Predicting major adverse cardiovascular events after orthotopic liver transplantation using a supervised machine learning model: A cohort study.

BACKGROUND: Liver transplant (LT) patients have become older and sicker. The rate of post-LT major adverse cardiovascular events (MACE) has increased, and this in turn raises 30-d post-LT mortality. Noninvasive cardiac stress testing loses accuracy when applied to pre-LT cirrhotic patients. AIM: To assess the feasibility and accuracy of a machine learning model used to predict post-LT MACE in a regional cohort. METHODS: This retrospective cohort study involved 575 LT patients from a Southern Brazilian academic center. We developed a predictive model for post-LT MACE (defined as a composite outcome of stroke, new-onset heart failure, severe arrhythmia, and myocardial infarction) using the extreme gradient boosting (XGBoost) machine learning model. We addressed missing data (below 20%) for relevant variables using the k-nearest neighbor imputation method, calculating the mean from the ten nearest neighbors for each case. The modeling dataset included 83 features, encompassing patient and laboratory data, cirrhosis complications, and pre-LT cardiac assessments. Model performance was assessed using the area under the receiver operating characteristic curve (AUROC). We also employed Shapley additive explanations (SHAP) to interpret feature impacts. The dataset was split into training (75%) and testing (25%) sets. Calibration was evaluated using the Brier score. We followed Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis guidelines for reporting. Scikit-learn and SHAP in Python 3 were used for all analyses. The supplementary material includes code for model development and a user-friendly online MACE prediction calculator. RESULTS: Of the 537 included patients, 23 (4.46%) developed in-hospital MACE, with a mean age at transplantation of 52.9 years. The majority, 66.1%, were male. The XGBoost model achieved an impressive AUROC of 0.89 during the training stage. This model exhibited accuracy, precision, recall, and F1-score values of 0.84, 0.85, 0.80, and 0.79, respectively. Calibration, as assessed by the Brier score, indicated excellent model calibration with a score of 0.07. Furthermore, SHAP values highlighted the significance of certain variables in predicting postoperative MACE, with negative noninvasive cardiac stress testing, use of nonselective beta-blockers, direct bilirubin levels, blood type O, and dynamic alterations on myocardial perfusion scintigraphy being the most influential factors at the cohort-wide level. These results highlight the predictive capability of our XGBoost model in assessing the risk of post-LT MACE, making it a valuable tool for clinical practice. CONCLUSION: Our study successfully assessed the feasibility and accuracy of the XGBoost machine learning model in predicting post-LT MACE, using both cardiovascular and hepatic variables. The model demonstrated impressive performance, aligning with literature findings, and exhibited excellent calibration. Notably, our cautious approach to prevent overfitting and data leakage suggests the stability of results when applied to prospective data, reinforcing the model's value as a reliable tool for predicting post-LT MACE in clinical practice.

Performance of eight predictive models for hepatocellular carcinoma recurrence after liver transplantation: A comparative study.

INTRODUCTION AND OBJECTIVES: Liver transplantation is the optimal treatment for patients with early hepatocellular carcinoma and cirrhosis. However, hepatocellular carcinoma recurs in approximately 15 % of individuals. This study aimed to assess the efficacy of predictive models for hepatocellular carcinoma recurrence after liver transplantation. PATIENTS AND METHODS: This retrospective study included 381 patients with HCC and evaluated the performance of the following models: R3-AFP score, alpha-fetoprotein (AFP) model, University of California, Los Angeles (UCLA) nomogram, Pre-Model of Recurrence after Liver Transplantation (MORAL), Post-MORAL, and Combo MORAL models, Risk Estimation of Tumor Recurrence (RETREAT) model and Platelet to Lymphocyte Ratio (PLR) model. RESULTS: The R3-AFP score, UCLA nomogram, AFP model, RETREAT, Combo MORAL, and Post-MORAL models exhibited comparable AUROCs, ranging from 0.785 to 0.733. The AUROCs for the R3-AFP model and AFP model were superior to those of the Pre-MORAL and PLR models. The UCLA nomogram, RETREAT score, Combo MORAL model, and Post-MORAL model performed similarly to the first two models, but were only superior to the PLR model. CONCLUSIONS: The R3-AFP model, UCLA nomogram, AFP model, RETREAT, Combo MORAL, and Post-MORAL models demonstrated a moderate predictive capacity for hepatocellular carcinoma recurrence following transplantation. No significant differences were observed among these models in their ability to predict recurrence.

Correction: Propensity-matched analysis of patients with intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma and hepatocellular carcinoma undergoing a liver transplant.

[This corrects the article on p. 688 in vol. 13, PMID: 36160465.].

WAITING LIST FOR LIVER TRANSPLANTATION: CLINICAL AND ECONOMIC BURDEN.

BACKGROUND: Burden of disease is an indicator that relates to health status. United States and European epidemiological data have shown that the burden of chronic liver disease has increased significantly in recent decades. There are no studies evaluating the impact of complications of chronic liver disease on the waiting list for deceased donor liver transplantation (LTx). OBJECTIVE: To determine the clinical and economic burden of complications of liver disease in wait-listed patients from the perspective of a transplant center. METHODS: The study retrospectively analyzed medical records of 104 patients wait-listed for deceased donor LTx from October 2012 to May 2016 and whose treatment was fully provided at the study transplant center. Clinical data were obtained from electronic medical records, while economic data were collected from a hospital management software. To allocate all direct medical costs, two methods were used: full absorption costing and micro-costing. RESULTS: The most common complication was refractory ascites (20.2%), followed by portosystemic encephalopathy (12.5%). The mean number of admissions per patient was 1.37±3.42. Variceal hemorrhage was the complication with longest median length of stay (18 days), followed by hepatorenal syndrome (13.5 days). Hepatorenal syndrome was the costliest complication (mean cost of $3,565), followed by portosystemic encephalopathy ($2,576) and variceal hemorrhage ($1,530). CONCLUSION: The burden of chronic liver disease includes a great cost for health systems. In addition, it is likely to be even greater as a result of the insidious course of the disease.

Lista de espera para transplante hepático: impacto clínico e econômico / Waiting list for liver transplantation: clinical and economic burden

ABSTRACT Background Burden of disease is an indicator that relates to health status. United States and European epidemiological data have shown that the burden of chronic liver disease has increased significantly in recent decades. There are no studies evaluating the impact of complications of chronic liver disease on the waiting list for deceased donor liver transplantation (LTx). Objective: To determine the clinical and economic burden of complications of liver disease in wait-listed patients from the perspective of a transplant center. Methods The study retrospectively analyzed medical records of 104 patients wait-listed for deceased donor LTx from October 2012 to May 2016 and whose treatment was fully provided at the study transplant center. Clinical data were obtained from electronic medical records, while economic data were collected from a hospital management software. To allocate all direct medical costs, two methods were used: full absorption costing and micro-costing. Results: The most common complication was refractory ascites (20.2%), followed by portosystemic encephalopathy (12.5%). The mean number of admissions per patient was 1.37±3.42. Variceal hemorrhage was the complication with longest median length of stay (18 days), followed by hepatorenal syndrome (13.5 days). Hepatorenal syndrome was the costliest complication (mean cost of $3,565), followed by portosystemic encephalopathy ($2,576) and variceal hemorrhage ($1,530). Conclusion: The burden of chronic liver disease includes a great cost for health systems. In addition, it is likely to be even greater as a result of the insidious course of the disease.

RESUMO Contexto O impacto da doença é um indicador relacionado ao estado de saúde. Dados epidemiológicos norte-americanos e europeus mostraram que, nas últimas décadas, o impacto da doença hepática crônica tem aumentado significativamente. Não há estudos que avaliem o impacto das descompensações da doença hepática crônica na lista de espera para transplante hepático (TxH) com doador falecido. Objetivo: Determinar o impacto clínico e econômico das descompensações da doença hepática nos pacientes em lista de espera sob a perspectiva do centro transplantador. Métodos Foram analisados, retrospectivamente, os prontuários de 104 pacientes incluídos em lista de espera para TxH com doador falecido entre outubro de 2012 e maio de 2016 e acompanhados integralmente no centro transplantador. Dados clínicos foram obtidos do prontuário eletrônico, enquanto dados econômicos foram coletados através de software de gestão hospitalar. A apropriação dos custos médicos diretos foi realizada sob duas metodologias: custeio por absorção pleno e microcusteio. Resultados: A descompensação com maior incidência foi a ascite refratária (20,2%) seguida de encefalopatia portossistêmica (12,5%). A média de internações por paciente foi de 1,37±3,42. A hemorragia digestiva alta varicosa foi a descompensação com maior tempo mediano de internação (18 dias), seguida da síndrome hepatorrenal (13,5 dias). A descompensação mais onerosa foi a síndrome hepatorrenal (custo médio de US$ 3.565), seguida encefalopatia portossistêmica (US$ 2.576) e a hemorragia digestiva alta varicosa (US$ 1.530). Conclusão O impacto da doença hepática crônica inclui um custo importante para os sistemas de saúde. Além disso, é provável que seja ainda maior em decorrência do curso insidioso da doença.

Propensity-matched analysis of patients with intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma and hepatocellular carcinoma undergoing a liver transplant.

BACKGROUND: Cholangiocarcinoma (CC) is a rare tumor that arises from the epithelium of the bile ducts. It is classified according to anatomic location as intrahepatic, perihilar, and distal. Intrahepatic CC (ICC) is rare in patients with cirrhosis due to causes other than primary sclerosing cholangitis. Mixed hepatocellular carcinoma-CC (HCC-CC) is a rare neoplasm that shows histologic findings of both HCC and ICC within the same tumor mass. Due to the difficulties in arriving at the correct diagnosis, patients eventually undergo liver transplantation (LT) with a presumptive diagnosis of HCC on imaging when, in fact, they have ICC or HCC-CC. AIM: To evaluate the outcomes of patients with intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma on pathological examination after liver transplant. METHODS: Propensity score matching was used to analyze tumor recurrence (TR), overall mortality (OM), and recurrence-free survival (RFS) in LT recipients with pathologically confirmed ICC or HCC-CC matched 1:8 to those with HCC. Progression-free survival and overall mortality rates were computed with the Kaplan-Meier method using Cox regression for comparison. RESULTS: Of 475 HCC LT recipients, 1.7% had the diagnosis of ICC and 1.5% of HCC-CC on pathological examination of the explant. LT recipients with ICC had higher TR (46% vs 11%; P = 0.006), higher OM (63% vs 23%; P = 0.002), and lower RFS (38% vs 89%; P = 0.002) than those with HCC when matched for pretransplant tumor characteristics, as well as higher TR (46% vs 23%; P = 0.083), higher OM (63% vs 35%; P = 0.026), and lower RFS (38% vs 59%; P = 0.037) when matched for posttransplant tumor characteristics. Two pairings were performed to compare the outcomes of LT recipients with HCC-CC vs HCC. There was no significant difference between the outcomes in either pairing. CONCLUSION: Patients with ICC had worse outcomes than patients undergoing LT for HCC. The outcomes of patients with HCC-CC did not differ significantly from those of patients with HCC.

Herb-induced liver injury: Systematic review and meta-analysis.

BACKGROUND: The use of herbal supplements and alternative medicines has been increasing in the last decades. Despite popular belief that the consumption of natural products is harmless, herbs might cause injury to various organs, particularly to the liver, which is responsible for their metabolism in the form of herb-induced liver injury (HILI). AIM: To identify herbal products associated with HILI and describe the type of lesion associated with each product. METHODS: Studies were retrieved using Medical Subject Headings Descriptors combined with Boolean operators. Searches were run on the electronic databases Scopus, Web of Science, MEDLINE, BIREME, LILACS, Cochrane Library for Systematic Reviews, SciELO, Embase, and Opengray.eu. Languages were restricted to English, Spanish, and Portuguese. There was no date of publication restrictions. The reference lists of the studies retrieved were searched manually. To access causality, the Maria and Victorino System of Causality Assessment in Drug Induced Liver Injury was used. Simple descriptive analysis were used to summarize the results. RESULTS: The search strategy retrieved 5918 references. In the final analysis, 446 references were included, with a total of 936 cases reported. We found 79 types of herbs or herbal compounds related to HILI. He-Shou-Wu, Green tea extract, Herbalife, kava kava, Greater celandine, multiple herbs, germander, hydroxycut, skullcap, kratom, Gynura segetum, garcinia cambogia, ma huang, chaparral, senna, and aloe vera were the most common supplements with HILI reported. Most of these patients had complete clinical recovery (82.8%). However, liver transplantation was necessary for 6.6% of these cases. Also, chronic liver disease and death were observed in 1.5% and 10.4% of the cases, respectively. CONCLUSION: HILI is normally associated with a good prognosis, once the implied product is withdrawn. Nevertheless, it is paramount to raise awareness in the medical and non-medical community of the risks of the indiscriminate use of herbal products.

CAPACITY OF EXERCISE AND SURVIVAL IN PATIENTS WITH CIRRHOSIS WITH AND WITHOUT HEPATOPULMONARY SYNDROME AFTER LIVER TRANSPLANTATION.

BACKGROUND: Hepatopulmonary syndrome (HPS) is a complication associated with cirrhosis that may contribute to worsening exercise capacity and reduced survival after liver transplantation (LT). OBJECTIVE: To evaluate exercise capacity, complications and survival after LT in patients with cirrhosis and HPS and to compare these results with the results of patients with cirrhosis without HPS. METHODS: A prospective cohort study, consisting initially of 178 patients, of whom 90 underwent LT (42 with HPS and 48 without HPS). A previous evaluation consisted of the six-minute walk test (6MWT), an exercise test and manovacuometry. Those who underwent LT were evaluated for the mechanical ventilation time (MV), noninvasive ventilation (NIV) use, and survival two years after the procedure. In the statistical analysis, we used the Kolmogorov-Smirnov test, Student's t-test, the linear association square test, and the Kaplan-Meier survival curve. The data were analyzed with the SPSS 16.00 program and considered significant at P<0.05. RESULTS: The HPS group demonstrated a lower peak of oxygen consumption (VO2peak) (14.2±2.3 vs 17.6±2.6) P<0.001 and a shorter distance walked on the 6MWT (340.8±50.9 vs 416.5±91.4) P<0.001 before LT compared with the non-HPS group. The transplanted patients with HPS remained longer hours in MV (19.5±4.3 vs 12.5±3.3) P=0.02, required more NIV (12 vs 2) P=0.01, and had lower survival two years after the procedure (P=0.01) compared with the transplanted patients without HPS. CONCLUSION: Patients with HPS had worse exercise capacity before LT, more complications and shorter survival after this procedure than patients without HPS.

Capacidade de exercício e sobrevida de pacientes cirróticos com e sem síndrome hepatopulmonar após o transplante hepático / Capacity of exercise and survival in patients with cirrhosis with and without hepatopulmonary syndrome after liver transplantation

ABSTRACT BACKGROUND: Hepatopulmonary syndrome (HPS) is a complication associated with cirrhosis that may contribute to worsening exercise capacity and reduced survival after liver transplantation (LT). OBJECTIVE: To evaluate exercise capacity, complications and survival after LT in patients with cirrhosis and HPS and to compare these results with the results of patients with cirrhosis without HPS. METHODS: A prospective cohort study, consisting initially of 178 patients, of whom 90 underwent LT (42 with HPS and 48 without HPS). A previous evaluation consisted of the six-minute walk test (6MWT), an exercise test and manovacuometry. Those who underwent LT were evaluated for the mechanical ventilation time (MV), noninvasive ventilation (NIV) use, and survival two years after the procedure. In the statistical analysis, we used the Kolmogorov-Smirnov test, Student's t-test, the linear association square test, and the Kaplan-Meier survival curve. The data were analyzed with the SPSS 16.00 program and considered significant at P<0.05. RESULTS: The HPS group demonstrated a lower peak of oxygen consumption (VO2peak) (14.2±2.3 vs 17.6±2.6) P<0.001 and a shorter distance walked on the 6MWT (340.8±50.9 vs 416.5±91.4) P<0.001 before LT compared with the non-HPS group. The transplanted patients with HPS remained longer hours in MV (19.5±4.3 vs 12.5±3.3) P=0.02, required more NIV (12 vs 2) P=0.01, and had lower survival two years after the procedure (P=0.01) compared with the transplanted patients without HPS. CONCLUSION: Patients with HPS had worse exercise capacity before LT, more complications and shorter survival after this procedure than patients without HPS.

RESUMO CONTEXTO: A síndrome hepatopulmonar (SHP) é uma complicação associada à cirrose que pode contribuir para piora da capacidade de exercício e menor sobrevida após o transplante hepático (TxH). OBJETIVO: Avaliar a capacidade de exercício, as complicações e a sobrevida após TxH em cirróticos com SHP e comparar com os resultados de cirróticos sem esse diagnóstico. MÉTODOS: Estudo de coorte prospectivo, composto inicialmente por 178 pacientes, dos quais 90 foram submetidos ao TxH (42 com SHP e 48 sem SHP). Foi realizada uma avaliação prévia composta pelo teste de caminhada dos seis minutos (TC6M), teste ergométrico e manovacuometria. Os submetidos ao TxH tiveram avaliados o tempo de ventilação mecânica (VM), uso de ventilação não invasiva (VNI), e a sobrevida dois anos após o procedimento. Na análise estatística utilizamos os testes de Kolmogorov-Smirnov, o teste t de Student, o teste do quadrado de associação linear, a curva de sobrevida de Kaplan Meier. Os dados foram analisados no programa SPSS 16.00 sendo considerado significativo P<0,05. RESULTADOS: O grupo SHP apresentou menor pico de consumo de oxigênio (VO2pico) (14,2±2,3 vs 17,6±2,6) P<0,001, e menor distância percorrida no TC6M (340,8±50,9 vs 416,5±91,4) P<0,001 antes do TxH. Os pacientes com SHP transplantados permaneceram mais horas em VM (19,5±4,3 vs 12,5±3,3) P=0,02, necessitaram mais de VNI (12 vs 2) P=0,01, e tiveram menor sobrevida dois anos após o procedimento (P=0,01). CONCLUSÃO: Pacientes com SHP apresentaram pior capacidade de exercício antes do TxH, mais complicações e menor sobrevida após a realização desse procedimento.

HEPATOCELLULAR CARCINOMA PATIENTS ARE ADVANTAGED IN THE CURRENT BRAZILIAN LIVER TRANSPLANT ALLOCATION SYSTEM. A COMPETING RISK ANALYSIS.

BACKGROUND: In Brazil, the Model for End-Stage Liver Disease (MELD) score is used to prioritize patients for deceased donor liver transplantation (DDLT). Patients with hepatocellular carcinoma (HCC) receive standardized MELD exception points to account for their cancer risk of mortality, which is not reflected by their MELD score. OBJECTIVE: To compare DDLT rates between patients with and without HCC in Rio Grande do Sul, the Southernmost state of Brazil. METHODS: - We retrospectively studied 825 patients on the liver-transplant waiting list from January 1, 2007, to December 31, 2016, in a transplant center located in Porto Alegre, the capital of Rio Grande do Sul, to compare DDLT rates between those with and without HCC. The time-varying hazard of waiting list/DDLT was estimated, reporting the subhazard ratio (SHR) of waiting list/DDLT/dropout with 95% confidence intervals (CI). The final competing risk model was adjusted for age, MELD score, exception points, and ABO group. RESULTS: Patients with HCC underwent a transplant almost three times faster than patients with a calculated MELD score (SHR 2.64; 95% CI 2.10-3.31; P<0.001). The DDLT rate per 100 person-months was 11.86 for HCC patients vs 3.38 for non-HCC patients. The median time on the waiting list was 5.6 months for patients with HCC and 25 months for patients without HCC. CONCLUSION: Our results demonstrated that, in our center, patients on the waiting list with HCC have a clear advantage over candidates listed with a calculated MELD score.

EVALUATION AND SELECTION OF CANDIDATES FOR LIVER TRANSPLANTATION: AN ECONOMIC PERSPECTIVE.

BACKGROUND: Over the next 20 years, the number of patients on the waiting list for liver transplantation (LTx) is expected to increase by 23%, while pre-LTx costs should raise by 83%. OBJECTIVE: To evaluate direct medical costs of the pre-LTx period from the perspective of a tertiary care center. METHODS: The study included 104 adult patients wait-listed for deceased donor LTx between October 2012 and May 2016 whose treatment was fully provided at the study transplant center. Clinical and economic data were obtained from electronic medical records and from a hospital management software. Outcomes of interest and costs of patients on the waiting list were compared through the Kruskal-Wallis test. A generalized linear model with logit link function was used for multivariate analysis. P-values <0.05 were considered statistically significant. RESULTS: The costs of patients who underwent LTx ($8,879.83; 95% CI 6,735.24-11,707.27; P<0.001) or who died while waiting ($6,464.73; 95% CI 3,845.75-10,867.28; P=0.04) were higher than those of patients who were excluded from the list for any reason except death ($4,647.78; 95% CI 2,469.35-8,748.04; P=0.254) or those who remained on the waiting list at the end of follow-up. CONCLUSION: Although protocols of inclusion on the waiting list vary among transplant centers, similar approaches exist and common problems should be addressed. The results of this study may help centers with similar socioeconomic realities adjust their transplant policies.

Pacientes com carcinoma hepatocelular são favorecidos no atual sistema brasileiro de alocação de fígados para transplante. Análise de riscos competitivos / Hepatocellular carcinoma patients are advantaged in the current brazilian liver transplant allocation system. a competing risk analysis

ABSTRACT BACKGROUND: In Brazil, the Model for End-Stage Liver Disease (MELD) score is used to prioritize patients for deceased donor liver transplantation (DDLT). Patients with hepatocellular carcinoma (HCC) receive standardized MELD exception points to account for their cancer risk of mortality, which is not reflected by their MELD score. OBJECTIVE: To compare DDLT rates between patients with and without HCC in Rio Grande do Sul, the Southernmost state of Brazil. METHODS - We retrospectively studied 825 patients on the liver-transplant waiting list from January 1, 2007, to December 31, 2016, in a transplant center located in Porto Alegre, the capital of Rio Grande do Sul, to compare DDLT rates between those with and without HCC. The time-varying hazard of waiting list/DDLT was estimated, reporting the subhazard ratio (SHR) of waiting list/DDLT/dropout with 95% confidence intervals (CI). The final competing risk model was adjusted for age, MELD score, exception points, and ABO group. RESULTS: Patients with HCC underwent a transplant almost three times faster than patients with a calculated MELD score (SHR 2.64; 95% CI 2.10-3.31; P<0.001). The DDLT rate per 100 person-months was 11.86 for HCC patients vs 3.38 for non-HCC patients. The median time on the waiting list was 5.6 months for patients with HCC and 25 months for patients without HCC. CONCLUSION: Our results demonstrated that, in our center, patients on the waiting list with HCC have a clear advantage over candidates listed with a calculated MELD score.

RESUMO CONTEXTO: No Brasil, o escore MELD (Model for End-Stage Liver Disease) é utilizado para priorizar os pacientes para transplante hepático de doador falecido (THDF). Pacientes com carcinoma hepatocelular (CHC) recebem pontos de exceção padronizados pelo MELD para contrapesar o risco de mortalidade do seu câncer, que não é refletido pelo seu escore MELD. OBJETIVO: Comparar as taxas de THDF entre pacientes com e sem CHC no Rio Grande do Sul, o Estado mais ao sul do Brasil. MÉTODOS: Foram estudados retrospectivamente 825 pacientes em lista de espera de transplante de fígado entre 1 de janeiro de 2007 e 31 de dezembro de 2016 em um centro de transplantes localizado em Porto Alegre, capital do Rio Grande do Sul, para comparação das taxas de THDF entre aqueles com e sem CHC. Foi estimado o risco variável no tempo de lista de espera/THDF, com relato da taxa de sub-risco (SHR) de lista de espera/THDF/desistência com intervalos de confiança (IC) de 95%. O modelo final de risco competitivo foi ajustado para idade, escore MELD, pontos de exceção e grupo ABO. RESULTADOS: Os candidatos com CHC foram submetidos a um transplante quase três vezes mais rápido do que os pacientes com um escore MELD calculado (SHR 2,64; IC 95% 2,10-3,31; P<0,001). A taxa de THDF por 100 pessoas-mês foi de 11,86 para os pacientes com CHC vs 3,38 para os pacientes sem CHC. O tempo mediano de permanência em lista de espera foi de 5,6 meses para os pacientes com CHC e 25 meses para os pacientes sem CHC. CONCLUSÃO: Nossos resultados demonstraram que, em nosso centro, pacientes em lista de espera com CHC têm evidente vantagem sobre candidatos listados com um escore MELD calculado.

Avaliação e seleção de candidatos para transplante hepático: uma perspectiva econômica / Evaluation and selection of candidates for liver transplantation: an economic perspective

ABSTRACT BACKGROUND: Over the next 20 years, the number of patients on the waiting list for liver transplantation (LTx) is expected to increase by 23%, while pre-LTx costs should raise by 83%. OBJECTIVE: To evaluate direct medical costs of the pre-LTx period from the perspective of a tertiary care center. METHODS: The study included 104 adult patients wait-listed for deceased donor LTx between October 2012 and May 2016 whose treatment was fully provided at the study transplant center. Clinical and economic data were obtained from electronic medical records and from a hospital management software. Outcomes of interest and costs of patients on the waiting list were compared through the Kruskal-Wallis test. A generalized linear model with logit link function was used for multivariate analysis. P-values <0.05 were considered statistically significant. RESULTS: The costs of patients who underwent LTx ($8,879.83; 95% CI 6,735.24-11,707.27; P<0.001) or who died while waiting ($6,464.73; 95% CI 3,845.75-10,867.28; P=0.04) were higher than those of patients who were excluded from the list for any reason except death ($4,647.78; 95% CI 2,469.35-8,748.04; P=0.254) or those who remained on the waiting list at the end of follow-up. CONCLUSION: Although protocols of inclusion on the waiting list vary among transplant centers, similar approaches exist and common problems should be addressed. The results of this study may help centers with similar socioeconomic realities adjust their transplant policies.

RESUMO CONTEXTO: Nos próximos 20 anos, estima-se um aumento de 23% no número de pacientes em lista de espera para transplante de fígado (TxF) e de 83% nos custos no período pré-TxF. OBJETIVO: Avaliar os custos médicos diretos do período pré-TxF sob a perspectiva de um centro de atenção terciária. MÉTODOS: Foram incluídos no estudo 104 adultos em lista de espera para TxF, com doador falecido, entre outubro de 2012 e maio de 2016, tratados integralmente no centro transplantador do estudo. Dados clínicos e econômicos foram obtidos do prontuário eletrônico e do software de gestão hospitalar. Os desfechos de interesse e os custos dos pacientes em lista de espera foram comparados através do teste de Kruskal-Wallis. Um modelo linear generalizado com função de ligação logarítmica foi utilizado para a análise multivariável. Valores de P<0.05 foram considerados estatisticamente significativos. RESULTADOS: Os custos com pacientes submetidos a TxF (US$ 8.879,83; IC 95% 6.735,24-11.707,27; P<0,001) ou que morreram enquanto estavam em lista (US$ 6.464,73; IC 95% 3.845,75-10.867,28; P=0,04) foram maiores do que com pacientes excluídos da lista por qualquer motivo, exceto óbito (US$ 4.647,78; IC 95% 2.469,35-8.748,04; P=0,254) ou daqueles que permaneceram em lista de espera ao final do seguimento. CONCLUSÃO: Embora os protocolos de inclusão em lista de espera variem entre os centros transplantadores, existem condutas semelhantes e problemas comuns devem ser considerados. Os resultados deste estudo podem auxiliar os centros com realidades socioeconômicas semelhantes na adequação das suas políticas de transplante.

THE COST OF ADULT LIVER TRANSPLANTATION IN A REFERRAL CENTER IN SOUTHERN BRAZIL.

BACKGROUND: Liver transplantation (LTx) is the primary and definitive treatment of acute or chronic cases of advanced or end-stage liver disease. Few studies have assessed the actual cost of LTx categorized by hospital unit. OBJECTIVE: To evaluate the cost of LTx categorized by unit specialty within a referral center in southern Brazil. METHODS: We retrospectively reviewed the medical records of 109 patients undergoing LTx between April 2013 and December 2014. Data were collected on demographic characteristics, etiology of liver disease, and severity of liver disease according to the Child-Turcotte-Pugh (CTP) and Model for End-stage Liver Disease (MELD) scores at the time of LTx. The hospital bill was transformed into cost using the full absorption costing method, and the costs were grouped into five categories: Immediate Pretransplant Kit; Specialized Units; Surgical Unit; Intensive Care Unit; and Inpatient Unit. RESULTS: The mean total LTx cost was US$ 17,367. Surgical Unit, Specialized Units, and Intensive Care Unit accounted for 31.9%, 26.4% and 25.3% of the costs, respectively. Multivariate analysis showed that total LTx cost was significantly associated with CTP class C (P=0.001) and occurrence of complications (P=0.002). The following complications contributed to significantly increase the total LTx cost: septic shock (P=0.006), massive blood transfusion (P=0.007), and acute renal failure associated with renal replacement therapy (dialysis) (P=0.005). CONCLUSION: Our results demonstrated that the total cost of LTx is closely related to liver disease severity scores and the development of complications.

O custo do transplante hepático adulto em um centro de referência na região sul do Brasil / The cost of adult liver transplantation in a referral center in southern brazil

ABSTRACT BACKGROUND: Liver transplantation (LTx) is the primary and definitive treatment of acute or chronic cases of advanced or end-stage liver disease. Few studies have assessed the actual cost of LTx categorized by hospital unit. OBJECTIVE: To evaluate the cost of LTx categorized by unit specialty within a referral center in southern Brazil. METHODS: We retrospectively reviewed the medical records of 109 patients undergoing LTx between April 2013 and December 2014. Data were collected on demographic characteristics, etiology of liver disease, and severity of liver disease according to the Child-Turcotte-Pugh (CTP) and Model for End-stage Liver Disease (MELD) scores at the time of LTx. The hospital bill was transformed into cost using the full absorption costing method, and the costs were grouped into five categories: Immediate Pretransplant Kit; Specialized Units; Surgical Unit; Intensive Care Unit; and Inpatient Unit. RESULTS: The mean total LTx cost was US$ 17,367. Surgical Unit, Specialized Units, and Intensive Care Unit accounted for 31.9%, 26.4% and 25.3% of the costs, respectively. Multivariate analysis showed that total LTx cost was significantly associated with CTP class C (P=0.001) and occurrence of complications (P=0.002). The following complications contributed to significantly increase the total LTx cost: septic shock (P=0.006), massive blood transfusion (P=0.007), and acute renal failure associated with renal replacement therapy (dialysis) (P=0.005). CONCLUSION: Our results demonstrated that the total cost of LTx is closely related to liver disease severity scores and the development of complications.

RESUMO CONTEXTO: O transplante hepático (TxH) é o principal e definitivo tratamento de casos agudos ou crônicos de doenças hepáticas avançadas ou terminais. Poucos estudos têm avaliado o custo real do TxH categorizado por setores hospitalares. OBJETIVO: Avaliar o custo do TxH categorizado por especialidade da unidade em um centro de referência na região sul do Brasil. MÉTODOS: Analisamos retrospectivamente os prontuários de 109 pacientes submetidos a TxH entre abril de 2013 e dezembro de 2014. Foram coletados dados sobre características demográficas, etiologia da doença hepática e gravidade da doença hepática de acordo com os escores Child-Turcotte-Pugh (CTP) e Model for End-stage Liver Disease (MELD) no momento do TxH. A conta hospitalar foi transformada em custo pelo método de custeio por absorção integral, e os custos foram agrupados em cinco categorias: Kit Pré-Transplante Imediato; Unidades Especializadas; Centro Cirúrgico; Unidade de Terapia Intensiva; e Unidade de Internação. RESULTADOS: O custo médio total do TxH foi de US$ 17.367. O Centro Cirúrgico, as Unidades Especializadas e a Unidade de Terapia Intensiva responderam por 31,9%, 26,4% e 25,3% dos custos, respectivamente. A análise multivariada demonstrou que o custo total do TxH se associou significativamente ao escore CTP classe C (P=0,001) e ao desenvolvimento de intercorrências (P=0,002). As seguintes intercorrências contribuíram para aumentar significativamente o custo do TxH: choque séptico (P=0,006), politransfusão sanguínea (P=0,007) e insuficiência renal aguda associada à terapia renal substitutiva (diálise) (P=0,005). CONCLUSÃO: Nossos resultados demonstraram que o custo total do TxH guarda uma estreita relação com os escores de gravidade da doença hepática e com o desenvolvimento de intercorrências.

Sofosbuvir, ribavirin and pegylated interferon for a daclatasvir-resistent genotype 3 hepatitis C virus: case report and review.

Chronic Hepatitis C relapse after liver transplantation can lead to graft failure within a short time period. The high efficacy and good safety profile of direct-acting antivirals has led to consensual recommendations for using interferon-free treatment after liver transplantation. However, pegylated interferon may still be required for genotype 3 non-responders. We treated a liver graft recipient with grade 1 fibrosis in the biopsy with daclatasvir and sofosbuvir for 12 weeks. He did not respond and progressed to grade 3 fibrosis. Lacking other options, we obtained a sustained virological response with pegylated interferon, ribavirin and sofosbuvir for 12 weeks. The combination of pegylated interferon, ribavirin and sofosbuvir is a viable option after the failure of direct acting antivirals in economically disadvantaged countries.

Low platelet count: Predictor of death and graft loss after liver transplantation.

BACKGROUND: The impact of platelets on liver transplantation (LT) is well recognized, but not completely understood. Platelets exert dichotomous effects on the graft and on the patient. On the one hand, they are essential for primary hemostasis and tissue repair and regeneration. On the other hand, they support ischemia/reperfusion injury and inflammatory processes. Recent evidence has shown a new role for platelet count (PC) in predicting outcomes after LT. AIM: To evaluate if low PC is a predictor of short- and long-term outcomes after LT. METHODS: Four hundred and eighty consecutive LT patients were retrospectively assessed. PC from the preoperative to the seventh postoperative day (POD) were considered. C-statistic analysis defined the ideal cutoff point for PC. Cox regression was performed to check whether low PC was a predictor of death, retransplantation or primary changes in graft function within one year after LT. RESULTS: The highest median PC was 86 × 109/L [interquartile range (IQR) = 65-100 × 109/L] on seventh POD, and the lowest was 51 × 109/L (IQR = 38-71 × 109/L) on third POD. The C-statistic defined a PC < 70 × 109/L on fifth POD as the ideal cutoff point for predicting death and retransplantation. In the multivariate analysis, platelets < 70 × 109/L on 5POD was an independent risk factor for death at 12 mo after LT [hazard ratio (HR) = 2.01; 95% confidence interval (CI) 1.06-3.79; P = 0.031]. In the Cox regression, patients with PC < 70 × 109/L on 5POD had worse graft survival rates up to one year after LT (HR = 2.76; 95%CI 1.52-4.99; P = 0.001). CONCLUSION: PC < 70 × 109/L on 5POD is an independent predictor of death in the first year after LT. These results are in agreement with other studies that indicate that low PC after LT is associated with negative outcomes.

Tiempo para el trasplante como predictor de la recurrencia del Carcinoma Hepatocelular después del trasplante hepático: Un estudio de cohorte retrospectivo / Time to transplantation as predictor of hepatocellular recurrence after liver transplantation: a retrospective cohort study

Hepatocellular recurrence after liver transplantation (LTx) is a major cause of morbidity and mortality. We aimed to investigate the association between waiting time and hepatocellular carcinoma (HCC) recurrence in patients undergoing LTx for HCC. We studied 250 patients who underwent LTx between 2007-2015. Survival and recurrence curves were calculated according to the Kaplan­Meier method and compared by the log-rank test. Univariate hazard ratios for predictors of post-LTx HCC recurrence were determined by Cox proportional hazards regressions. There were no signifcant differences in recurrence rates when stratifed by wait time to transplant. There were also no signifcant differences in rates of recurrence when the short (< 165 days) and long (> 335 days) wait-time groups were combined, although in this pooled group the 1-year and 5-year cumulative likelihoods of HCC recurrence were higher than in the group with a wait time of 165-334 days. Other predictors of recurrence were microvascular invasion, explant beyond Milan Brazil criteria and tumor diameter ≥ 2.6. This study found no association between wait time to transplantation and recurrence rates in patients who received LTx for HCC and confrmed that variables associated with tumor biology are associated with HCC recurrence.

La recurrencia hepatocelular después del trasplante de hígado (TxH) es una de las principales causas de morbi-mortalidad. Nuestro objetivo fue investigar la asociación entre el tiempo de espera y la recurrencia del carcinoma hepatocelular (CHC) en pacientes sometidos a TxH para CHC. Estudiamos 250 pacientes que se sometieron a TxH entre 2007-2015. Las curvas de supervivencia y recurrencia se calcularon de acuerdo con el método Kaplan-Meier y se compararon mediante logrank test. Las proporciones de riesgo univariados para los predictores de recurrencia posterior al TxH fueron determinadas por las regresiones proporcionales de riesgos de Cox. No hubo diferencias signifcativas en las tasas de recurrencia cuando se estratifcaron por el tiempo de espera para el trasplante. Tampoco hubo diferencias signifcativas en las tasas de recurrencia cuando se combinaron los grupos de tiempo de espera cortos (< 165 días) y largos (> 335 días), aunque en este ultimo grupo las probabilidades acumuladas de recurrencia de HCC de 1 año y 5 años fueron mayores que en el grupo con un tiempo de espera de 165-334 días. Otros predictores de recurrencia fueron la invasión microvascular, nu cumplir con criterios de Milán Brasil y el diámetro del tumor ≥2,6. Este estudio no encontró ninguna asociación entre el tiempo de espera para trasplante y las tasas de recurrencia en pacientes que recibieron LTx para HCC y confrmó que las variables asociadas con la biología tumoral están asociadas con la recurrencia del HCC.

Cardiac stress testing and coronary artery disease in liver transplantation candidates: Meta-analysis.

AIM: To evaluate the diagnostic value of dobutamine stress echocardiography (DSE) and myocardial perfusion scintigraphy (MPS) in predicting coronary artery disease (CAD) in cirrhotic patients listed for liver transplantation (LT), using invasive coronary angiography (ICA) as gold-standard. METHODS: Retrieval of studies was based on Medical Subject Headings and Health Sciences Descriptors, which were combined using Boolean operators. Searches were run on the electronic databases Scopus, Web of Science, EMBASE, MEDLINE (PubMed), BIREME (Biblioteca Regional de Medicina), LILACS (Latin American and Caribbean Health Sciences Literature), Cochrane Library for Systematic Reviews and Opengray.eu. There was no language or date of publication restrictions. The reference lists of the studies retrieved were searched manually. RESULTS: The search strategy retrieved 322 references for DSE and 90 for MPS. In the final analysis, 10 references for DSE and 10 for MPS were included. Pooled sensitivity was 28% and 61% for DSE and MPS and specificity was 82% and 74%, for diagnosis of CAD using ICA as gold-standard, respectively. CONCLUSION: DSE and MPS do not have adequate sensitivity for determination of whether CAD is present, despite having significant specificity.

Liver transplantation and alcoholic liver disease: History, controversies, and considerations.

Alcohol consumption accounts for 3.8% of annual global mortality worldwide, and the majority of these deaths are due to alcoholic liver disease (ALD), mainly alcoholic cirrhosis. ALD is one of the most common indications for liver transplantation (LT). However, it remains a complicated topic on both medical and ethical grounds, as it is seen by many as a "self-inflicted disease". One of the strongest ethical arguments against LT for ALD is the probability of relapse. However, ALD remains a common indication for LT worldwide. For a patient to be placed on an LT waiting list, 6 mo of abstinence must have been achieved for most LT centers. However, this "6-mo rule" is an arbitrary threshold and has never been shown to affect survival, sobriety, or other outcomes. Recent studies have shown similar survival rates among individuals who undergo LT for ALD and those who undergo LT for other chronic causes of end-stage liver disease. There are specific factors that should be addressed when evaluating LT patients with ALD because these patients commonly have a high prevalence of multisystem alcohol-related changes. Risk factors for relapse include the presence of anxiety or depressive disorders, short pre-LT duration of sobriety, and lack of social support. Identification of risk factors and strengthening of the social support system may decrease relapse among these patients. Family counseling for LT candidates is highly encouraged to prevent alcohol consumption relapse. Relapse has been associated with unique histopathological changes, graft damage, graft loss, and even decreased survival in some studies. Research has demonstrated the importance of a multidisciplinary evaluation of LT candidates. Complete abstinence should be attempted to overcome addiction issues and to allow spontaneous liver recovery. Abstinence is the cornerstone of ALD therapy. Psychotherapies, including 12-step facilitation therapy, cognitive-behavioral therapy, and motivational enhancement therapy, help support abstinence. Nutritional therapy helps to reverse muscle wasting, weight loss, vitamin deficiencies, and trace element deficiencies associated with ALD. For muscular recovery, supervised physical activity has been shown to lead to a gain in muscle mass and improvement of functional activity. Early LT for acute alcoholic hepatitis has been the subject of recent clinical studies, with encouraging results in highly selected patients. The survival rates after LT for ALD are comparable to those of patients who underwent LT for other indications. Patients that undergo LT for ALD and survive over 5 years have a higher risk of cardiorespiratory disease, cerebrovascular events, and de novo malignancy.