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.

Role of the phase angle in the prognosis of the cirrhotic patient: 15 years of follow-up.

BACKGROUND: In 2019, cirrhosis accounted for 2.4% of global deaths. The projection for 2030 is an increase in this index. In recent years, hospitalization costs have escalated by 36% for compensated cirrhosis and 24% for decompensated cirrhosis. Therefore, it is necessary to identify a tool capable of predicting the mortality of these patients according to their clinical condition and consequently extending their survival time. Different studies have shown that the phase angle (PA) can be a feasible method in clinical practice, with the potential to guide assertive patient management in the therapeutic of chronic liver disease. AIM: To evaluate the prognostic role of PA in cirrhotic patients over a 15-year follow-up period. METHODS: Retrospective cohort study with 129 cirrhotic patients of both sexes over 18 years old. Diagnosis of cirrhosis by liver biopsy. The first year of data collection was 2007, and data regarding outcomes was collected in 2023. Data were gathered from medical records, such as esophageal varices (EV), EV bleeding, ascites, spontaneous bacterial peritonitis (SBP), encephalopathy, laboratory findings and PA. The cut-off value for the PA was 5.4°, a value described in 2012 by Fernandes et al for 129 patients evaluated in this study and the cut-off points for the Brazilian population presented in percentiles (P), as described by Mattiello et al. The mortality was assessed using the PA percentile through Kaplan-Meier curves and multivariate binary logistic regression models. RESULTS: Patients were divided into two groups according to the PA 5.4th (PA > 5.4°, n = 40; PA ≤ 5.4°, n = 89) PA percentile (< P50, n = 56; ≥ P50 n = 73). The percentile classification was more accurate in identifying long-term deaths than the 5.4º PA. Patients with < P50 had a higher number of relevant complications such as ascites, SBP, liver encephalopathy and HCC. PA is strongly correlated with serum albumin (P < 0.001), International Normalized Ratio (P = 0.01), total bilirubin (P = 0.02) and direct bilirubin (P = 0.003). PA is correlated with survival time (P < 0.001) and length of stay (P = 0.02). Logistic regression analysis shows that an increase of 1° in PA enlarges the cirrhotic patient's chance of survival by 17.7%. CONCLUSION: PA is a good predictor of morbidity and mortality for cirrhotic patients. The PA by percentile showed greater sensitivity in predicting mortality compared to the cut-off point of 5.4º.

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.].

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.

Exercício na reabilitação física de cirróticos: um estudo piloto randomizado / Exercise in the physical rehabilitation of cirrotics: a randomized pilot study

ABSTRACT Background: Physical exercise delays the sarcopenic process and can reverse the loss of muscle strength, improve quality of life and prognosis in cirrhotic patients. Objective: The aim was to verify the effects of face-to-face versus home aerobic exercise on the variables fatigue, respiratory and peripheral muscle strength, functional capacity and quality of life in patients with compensated cirrhosis. Methods: Patients were selected by convenience, stratified and randomized into supervised face-to-face exercise (n=13) and home exercise without daily supervision (n=12). Patients were submitted to a program of aerobic physical exercises, with progressive duration of 30 to 50 minutes, twice a week for twelve weeks. Before starting the program and every four weeks, all patients in both groups were assessed for fatigue (fatigue severity scale), respiratory (Pimáx and Pemáx) and peripheral (concentric quadriceps peak torque) muscle strength, functional capacity (6-minute walking distance) and quality of life (Short Form-36 Health Survey questionnaire). Results: The face-to-face group showed reduced fatigue (P<0.001), increased inspiratory (P<0.001), expiratory (P<0.001) and peripheral (P<0.001) muscle strength of the 6MWD (P<0.001) and improved quality of life. The home group showed no significant improvement in these variables. Conclusion: A face-to-face program of moderate aerobic exercise in patients with compensated cirrhosis reduces fatigue, improves functional capacity and quality of life and increases respiratory and peripheral muscle strength. Home physical exercises do not cause the same adaptive effects in this population.

RESUMO Contexto: O exercício físico retarda o processo sarcopênico e pode reverter a perda de força muscular, melhorar a qualidade de vida e prognóstico em cirróticos. Objetivo: O objetivo foi verificar os efeitos do exercício aeróbico presencial versus domiciliar sobre variáveis fadiga, força muscular respiratória e periférica, capacidade funcional e qualidade de vida em pacientes com cirrose compensada. Métodos: Os pacientes foram selecionados por conveniência, estratificados e randomizados em exercício presencial supervisionado (n=13) e exercício domiciliar sem supervisão diária (n=12). Os pacientes foram submetidos a um programa de exercícios físicos aeróbicos, com duração progressiva de 30 minutos a 1 hora, duas vezes por semana durante 12 semanas. Antes de iniciar o programa e a cada 4 semanas, todos os pacientes de ambos os grupos foram avaliados quanto à fadiga (escala de gravidade da fadiga), força muscular respiratória (Pimáx e Pemáx) e periférica (pico de torque do quadríceps concêntrico), capacidade funcional (distância caminhada de 6 minutos) e qualidade de vida (questionário Short Form-36 Health Survey). Resultados: O grupo presencial apresentou redução da fadiga (P<0,001), aumento da força muscular inspiratória (P<0,001), expiratória (P<0,001), e periférica (P<0,001), da DTC6 (P<0,001) e melhora da qualidade de vida. O grupo domiciliar não apresentou melhora significativa nessas variáveis. Conclusão: Um programa presencial de exercícios aeróbicos moderados em pacientes com cirrose compensada reduz a fadiga, melhora a capacidade funcional e qualidade de vida, aumenta força muscular respiratória e periférica. Os exercícios físicos domiciliares não provocam os mesmos efeitos adaptativos nesta população.

Melatonin Attenuates Inflammation, Oxidative Stress, and DNA Damage in Mice with Nonalcoholic Steatohepatitis Induced by a Methionine- and Choline-Deficient Diet.

Nonalcoholic steatohepatitis (NASH) is a disease with a high incidence worldwide, but its diagnosis and treatment are poorly managed. In this study, NASH pathophysiology and DNA damage biomarkers were investigated in mice with NASH treated and untreated with melatonin (MLT). C57BL/6 mice were fed a methionine- and choline-deficient (MCD) diet for 4 weeks to develop NASH. Melatonin was administered at 20 mg/kg during the last 2 weeks. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured, and hepatic tissue was dissected for histological analysis, evaluation of lipoperoxidation, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as nuclear factor-erythroid 2 (Nrf2), tumor necrosis factor alpha (TNF-α), inducible nitric oxide synthase (iNOS), and transforming growth factor beta (TGF-ß) expression by immunohistochemistry. DNA damage was evaluated using Comet assay, while a micronucleus test in bone marrow was performed to assess the genomic instability associated with the disease. Melatonin decreased AST and ALT, liver inflammatory processes, balloonization, and fibrosis in mice with NASH, decreasing TNF-α, iNOS, and TGF-ß, as well as oxidative stress, shown by reducing lipoperoxidation and intensifying Nrf2 expression. The SOD and GPx activities were increased, while CAT was decreased by treatment with MLT. Although the micronucleus frequency was not increased in mice with NASH, a protective effect on DNA was observed with MLT treatment in blood and liver tissues using Comet assay. As conclusions, MLT slows down the progression of NASH, reducing hepatic oxidative stress and inflammatory processes, inhibiting DNA damage via anti-inflammatory and antioxidant actions.

Sarcopenia, oxidative stress and inflammatory process in muscle of cirrhotic rats - Action of melatonin and physical exercise.

Sarcopenia is one of the most common features of cirrhosis, contributing to morbidity and mortality in this population. We aimed to evaluate the effect of melatonin (MLT) and exercise (EX) on the quadriceps muscle in rats with biliary cirrhosis induced by bile duct ligation (BDL). We used 48 males (mean weight = 300 g), divided into eight groups. A 20 mg/Kg MLT dose was administered via i.p. (1 x daily), and the EX, the animals were set to swim in couples for 10 min each day. Upon completion, blood, liver, and quadriceps samples were taken for analysis. In the liver enzymes analysis and comet assay results, a reduction was observed in the groups treated with MLT with/or EX comparing to the BDL group. In the evaluation of substances that react to thiobarbituric acid (TBARS), nitric oxide levels (NO), and tumor necrosis factor-alpha levels (TNF-α), there was a significant increase in the BDL group and a reduction in the treated groups. In the activity of the superoxide dismutase enzyme (SOD) and interleukin-10 levels (IL-10) concentrations, there was a significant increase in the treated groups of the BDL group. Histological analysis revealed muscle hypotrophy in the BDL group in comparison with the control group (CO) and increased muscle mass in the treated groups. There was an increase in weight gain and phase angle in the groups treated with MLT with/or EX comparing to the BDL group. We suggest that treatments may contribute to the reduction of muscle changes in cirrhotic patients.

Resting energy expenditure in cirrhotic patients with and without hepatocellular carcinoma.

BACKGROUND: The diagnosis of malnutrition in patients with independent hepatocellular carcinoma (HCC) varies from 20% to 50%, is related to important complications and has a direct impact on the prognosis. Determination of the resting energy expenditure (REE) has become an important parameter in this population, as it allows therapeutic adjustments to recover their nutritional status. The REE in cirrhosis, with and without HCC, is not clearly defined, and requires the identification and definition of the best nutritional approach. AIM: To evaluate the REE of patients with cirrhosis, with and without HCC. METHODS: This is a prospective observational study evaluating the REE of 118 patients, 33 with cirrhosis and hepatocellular carcinoma and a control group of 85 patients with cirrhosis without HCC, using indirect calorimetry (IC), bioimpedance, and predictive formulas. RESULTS: The REE determined by IC in cirrhotic patients with HCC was 1643 ± 364 and in those without HCC was 1526 ± 277 (P = 0.064). The REE value as assessed by bioimpedance was 1529 ± 501 for those with HCC and 1660 ± 385 for those without HCC (P = 0.136). When comparing the values of REE determined by IC and predictive formulas in cirrhotics with HCC, it was observed that only the formulas of the Food and Agriculture Organization (FAO)/World Health Organization (WHO) (1985) and Cunningham (1980) presented values similar to those determined by IC. When comparing the REE values determined by IC and predictive formulas in cirrhotics without HCC, it was observed that the formulas of Schofield (1985), FAO/WHO (1985), WHO (2000), Institute of Medicine (IOM) (2005) and Katch and McArdie (1996) presented values similar to those determined by IC. CONCLUSION: The FAO/WHO formula (1985) could be used for cirrhotic patients with or without HCC; as it is the one with the values closest to those obtained by IC in these cirrhotic patients.

Phase angle and non-alcoholic fatty liver disease before and after bariatric surgery.

BACKGROUND: Obesity is a global health problem that is continuing to increase in the young population. In Brazil, the frequency of obesity in 2018 was 19.8%. Several comorbidities are directly associated with obesity, such as non-alcoholic fatty liver disease (NAFLD), which is considered the most common liver disorder in Western countries and affects up to 46% of adults. Bariatric surgery is effective in treating obesity and can improve NAFLD; however, the effect of bariatric surgery on body composition, phase angle (PA), and improving NAFLD needs to be further studied. AIM: To analyze the PA in the postoperative period of bariatric surgery and to correlate it with changes in body composition and liver disease. METHODS: This study is a retrospective cohort study of the analysis of the medical records of patients undergoing bariatric surgery in a reference center of a teaching hospital in Porto Alegre over a 2-year period. Patients older than 18 years whose record contained all information relevant to the study were included. The data analyzed were body composition and PA through electrical bioimpedance and NAFLD through liver biopsy in the pre- and postoperative period. The level of significance adopted for the statistical analyses was 5%. RESULTS: We evaluated 379 patients with preoperative data. Regarding PA, 169 patients were analyzed, and 33 patients had liver biopsy pre- and postoperatively with NAFLD information. In total, 79.4% were female, with a mean age of 39.1 ± 10.6 years. The average body mass index (BMI) was 45.9 ± 7.5 kg/m². The PA showed a mean of 5.8 ± 0.62° in the preoperative period and a significant reduction in the postoperative period. A postoperative reduction in body composition data (skeletal muscle mass, fat percentage, fat mass, body cell mass, BMI and visceral fat area) was shown as well. Regarding liver disease, all patients presented a reduction in the degrees and stages of liver disease in the postoperative period, and some had no degree of liver disease at all. CONCLUSION: PA decreased after bariatric surgery, with a direct correlation with weight loss and changes in body composition. The decrease in PA was not correlated with the improvement in NAFLD.

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.

Nutritional diagnosis of patients with hepatocellular carcinoma: what is the best method?

INTRODUCTION: Introduction: malnutrition is a frequent finding among cancer patients. Despite its prognostic significance, there are still few studies evaluating the nutritional status of patients with hepatocellular carcinoma (HCC). Objectives: to evaluate the nutritional status of patients with HCC by different methods. Methods: patients with HCC were evaluated in an outpatient clinic at the Hospital Santa Casa de Misericórdia de Porto Alegre. The methods used for the nutritional assessment were body mass index (BMI), tricipital skinfold (TSF), arm circumference (AC), arm muscle circumference (AMC), hand grip strength (HGS), adductor pollicis muscle (APM), patient-generated subjective global assessment (PG-SGA) and phase angle (PA). Results: forty-three patients with HCC were evaluated; all of them were cirrhotic. The mean age was 64.0 ± 5.8 years and the prevalent gender was male (72.1%). APM, PA, PG-SGA and AMC were the most sensitive methods for the diagnosis of malnutrition. There was a negative correlation between TSF and Child-Pugh score (p = 0.004) and a positive correlation between APM and BCLC stage (Barcelona Clinic Liver Cancer Group) (p = 0.006). Conclusions: there was high variation in the diagnosis of malnutrition among the methods studied. APM, AMC, PA and PG-SGA can be indicated as tools of choice in the nutritional assessment of the HCC patient because they were the most sensitive methods in the diagnosis of malnutrition. TSF and APM correlate with disease severity.

INTRODUCCIÓN: Introducción: la desnutrición es un hallazgo frecuente entre pacientes oncológicos. A pesar de su significancia pronóstica, todavía son escasos los estudios que evalúan el estado nutricional de pacientes con carcinoma hepatocelular (CHC). Objetivos: evaluar el estado nutricional de pacientes con CHC por diferentes métodos. Métodos: se evaluaron pacientes con CHC en seguimiento ambulatorio en el Hospital Santa Casa de Misericordia de Porto Alegre. Los métodos empleados para la evaluación nutricional fueron índice de masa corporal (IMC), pliegue cutáneo tricipital (PCT), circunferencia del brazo (CB), circunferencia muscular del brazo (CMB), fuerza del apretón de manos (FAM), músculo aductor del pulgar (MAP), evaluación subjetiva global producida por el paciente (ASG-PPP) y ángulo de fase (AF). Resultados: se evaluaron 43 pacientes con CHC, todos cirróticos. El promedio de edad fue de 64,0 ± 5,8 años y el sexo prevalente, el masculino (72,1%). MAP, AF, ASG-PPP y CMB fueron los métodos más sensibles para el diagnóstico de desnutrición. Se observó una correlación negativa entre la PCT y la puntuación Child-Pugh (p = 0,004) y una correlación positiva entre MAP y la estadificación BCLC (p = 0,006). Conclusiones: hubo gran variación en el diagnóstico de desnutrición entre los métodos estudiados. MAP, CMB, AF y ASG-PPP se pueden indicar como herramientas de elección en la evaluación nutricional del paciente con CHC por haber sido los métodos más sensibles en el diagnóstico de desnutrición. PCT y MAP se correlacionan con la gravedad de la enfermedad.

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.

THE CORRELATION OF NECK CIRCUMFERENCE AND INSULIN RESISTANCE IN NAFLD PATIENTS.

BACKGROUND: Insulin resistance, especially that induced by obesity, plays a central role in the development of non-alcoholic fatty liver disease. Although the evaluation of overweight patients is important, the nutritional assessment tools used in clinical practice have limitations. Neck circumference (NC), from this, becomes a viable and low-cost alternative, which seems to be related to the accumulation of fat in the hepatic tissue. OBJECTIVE: To evaluate the association between NC and metabolic alterations in patients with non- alcoholic fatty liver disease. METHODS: A cross-sectional study performed in 82 patients, of whom 76 underwent liver biopsy. We performed weight, height, abdominal circumference and NC measures. Values of NC ≥42 cm and ≥36 cm were considered as altered for men and women, respectively. Laboratory tests and liver biopsy result were collected in the participants' charts. We evaluated fasting blood glucose levels, insulin, glycosylated hemoglobin, triglycerides, total cholesterol, high density lipoprotein (HDL-C), low density lipoprotein (LDL-C), ferritin, alkaline phosphatase, gamma glutamyltransferase, albumin, total bilirubin, direct bilirubin, glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase and the HOMA-IR index. RESULTS: We evaluated eighty-two patients. Patients with altered NC had increased body mass index (P=0.043), abdominal circumference (P=0.007), insulin (P=0.003) and HOMA-IR (P=0.029) when compared to those with adequate NC. NC was significantly correlated with reduced levels of high-density cholesterol (HDL-C) in men (r= -042, P<0.05), increased insulin levels in men and female (rs=0.47; P<0.05 and rs=0.51; P<0.01, respectively), as well as higher HOMA-IR index both males (rs=0.49; P<0.01) and female (rs=0.30; P<0.05). There was no significant association between NC and liver outcomes (r=0.145; P=0.36). CONCLUSION: NC is associated with the HOMA-IR index in patients with non-alcoholic fatty liver disease. NC can be used in the screening of insulin resistance in these patients, considering that insulin resistance plays a key role in the progression of the disease.

Correlação entre a circunferência do pescoço e resistência a insulina em pacientes com DHGNA / The correlation of neck circumference and insulin resistance in nafld patients

ABSTRACT BACKGROUND: Insulin resistance, especially that induced by obesity, plays a central role in the development of non-alcoholic fatty liver disease. Although the evaluation of overweight patients is important, the nutritional assessment tools used in clinical practice have limitations. Neck circumference (NC), from this, becomes a viable and low-cost alternative, which seems to be related to the accumulation of fat in the hepatic tissue. OBJECTIVE: To evaluate the association between NC and metabolic alterations in patients with non- alcoholic fatty liver disease. METHODS: A cross-sectional study performed in 82 patients, of whom 76 underwent liver biopsy. We performed weight, height, abdominal circumference and NC measures. Values of NC ≥42 cm and ≥36 cm were considered as altered for men and women, respectively. Laboratory tests and liver biopsy result were collected in the participants' charts. We evaluated fasting blood glucose levels, insulin, glycosylated hemoglobin, triglycerides, total cholesterol, high density lipoprotein (HDL-C), low density lipoprotein (LDL-C), ferritin, alkaline phosphatase, gamma glutamyltransferase, albumin, total bilirubin, direct bilirubin, glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase and the HOMA-IR index. RESULTS: We evaluated eighty-two patients. Patients with altered NC had increased body mass index (P=0.043), abdominal circumference (P=0.007), insulin (P=0.003) and HOMA-IR (P=0.029) when compared to those with adequate NC. NC was significantly correlated with reduced levels of high-density cholesterol (HDL-C) in men (r= -042, P<0.05), increased insulin levels in men and female (rs=0.47; P<0.05 and rs=0.51; P<0.01, respectively), as well as higher HOMA-IR index both males (rs=0.49; P<0.01) and female (rs=0.30; P<0.05). There was no significant association between NC and liver outcomes (r=0.145; P=0.36). CONCLUSION: NC is associated with the HOMA-IR index in patients with non-alcoholic fatty liver disease. NC can be used in the screening of insulin resistance in these patients, considering that insulin resistance plays a key role in the progression of the disease.

RESUMO CONTEXTO: A resistência à insulina, em especial a induzida pela obesidade, desempenha papel central no desenvolvimento da doença hepática gordurosa não alcoólica (DHGNA). Embora seja importante a avaliação de pacientes com excesso de peso, as ferramentas de avaliação nutricional utilizadas na prática clínica apresentam limitações. A circunferência do pescoço, a partir disso, torna-se uma alternativa viável e de baixo custo, a qual parece estar relacionada ao acúmulo de gordura no tecido hepático. OBJETIVO: Avaliar a associação entre a circunferência do pescoço (CP) e as alterações metabólicas em pacientes com DHGNA. MÉTODOS: Estudo transversal realizado em 82 pacientes, dos quais 76 foram submetidos à biópsia hepática. Foram realizadas as medidas de peso, altura, circunferência abdominal e CP. Valores de CP ≥42 cm e ≥36 cm foram considerados alterados para homens e mulheres, respectivamente. Os exames laboratoriais e o resultado da biópsia hepática foram coletados dos prontuários dos participantes. Foram avaliados os níveis glicêmicos em jejum, insulina, hemoglobina glicosilada, triglicerídeos, colesterol total, lipoproteína de alta densidade (HDL-C), lipoproteína de baixa densidade (LDL-C), ferritina, fosfatase alcalina, gama glutamiltransferase, albumina, bilirrubina total, bilirrubina direta, transaminase glutâmico-oxalacética, transaminase glutâmico-pirúvica e o índice HOMA-IR. RESULTADOS: Foram avaliados 82 pacientes. Os pacientes com CP alterada apresentaram aumento do índice de massa corporal (P=0,043), circunferência abdominal (P=0,007), insulina (P=0,003) e HOMA-IR (P=0,029) quando comparados àqueles com CP adequada. A CP foi significativamente correlacionada com níveis reduzidos de colesterol de alta densidade (HDL-C) em homens (r= -042, P<0,05), aumento dos níveis de insulina em homens e mulheres (rs=0,47, P<0,05 e rs = 0,51; P<0,01, respectivamente), bem como maior índice HOMA-IR, tanto do sexo masculino (rs=0,49; P<0,01) quanto do feminino (rs=0,30; P<0,05). Não houve associação significativa entre CP e os desfechos hepáticos (r=0,145, P=0,36). CONCLUSÃO: A CP está associada com o índice HOMA-IR em pacientes com DHGNA. A CP pode ser utilizada no rastreamento da resistência à insulina nesses pacientes, considerando que a resistência à insulina desempenha um papel fundamental na progressão da doença.

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.

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.

Propriedade psicométrica da escala de severidade de fadiga e correlação com depressão e qualidade de vida em cirróticos / Psychometric property of fatigue severity scale and correlation with depression and quality of life in cirrhotics

ABSTRACT BACKGROUND: Fatigue is a common complaint in cirrhotic patients and may be considered a debilitating symptom with negative impact on quality of life. Research on its etiology and treatment has been hampered by the lack of relevant and reproducible measures of fatigue. OBJECTIVE: To evaluate the psychometric properties of the Fatigue Severity Scale (FSS) in cirrhotic patients and to correlate with depressive symptomatology and quality of life. METHODS: Cross-sectional study with a convenience sample of 106 cirrhotic patients, aged between 18 and 70 years, both genders, literate, pre and post liver transplantation in outpatient follow-up. Internal consistency, reproducibility, discriminant validity, criterion validity, construct validity, responsiveness criterion, depressive symptomatology and quality of life were evaluated through questionnaires between January and October 2015. RESULTS: The mean age was 54.75±9.9 years, 65.1% male and 32.1% of the sample had cirrhosis due to hepatitis C virus. The mean FSS score was 4.74±1.64. Cronbach's alpha was 0.93, and the Intraclass Correlation Coefficient was 0.905 (95% CI: 0.813-0.952). For discriminant validity, FSS differentiated scores from different groups (P=0.009) and presented a correlation with the Modified Fatigue Impact Scale (r=0.606, P=0.002). FSS correlated significantly and positively with depressive symptomatology and correlated negatively with the SF-36 domains for construct validity. For responsiveness, no significant changes were observed in the fatigue scores in the pre and post-liver transplantation periods (P=0.327). CONCLUSION: FSS showed good psychometric performance in the evaluation of fatigue in patients with cirrhosis. Fatigue presented a strong correlation with depressive symptomatology and quality of life.

RESUMO CONTEXTO: A fadiga é uma queixa comum em pacientes cirróticos e pode ser considerada um sintoma debilitante com impacto negativo na qualidade de vida. A investigação sobre a sua etiologia e tratamento tem sido dificultada pela falta de medidas relevantes e reprodutíveis da fadiga. OBJETIVO: Avaliar as propriedades psicométricas da Escala de Gravidade da Fadiga (FSS) em pacientes cirróticos e correlacionar com sintomatologia depressiva e qualidade de vida. MÉTODOS: Estudo transversal com amostra de conveniência de 106 pacientes cirróticos, com idade entre 18 e 70 anos, ambos os sexos, alfabetizados, pré e pós-transplante hepático em acompanhamento ambulatorial. Foram avaliados: consistência interna, reprodutibilidade, validade discriminante, validade de critério, validade de construto, critério de responsividade, sintomatologia depressiva e qualidade de vida através de questionários, entre janeiro e outubro de 2015. RESULTADOS: A média de idade foi 54,75±9,9 anos, 65,1% do sexo masculino e 32,1% da amostra apresentava cirrose pelo vírus da hepatite C. O escore médio no FSS foi de 4,74±1,64. O alfa de Cronbach foi de 0,93, e o coeficiente de correlação intraclasse foi de 0,905 (IC 95%: 0,813-0,952). Para validade discriminante, o FSS diferenciou escores de grupos distintos (P=0,009) e apresentou correlação com a Escala de Impacto de Fadiga Modificada (r=0,606, P=0,002). O FSS se correlacionou significativamente e positivamente com sintomatologia depressiva e, negativamente com os domínios SF-36 para a validade de construto. Para responsividade, não foram observadas alterações significativas nos escores de fadiga nos períodos de transplante pré e pós-fígado (P=0,327). CONCLUSÃO: O FSS mostrou bom desempenho psicométrico na avaliação da fadiga em pacientes com cirrose. A fadiga apresentou forte correlação com sintomatologia depressiva e qualidade de vida.

Ventilatory support and hospital stay after liver transplant in cirrhotic patients with hepatopulmonary syndrome / Suporte ventilatório e tempo de hospitalização após transplante hepático em cirróticos com síndrome hepatopulmonar

ABSTRACT Objective To compare mechanical ventilation time, need for non-invasive ventilation, length of intensive care unit stay, and hospital stay after liver transplant in cirrhotic patients with and with no diagnosis of hepatopulmonary syndrome. Methods This was a prospective cohort study with a convenience sample of 178 patients (92 with hepatopulmonary syndrome) who were diagnosed as alcoholic or hepatitis C virus cirrhosis. The statistical analysis included Kolmogorov-Smirnov test and Students t test. Data were analyzed using SPSS version 16.0, and p values <0.05 were considered significant. Results Out of 178 patients, 90 underwent transplant (48 with no hepatopulmonary syndrome). The Group diagnosed with Hepatopulmonary Syndrome had longer mechanical ventilation time (19.5±4.3 hours versus 12.5±3.3 hours; p=0.02), an increased need for non-invasive ventilation (12 versus 2; p=0.01), longer intensive care unit stay (6.7±2.1 days versus 4.6±1.5 days; p=0.02) and longer hospital stay (24.1±4.3 days versus 20.2±3.9 days; p=0.01). Conclusion Cirrhotic patients Group diagnosed with Hepatopulmonary Syndrome had higher mechanical ventilation time, more need of non-invasive ventilation, as well as longer intensive care unit and hospital stay.

RESUMO Objetivo Comparar tempo de ventilação mecânica, necessidade de uso de ventilação não invasiva, tempo de permanência na unidade de terapia intensiva e tempo de hospitalização após transplante hepático em cirróticos com e sem diagnóstico de síndrome hepatopulmonar. Métodos Estudo de coorte prospectiva com amostra de conveniência composta por 178 pacientes (92 com síndrome hepatopulmonar) com diagnóstico de cirrose por álcool ou pelo vírus da hepatite C. A análise estatística foi realizada por meio do teste Kolmogorov-Smirnov e do teste t de Student. Os dados foram analisados pelo programa SPSS versão 16.0, e valores de p<0,05 foram considerados significantes. Resultados Dos 178 pacientes, 90 foram transplantados (48 sem síndrome hepatopulmonar). O Grupo com Síndrome Hepatopulmonar apresentou maior tempo de ventilação mecânica (19,5±4,3 horas versus 12,5±3,3 horas; p=0,02), maior necessidade de uso de ventilação não invasiva (12 versus 2; p=0,01), maior permanência na unidade de terapia intensiva (6,7±2,1 dias versus 4,6±1,5 dias; p=0,02) e maior tempo de hospitalização (24,1±4,3 dias versus 20,2±3,9 dias; p=0,01). Conclusão O Grupo com Síndrome Hepatopulmonar apresentou maiores tempo de ventilação mecânica, necessidade de uso de ventilação não invasiva, permanência na unidade de terapia intensiva e tempo de hospitalização.

Ductular reaction, cytokeratin 7 positivity, and gamma-glutamyl transferase in multistage hepatocarcinogenesis in rats.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is characterized by multistage formation. The presence of ductular reaction, cytokeratin 7 positivity (PCK7), and increased levels of gamma glutamyltransferase (γGT) has been observed during liver carcinogenesis and contribute to tumor progression. Our goal was to evaluate the ductular reaction in multistage carcinogenesis and to correlate PCK7 and γGT levels with tumor incidence, histological characteristics, liver DNA damage index, and the expression of oxidative stress proteins. HCC was induced in 24 male Wistar rats weighing 145-150 g by chronic and intermittent exposure to 50 or 100 mg/kg diethylnitrosamine (DEN). Six control animals received only vehicle. Blood was collected to determine hepatic enzyme levels. Animals were divided into three groups: control (CO), precancerous lesions (PL), and advanced HCC. Liver samples were obtained for immunohistochemical analyses and the measurement of protein expression. Statistical analyses included Tukey's test and Pearson's correlation analyses. We observed an extensive ductular reaction in advanced HCC and a strong correlation between PCK7 and levels of γGT and the poor prognosis and aggressiveness of HCC. The extent of PCK7 and high γGT levels were associated with overexpression of inducible nitric oxide synthase (iNOS) and heat shock factor protein 1 (HSF-1). However, PCK7 and γGT levels were negatively correlated with protein expression of nuclear factor erythroid 2-related factor 2 (NRF2) and inducible heat shock protein 70 (iHSP70). These findings suggest that ductular reaction is involved in the progression of multistage hepatocarcinogenesis.

Alteration of taste buds in experimental cirrhosis. Is there correlation with human hypogeusia? / Alteração de paladar em um modelo experimental de cirrose. Existe correlação com hipogeusia humana?

ABSTRACT Background The inherent complications of cirrhosis include protein-calorie malnutrition and micronutrient deficiencies.Changes in taste are detrimental to the nutritional status, and the mechanism to explain these changes is not well documented in the cirrhotic patients. Objective To evaluate the taste buds of cirrhotic rats. Methods Fourteen male Wistar rats were evaluated. After 16 weeks, the liver was removed to histologically diagnose cirrhosis, and blood was collected to perform liver integrity tests. The tongue was removed for histological examination and immunohistochemistry using antibodies against protein gene product PGP 9.5 and the sweet taste receptors T1R2 and T1R3. Morphological changes were determined by scanning electron microscopy. Serum zinc levels were measured. Results The cirrhotic animals, but not the control animals, exhibited zinc deficiency. In both groups, there was positive immunoreactivity for type II and III cells and T1R2 receptors. The cirrhotic animals had no immunoreactivity for T1R3 receptors. Scanning electron microscopy analysis of the cirrhotic group revealed a uniform tapering of the gustatory papillae. Conclusion In conclusion the experimental cirrhosis model mimicked the biochemical and histological parameters of human cirrhosis, therefore enabling a study of the gustatory papillae and taste buds.

RESUMO Contexto As complicações inerentes de cirrose incluem a desnutrição proteico-calórica e deficiências de micronutrientes. Alterações no paladar são prejudiciais para o estado nutricional e o mecanismo para explicar essas mudanças não é bem documentada nos pacientes cirróticos. Objetivo Avaliar as papilas gustativas de ratos cirróticos. Métodos Foram avaliados 14 ratos Wistar machos. Após 16 semanas, o fígado foi removido para diagnosticar histologicamente cirrose, e o sangue foi colhido para efetuar testes de integridade hepática. A língua foi removida para exame histológico e imuno-histoquímica utilizando anticorpos contra o gene da proteína PGP 9.5 e os receptores de sabor doce T1R2 e T1R3. As alterações morfológicas foram determinadas por microscopia eletrônica de varredura e os níveis de zinco no soro foram medidos. Resultados Os animais cirróticos, em relação aos animais controle, apresentaram deficiência de zinco significativa. Em ambos os grupos, houve imunorreatividade positiva para o tipo II e células III e receptores T1R2. Os animais cirróticos não tinham imunoreactividade para receptores T1R3. Microscopia eletrônica de varredura do grupo cirrótico revelou um afilamento uniforme das papilas gustativas. Conclusão O modelo de cirrose experimental imitou os parâmetros bioquímicos e histológicos de cirrose humana, portanto, permitindo um estudo das papilas gustativas e paladar.