclusões: o PNTH do Uruguai cumpre a maioria dos indicadores de qualidade, apresentando resultados de sobrevivência acima dos padrões internacionais.

Optimización del diagnóstico de hepatitis por citomegalovirus en receptores de trasplante hepático: diez años de experiencia / Cytomegalovirus hepatitis diagnosis optimization in liver transplant recipients: 10 years of experience

Resumen Introducción: Para los pacientes receptores de trasplante hepático (TH) la hepatitis por citomegalovirus (CMV) constituye una entidad de difícil diagnóstico. Nuestro objetivo fue determinar la real incidencia de hepatitis por CMV aplicando técnicas diagnósticas más específicas. Material y Métodos: Estudio retrospectivo/ prospectivo, en un centro de trasplante hepático. Período de estudio: años 2009 al 2019. Se incluyeron los TH que presentaron elementos sugestivos y/o específicos de CMV en la histopatología de la punción biopsia hepática (PBH), a los que se les realizó inmunohistoquimica (IHQ) en la PBH. Población control n = 17. Resultados: 41 casos cumplieron los criterios de inclusión. La IHQ fue positiva en n = 6 (14,6%). En la población control, la IHQ fue negativa en el 100% de los casos. Esto traduce un valor predictor negativo de 100% para la histopatología en el diagnóstico de hepatitis por CMV, con un valor predictor positivo de 14,6%. En 85% de los pacientes con IHQ negativa, hubo diagnósticos alternativos. La terapia antiviral en la fase retrospectiva se indicó en 48% y en la prospectiva en 21%. Conclusiones: Combinar la histopatología con la IHQ optimiza el diagnóstico de hepatitis por CMV; lo que permite la racionalización del uso de antivirales de alto costo y la búsqueda de etiologías diferenciales.

Abstract Background: Cytomegalovirus (CMV) hepatitis constitutes a challenging diagnostic entity in liver transplant (LT) recipients. Aim: To determine the real incidence of CMV hepatitis using more specific diagnostic tools as those currently used before. Methods: Retrospective/prospective study conducted in a hepatic transplant unit from 2009 to 2019. LT recipients with CMV specific or suggestive elements in histopathology of hepatic biopsies were included. Immunohistochemistry (IHQ) was performed in tissue samples of the studied cohort as well as in a control one. Results: 41 patients met the inclusion criteria. IHQ was diagnostic in 6 (14.6%), and was negative in 100% of the control population. The negative predictive value of the histopathology for CMV hepatitis diagnosis was 100% and the positive predictive value was 14.6%. 85% of patients in whom the IHQ was negative had alternative diagnosis Antiviral therapy in the retrospective analysis was indicated in 48% of patients and in 21% of the prospectively analyzed cohort. Conclusions: Histopathology and IHQ combination improves the diagnostic accuracy of CMV hepatitis which translates into a rational us of expensive antiviral therapy and to search for differential diagnosis

Latin American Association for the study of the liver (ALEH) practice guidance for the diagnosis and treatment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) currently represents an epidemic worldwide. NAFLD is the most frequently diagnosed chronic liver disease, affecting 20-30% of the general population. Furthermore, its prevalence is predicted to increase exponentially in the next decades, concomitantly with the global epidemic of obesity, type 2 diabetes mellitus (T2DM), and sedentary lifestyle. NAFLD is a clinical syndrome that encompasses a wide spectrum of associated diseases and hepatic complications such as hepatocellular carcinoma (HCC). Moreover, this disease is believed to become the main indication for liver transplantation in the near future. Since NAFLD management represents a growing challenge for primary care physicians, the Asociación Latinoamericana para el Estudio del Hígado (ALEH) has decided to organize this Practice Guidance for the Diagnosis and Treatment of Non-Alcoholic Fatty Liver Disease, written by Latin-American specialists in different clinical areas, and destined to general practitioners, internal medicine specialists, endocrinologists, diabetologists, gastroenterologists, and hepatologists. The main purpose of this document is to improve patient care and awareness of NAFLD. The information provided in this guidance may also be useful in assisting stakeholders in the decision-making process related to NAFLD. Since new evidence is constantly emerging on different aspects of the disease, updates to this guideline will be required in future.

[Cytomegalovirus hepatitis diagnosis optimization in liver transplant recipients: 10 years of experience]. / Optimización del diagnóstico de hepatitis por citomegalovirus en receptores de trasplante hepático: diez años de experiencia.

BACKGROUND: Cytomegalovirus (CMV) hepatitis constitutes a challenging diagnostic entity in liver transplant (LT) recipients. AIM: To determine the real incidence of CMV hepatitis using more specific diagnostic tools as those currently used before. METHODS: Retrospective/prospective study conducted in a hepatic transplant unit from 2009 to 2019. LT recipients with CMV specific or suggestive elements in histopathology of hepatic biopsies were included. Immunohistochemistry (IHQ) was performed in tissue samples of the studied cohort as well as in a control one. RESULTS: 41 patients met the inclusion criteria. IHQ was diagnostic in 6 (14.6%), and was negative in 100% of the control population. The negative predictive value of the histopathology for CMV hepatitis diagnosis was 100% and the positive predictive value was 14.6%. 85% of patients in whom the IHQ was negative had alternative diagnosis Antiviral therapy in the retrospective analysis was indicated in 48% of patients and in 21% of the prospectively analyzed cohort. CONCLUSIONS: Histopathology and IHQ combination improves the diagnostic accuracy of CMV hepatitis which translates into a rational us of expensive antiviral therapy and to search for differential diagnosis.

Locally Acquired Chronic Hepatitis E Followed by Epstein-Barr Virus Reactivation and Burkitt Lymphoma as a Suspected Extrahepatic Manifestation in a Liver Transplant Recipient.

BACKGROUND Hepatitis E virus (HEV) is a common cause of acute hepatitis in developing regions. In high-income countries, hepatitis E is an emergent zoonotic disease of increasing concern. Clinically, the infection is usually acute and self-limited in immunocompetent individuals, although rare chronic cases in immunocompromised patients have been reported. Both acute and chronic infections have been recently associated with several extrahepatic manifestations, including neurological and hematological disorders. CASE REPORT A case of autochthonous chronic HEV infection in a liver-transplanted man from a non-endemic country is presented. Phylogenetic analysis revealed a swine origin of the HEV human infection. Chronic hepatitis E was treated with a 9-week course of ribavirin, after which viral clearance was achieved. Subsequently, the patient developed a post-transplant lymphoproliferative disorder (PTLD) in the form of Burkitt lymphoma. At the time of lymphoma diagnosis, the patient had shown a strong reactivation of Epstein-Barr virus (EBV) infection. After additional antiviral ganciclovir therapy and chemotherapy, the patient had a complete recovery with no sequelae. CONCLUSIONS The differential diagnosis of persistently elevated transaminases in transplanted and/or immunocompromised patients should include testing for HEV by appropriate nucleic acid techniques (NATs). Cases of HEV infection with an atypical clinical outcome, such as the one presented herein, highlights the need for increased awareness of chronic hepatitis E and its association with a wide range of extrahepatic manifestations.

Acute Liver Failure due to Wilson Disease: Eight Years of the National Liver Transplant Program in Uruguay.

INTRODUCTION AND AIM: Wilson's disease (WD) is an uncommon cause of acute liver failure (ALF). Our aim was to describe clinical features, diagnostic findings, treatments, and outcomes of patients with ALF due to WD. MATERIAL AND METHODS: Retrospective medical record reviews of all patients with ALF due to WD in eight years in Uruguay. RESULTS: WD was the cause of six (15%) of thirty-nine ALF cases. All patients were females, with a mean age of 18 years. Four patients presented with hyperacute liver failure and two with acute failure. Jaundice was the main complaint of all patients. Mean total bilirubin (TB), alkaline phosphatase (AP), AST, and ALT were 27.5 mg/dL, 45.5 lU/l, 156 IU/L, and 51 IU/L, respectively. Ceruloplasmin levels were low in four patients, urinary cooper was high in four, and two had Kayser-Fleischer rings. All patients had Coombs-negative hemolytic anemia, acute kidney injury, histochemical identifiable copper, and advanced fibrosis on liver histology. The average MELD score was 36. All patients were treated with d-penicillamine and listed for urgent liver transplantation (LT). Prometheus® was performed in one patient. Three patients died: two without LT and one after LT. Three patients survived: one without LT (New Wilson Index<11) and two with LT. The referral time to the program and the total time (referral plus waiting list time) were longer for non-survivors than for survivors (14 vs. 3 days and 23 vs. 8 respectively). CONCLUSION: All cases had typical clinical, analytical and histopathology characteristics. Early referral was determinant of prognosis.

Activity of the Calcineurin Pathway in Patients on the Liver Transplantation Waiting List: Factors of Variability and Response to Tacrolimus Inhibition.

BACKGROUND: We sought to evaluate, in patients on a liver transplantation waiting list, potential biomarkers of the base calcineurin pathway activity with use of a new model of nonstimulated peripheral blood mononuclear cells (PBMC) and ex vivo response to tacrolimus (TAC). METHODS: The calcineurin pathway activity was explored ex vivo in stimulated and nonstimulated PBMC from 19 patients. The inhibition of NFAT1 translocation to PBMC nuclei, expression of intracellular IL-2, and membrane CD25 in different T-cell subsets were measured by multiparametric flow cytometry before and after exposure to TAC. We also studied the influence on the individual response of polymorphisms in 3 key genes of the calcineurin pathway: PPIA, PPP3CA, and IL2RA. RESULTS: All pharmacodynamics profiles closely fitted an I/Imax sigmoid model. Interindividual variability was higher in nonstimulated than in stimulated conditions, as well as in the presence of TAC. IL-2+CD8+ cells at TAC Imax showed the highest interindividual variability, suggesting its usefulness as a biomarker of individual TAC effects integrating many different sources of regulation and variability. Moreover, in the absence of TAC, patients with end-stage liver disease exhibited lower NFAT1 translocation and T-cell activation than healthy volunteers from a previous study under similar conditions. Multivariate statistical analysis showed strong and significant associations between TAC pharmacodynamic parameters and 2 polymorphisms in the gene-coding cyclophilin A (rs8177826 and rs6850). CONCLUSIONS: We show the feasibility of using nonstimulated PBMCs to explore the calcineurin pathway under more physiologic conditions and point toward potential biomarkers for TAC pharmacodynamic monitoring. ClinicalTrials.gov Identifier: NCT01760356.

Sistema de Soporte Hepático Artificial: ¿Cuándo, a quien y por qué? / Artificial Hepatic Support System: When, to whom and why?

Resumen La falla hepática es un problema de salud debido a su incidencia y su elevada mortalidad a corto plazo (40-80%). La súbita alteración de la función hepática lleva a las manifestaciones clínicas características, con desarrollo de encefalopatía hepática, ictericia, coagulopatía, susceptibilidad aumentada a infecciones, síndrome hepato-renal y falla multi-orgánica. Puede ocurrir en pacientes sin enfermedad hepática preexistente (Falla Hepática Aguda) o en un paciente con enfermedad hepática crónica que sufre una descompensación aguda (Falla Aguda sobre Crónica).El trasplante hepático sigue siendo la única alternativa terapéutica con beneficio demostrado en la sobrevida de estos pacientes. Sin embargo este no siempre puede llevarse a cabo debido a la escasez de órganos y/o la presencia de contraindicaciones para el mismo. En este escenario el sistema de soporte hepático artificial extracorpóreo Prometheus® disponible en Uruguay, es fundamental para mantener la condición del paciente hasta la recuperación espontánea de la función hepática o hasta que exista un órgano disponible para el trasplante.

Abstract Liver Failure is a health problem because of its incidence and high mortality in short terms (40% to 80%). The sudden impairment of liver function leads to its characteristic clinical manifestations with the development of hepatic encephalopathy, jaundice, coagulation disturbances, increased susceptibility to infections, hemodynamic instability, hepatorenal syndrome and multiorgan failure. It may develop in patients without preexisting liver disease (Acute Liver Failure) or in patients with chronic liver disease with an acute decompensation (Acute on Chronic Liver Failure). Liver transplantation is the only therapeutic choice with demonstrated benefit on survival. However it cannot always be done due to the shortage of donor organs and/or the presence of contraindications. In this scenario the extracorporeal liver support system Prometheus® available in Uruguay is really important for maintaining the patient s condition until the spontaneous recovery of the liver function or until a donor organ becomes available.

Detection and molecular characterization of Torque Teno Virus (TTV) in Uruguay.

Torque Teno Virus (TTV), member of Anelloviridae family, is considered a worldwide distributed emergent virus and is currently classified into seven genogroups. Interestingly, the pathogenicity of TTV remains unclear. However, it has been constantly associated to hepatitis cases of unknown etiology (HUE) as well as extensively studied in concurrent infections with Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) and Human Immunodeficiency Virus type 1 (HIV-1). In South America, TTV epidemiological data is scant, involving some studies from Brazil, Venezuela, Colombia and Bolivia. The aim of this work was to investigate for the first time in Uruguay the presence of TTV by a nested-PCR system in 85 human serum samples infected with HBV and/or HCV and/or HIV-1 and in HUE cases. Overall, our results reported a TTV infection rate of 79% (67/85). Furthermore, the molecular characterization of Uruguayan strains revealed that one of them clustered in genogroup 1, while the remaining ones formed separate clusters closely related to genogroup 3, which should be confirmed by complete genome sequencing. Further investigation about TTV circulation in Uruguayan population is needed in order to provide additional information about the genetic variability and TTV epidemiology in South America.

Primer caso de falla hepática aguda por virus de la Hepatitis E en Uruguay / First case of Hepatitis E Virus- induced acute liver failure in Uruguay

Resumen: La infección por el Virus de la Hepatitis E (VHE) en individuos inmunocompetentes generalmente se presenta como hepatitis aguda autolimitada. En determinados escenarios clínicos (embarazadas y pacientes con enfermedad hepática crónica) puede manifestarse como falla hepática aguda. Se han descripto casos de hepatitis crónica en inmunocomprometidos. En Uruguay se han reportado 14 casos de hepatitis aguda autolimitada por VHE. En el presente artículo se describe el primer caso de falla hepática aguda por VHE en Uruguay.

Abstract: Hepatitis E Virus (HEV) typically causes an acute and self-limiting infection in immune-competent individuals, though acute liver failure is described in some settings (pregnancy, chronic liver disease). Chronic hepatitis has been described in immunosuppressed patients. Fourteen autochthonous cases of self-limiting acute hepatitis for HEV were reported in Uruguay. The first case of acute liver failure for HEV is described in the present article.

Tacrolimus pharmacodynamics and pharmacogenetics along the calcineurin pathway in human lymphocytes.

BACKGROUND: Although therapeutic drug monitoring has improved the clinical use of immunosuppressive drugs, there is still interpatient variability in efficacy and toxicity that pharmacodynamic monitoring may help to reduce. To select the best biomarkers of tacrolimus pharmacodynamics, we explored the strength and variability of signal transduction and the influence of polymorphisms along the calcineurin pathway. METHODS: Peripheral blood mononuclear cells from 35 healthy volunteers were incubated with tacrolimus (0.1-50 ng/mL) and stimulated ex vivo. Inhibition of NFAT1 (nuclear factor of activated T cells 1) translocation to the nucleus and intracellular expression of interleukin-2 in CD4(+) and CD8(+) T cells and the surface activation marker CD25 in CD3(+) cells were measured by flow cytometry. We sequenced the promoter regions of immunophilins and calcineurin subunits and characterized selected single nucleotide polymorphisms in the genes of the calcineurin pathway with allelic discrimination assays. RESULTS: All responses closely fitted an I/Imax sigmoid model. Large interindividual variability (n = 30) in I0 and IC50 was found for all biomarkers. Moreover, strong and statistically significant associations were found between tacrolimus pharmacodynamic parameters and polymorphisms in the genes coding cyclophilin A, the calcineurin catalytic subunit α isoenzyme, and CD25. CONCLUSIONS: This study demonstrates the consistency and large interindividual variability of signal transduction along the calcineurin pathway, as well as the strong influence of pharmacogenetic polymorphisms in the calcineurin cascade on both the physiological activity of this route and tacrolimus pharmacodynamics.