Performance of pre-transplant criteria in prediction of hepatocellular carcinoma progression and waitlist dropout.

BACKGROUND & AIM: Liver transplantation (LT) selection models for hepatocellular carcinoma (HCC) have not been proposed to predict waitlist dropout because of tumour progression. The aim of this study was to compare the alpha-foetoprotein (AFP) model and other pre-LT models in their prediction of HCC dropout. METHODS: A multicentre cohort study was conducted in 20 Latin American transplant centres, including 994 listed patients for LT with HCC from 2012 to 2018. Longitudinal tumour characteristics, and patterns of progression were recorded at time of listing, after treatments and at last follow-up over the waitlist period. Competing risk regression models were performed, and model's discrimination was compared estimating Harrell's adapted c-statistics. RESULTS: HCC dropout rate was significantly higher in patients beyond (24% [95% CI 16-28]) compared to those within Milan criteria (8% [95% IC 5%-12%]; p < .0001), with a SHR of 3.01 [95% CI 2.03-4.47]), adjusted for waiting list time and bridging therapies (c-index 0.63 [95% CI 0.57; 0.69). HCC dropout rates were higher in patients with AFP scores >2 (adjusted SHR of 3.17 [CI 2.13-4.71]), c-index of 0.71 (95% CI 0.65-0.77; p = .09 vs Milan). Similar discrimination power for HCC dropout was observed between the AFP score and the Metroticket 2.0 model. In patients within Milan, an AFP score >2 points discriminated two populations with a higher risk of HCC dropout (SHR 1.68 [95% CI 1.08-2.61]). CONCLUSIONS: Pre-transplant selection models similarly predicted HCC dropout. However, the AFP model can discriminate a higher risk of dropout among patients within Milan criteria.

Glutathione-related genetic polymorphisms are associated with mercury retention and nephrotoxicity in gold-mining settings of a Colombian population.

Mercury (Hg) vapor can produce kidney injury, where the proximal tubule region of the nephron is the main target of the Hg-induced oxidative stress. Hg is eliminated from the body as a glutathione conjugate. Thus, single nucleotide polymorphisms (SNPs) in glutathione-related genes might modulate the negative impact of this metal on the kidneys. Glutathione-related SNPs were tested for association with levels of Hg and renal function biomarkers between occupationally exposed (n = 160) and non-exposed subjects (n = 121). SNPs were genotyped by TaqMan assays in genomic DNA samples. Total mercury concentration was measured in blood, urine and hair samples. Regression analyses were performed to estimate the effects of SNPs on quantitative traits. Alleles GCLM rs41303970-T and GSTP1 rs4147581-C were significantly overrepresented in the exposed compared with the non-exposed group (P < 0.01). We found significant associations for GCLM rs41303970-T with higher urinary clearance rate of Hg (ß = 0.062, P = 0.047), whereas GCLC rs1555903-C was associated with lower levels of estimated glomerular filtration rate in the non-exposed group (eGFR, ß = - 3.22, P = 0.008) and beta-2-microglobulin in the exposed group (ß-2MCG, ß = - 19.32, P = 0.02). A SNP-SNP interaction analysis showed significant epistasis between GSTA1 rs3957356-C and GSS rs3761144-G with higher urinary levels of Hg in the exposed (ß = 0.13, P = 0.04) but not in the non-exposed group. Our results suggest that SNPs in glutathione-related genes could modulate the pathogenesis of Hg nephrotoxicity in our study population by modulating glutathione concentrations in individuals occupationally exposed to this heavy metal.

Recurrence of hepatocellular carcinoma after liver transplantation: Prognostic and predictive factors of survival in a Latin American cohort.

BACKGROUND & AIM: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) has a poor prognosis, and the adjusted effect of different treatments on post-recurrence survival (PRS) has not been well defined. This study aims to evaluate prognostic and predictive variables associated with PRS. METHODS: This Latin American multicenter retrospective cohort study included HCC patients who underwent LT between the years 2005-2018. We evaluated the effect of baseline characteristics at time of HCC recurrence diagnosis and PRS (Cox regression analysis). Early recurrences were those occurring within 12 months of LT. To evaluate the adjusted treatment effect for HCC recurrence, a propensity score matching analysis was performed to assess the probability of having received any specific treatment for recurrence. RESULTS: From a total of 1085 transplanted HCC patients, the cumulative incidence of recurrence was 16.6% (CI 13.5-20.3), with median time to recurrence of 13.0 months (IQR 6.0-26.0). Factors independently associated with PRS were early recurrence (47.6%), treatment with sorafenib and surgery/trans-arterial chemoembolization (TACE). Patients who underwent any treatment presented "early recurrences" less frequently, and more extrahepatic metastasis. This unbalanced distribution was included in the propensity score matching, with correct calibration and discrimination (receiving operator curve of 0.81 [CI 0.72;0.88]). After matching, the adjusted effect on PRS for any treatment was HR of 0.2 (0.10;0.33); P < .0001, for sorafenib therapy HR of 0.4 (0.27;0.77); P = .003, and for surgery/TACE HR of 0.4 (0.18;0.78); P = .009. CONCLUSION: Although early recurrence was associated with worse outcome, even in this population, systemic or locoregional treatments were associated with better PRS.

Liver transplantation for hepatocellular carcinoma: impact of expansion criteria in a multicenter cohort study from a high waitlist mortality region.

This study aimed to compare liver transplantation (LT) outcomes and evaluate the potential rise in numbers of LT candidates with hepatocellular carcinoma (HCC) of different allocation policies in a high waitlist mortality region. Three policies were applied in two Latin American cohorts (1085 HCC transplanted patients and 917 listed patients for HCC): (i) Milan criteria with expansion according to UCSF downstaging (UCSF-DS), (ii) the AFP score, and (iii) restrictive policy or Double Eligibility Criteria (DEC; within Milan + AFP score ≤2). Increase in HCC patient numbers was evaluated in an Argentinian prospective validation set (INCUCAI; NCT03775863). Expansion criteria in policy A showed that UCSF-DS [28.4% (CI 12.8-56.2)] or "all-comers" [32.9% (CI 11.9-71.3)] had higher 5-year recurrence rates compared to Milan, with 10.9% increase in HCC patients for LT. The policy B showed lower recurrence rates for AFP scores ≤2 points, even expanding beyond Milan criteria, with a 3.3% increase. Patients within DEC had lower 5-year recurrence rates compared with those beyond DEC [13.3% (CI 10.1-17.3) vs 24.2% (CI 17.4-33.1; P = 0.0006], without significant HCC expansion. In conclusion, although the application of a stricter policy may optimize the selection process, this restrictive policy may lead to ethical concerns in organ allocation (NCT03775863).

Direct-Acting Antivirals and Hepatocellular Carcinoma: No Evidence of Higher Wait-List Progression or Posttransplant Recurrence.

The association between direct-acting antivirals (DAAs) and hepatocellular carcinoma (HCC) wait-list progression or its recurrence following liver transplantation (LT) remains uncertain. We evaluated the impact of DAAs on HCC wait-list progression and post-LT recurrence. This Latin American multicenter retrospective cohort study included HCC patients listed for LT between 2012 and 2018. Patients were grouped according to etiology of liver disease: hepatitis C virus (HCV) negative, HCV+ never treated with DAAs, and HCV+ treated with DAAs either before or after transplantation. Multivariate competing risks models were conducted for both HCC wait-list progression adjusted by a propensity score matching (pre-LT DAA effect) and for post-LT HCC recurrence (pre- or post-LT DAA effect). From 994 included patients, 50.6% were HCV-, 32.9% were HCV+ never treated with DAAs, and 16.5% were HCV+ treated with DAAs either before (n = 66) or after LT (n = 98). Patients treated with DAAs before LT presented similar cumulative incidence of wait-list tumor progression when compared with those patients who were HCV+ without DAAs (26.2% versus 26.9%; P = 0.47) and a similar HCC-related dropout rate (12.1% [95% CI, 0.4%-8.1%] versus 12.9% [95% CI, 3.8%-27.2%]), adjusted for baseline tumor burden, alpha-fetoprotein values, HCC diagnosis after listing, bridging therapies, and by the probability of having received or not received DAAs through propensity score matching (subhazard ratio [SHR], 0.9; 95% CI, 0.6-1.6; P = 0.95). A lower incidence of posttransplant HCC recurrence among HCV+ patients who were treated with pre- or post-LT DAAs was observed (SHR, 0.7%; 95% CI, 0.2%-4.0%). However, this effect was confounded by the time to DAA initiation after LT. In conclusion, in this multicenter cohort, HCV treatment with DAAs did not appear to be associated with an increased wait-list tumor progression and HCC recurrence after LT.

A changing etiologic scenario in liver transplantation for hepatocellular carcinoma in a multicenter cohort study from Latin America.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of hepatocellular carcinoma (HCC) and liver transplantation (LT). Our study focused on changing trends of liver related HCC etiologies during the last years in Latin America. METHODS: From a cohort of 2761 consecutive adult LT patients between 2005 and 2012 in 17 different centers, 435 with HCC were included. Different periods including years 2005-2006, 2007-2008, 2009-2010 and 2011-2012 were considered. Etiology of liver disease was confirmed in the explant. RESULTS: Participating LT centers per country included 2 from Brazil (n=191), 5 transplant programs from Argentina (n=98), 2 from Colombia (n=65), 4 from Chile (n=49), 2 from Mexico (n=12), and 1 from Peru (n=11) and Uruguay (n=9). Chronic hepatitis C infection was the leading cause of HCC in the overall cohort (37%), followed by HBV (25%) and alcoholic liver disease (17%). NAFLD and cryptogenic cirrhosis accounted for 6% and 7%, respectively. While HCV decreased from 48% in 2005-06 to 26% in 2011-12, NAFLD increased from 1.8% to 12.8% during the same period, accounting for the third cause of HCC. This represented a 6-fold increase in NAFLD-HCC, whereas HCV had a 2-fold decrease. Patients with NAFLD were older, had lower pre-LT serum AFP values and similar 5-year survival and recurrence rates than non-NAFLD. CONCLUSION: There might be a global changing figure regarding etiologies of HCC in Latin America. This epidemiological change on the incidence of HCC in the world, although it has been reported, should still be confirmed in prospective studies.

Results of Liver Transplantation for Hepatocellular Carcinoma in a Multicenter Latin American Cohort Study.

BACKGROUND AND AIMS: Heterogeneous data has been reported regarding liver transplantation (LT) for hepatocellular carcinoma (HCC) in Latin America. We aimed to describe treatment during waiting list, survival and recurrence of HCC after LT in a multicenter study from Latin America. MATERIAL AND METHODS: Patients with HCC diagnosed prior to transplant (cHCC) and incidentally found in the explanted liver (iHCC) were included. Imaging-explanted features were compared in cHCC (non-discordant if pre and post-LT were within Milan, discordant if pre-LT was within and post-LT exceeding Milan). RESULTS: Overall, 435 patients with cHCC and 92 with iHCC were included. At listing, 81% and 91% of cHCC patients were within Milan and San Francisco criteria (UCSF), respectively. Five-year survival and recurrence rates for cHCC within Milan, exceeding Milan/within UCSF and beyond UCSF were 71% and 16%; 66% and 26%; 46% and 55%, respectively. Locoregional treatment prior to LT was performed in 39% of cHCC within Milan, in 53% beyond Milan/within UCSF and in 83% exceeding UCSF (p < 0.0001). This treatment difference was not observed according to AFP values (≤100, 44%; 101-1,000, 39%, and > 1,000 ng/mL 64%; p = 0.12). Discordant imaging-explanted data was observed in 29% of cHCC, showing lower survival HR 2.02 (CI 1.29; 3.15) and higher recurrence rates HR 2.34 when compared to AFP <100 ng/mL. Serum AFP > 1,000 ng/mL at listing was independently associated with a higher 5-year recurrence rate and a HR of 3.24 when compared to AFP <100 ng/mL. CONCLUSION: Although overall results are comparable to other regions worldwide, pre-LT treatment not only considering imaging data but also AFP values should be contemplated during the next years.

Hepatocyte Growth Factor Reduces Free Cholesterol-Mediated Lipotoxicity in Primary Hepatocytes by Countering Oxidative Stress.

Cholesterol overload in the liver has shown toxic effects by inducing the aggravation of nonalcoholic fatty liver disease to steatohepatitis and sensitizing to damage. Although the mechanism of damage is complex, it has been demonstrated that oxidative stress plays a prominent role in the process. In addition, we have proved that hepatocyte growth factor induces an antioxidant response in hepatic cells; in the present work we aimed to figure out the protective effect of this growth factor in hepatocytes overloaded with free cholesterol. Hepatocytes from mice fed with a high-cholesterol diet were treated or not with HGF, reactive oxygen species present in cholesterol overloaded hepatocytes significantly decreased, and this effect was particularly associated with the increase in glutathione and related enzymes, such as γ-gamma glutamyl cysteine synthetase, GSH peroxidase, and GSH-S-transferase. Our data clearly indicate that HGF displays an antioxidant response by inducing the glutathione-related protection system.

Liver transplantation for hepatocellular carcinoma: evaluation of the alpha-fetoprotein model in a multicenter cohort from Latin America.

BACKGROUND & AIMS: The French alpha-fetoprotein (AFP) model has recently shown superior results compared to Milan criteria (MC) for prediction of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) in European populations. The aim of this study was to explore the predictive capacity of the AFP model for HCC recurrence in a Latin-American cohort. METHODS: Three hundred twenty-seven patients with HCC were included from a total of 2018 patients transplanted at 15 centres. Serum AFP and imaging data were both recorded at listing. Predictability was assessed by the Net Reclassification Improvement (NRI) method. RESULTS: Overall, 82 and 79% of the patients were within MC and the AFP model respectively. NRI showed a superior predictability of the AFP model against MC. Patients with an AFP score >2 points had higher risk of recurrence at 5 years Hazard Ratio (HR) of 3.15 (P = 0.0001) and lower patient survival (HR = 1.51; P = 0.03). Among patients exceeding MC, a score ≤2 points identified a subgroup of patients with lower recurrence (5% vs 42%; P = 0.013) and higher survival rates (84% vs 45%; P = 0.038). In cases treated with bridging procedures, following restaging, a score >2 points identified a higher recurrence (HR 2.2, P = 0.12) and lower survival rate (HR 2.25, P = 0.03). A comparative analysis between HBV and non-HBV patients showed that the AFP model performed better in non-HBV patients. CONCLUSIONS: The AFP model could be useful in Latin-American countries to better select patients for LT in subgroups presenting with extended criteria. However, particular attention should be focused on patients with HBV.

Hepatitis C screening in the general population.

BACKGROUND: A significant number of patients infected with hepatitis C virus remain unaware of their infection, as this is a silent disease for many years. Patients are frequently detected at advance stages of the disease. OBJECTIVE: To identify the prevalence and viremic stage of hepatitis C among a general population cohort. METHODS: Anti-hepatitis C virus detection and viral RNA were offered without cost to individuals who voluntarily considered it relevant to be examined, as part of the World Hepatitis Day annually from 2007-2014. RESULTS: A total of 32,945 individuals were analyzed; 57% were female and 43% male. Of them, 75.7% were between 21-50 years old. In 59%, the sample was obtained at their work place and in 41% at the facilities of 12 private laboratories. Anti-hepatitis C virus was positive in 194 patients (0.58%), of which 129 (66%) were confirmed positive by polymerase chain reaction. The overall prevalence of viremic cases in the sample was 0.39%. CONCLUSIONS: Adequate estimation of the prevalence of anti-hepatitis C virus and viremic population, not only among high-risk groups but also in the general population, is central to the allocation of resources in an effort to reduce the consequences of the disease.

Trypanosoma cruzi: prevalencia y factores de riesgo de seropositividad en donantes de sangre del Hemocentro y Unidad de Aféresis, Valledupar, Colombia, 2013-2014 / Trypanosoma cruzi: prevalence and risk factors for seropositivity in blood donors of Hemocentro y Unidad de Aféresis, Valledupar, Colombia, 2013-2014

Introducción: La transmisión de Trypanosoma cruzi por transfusiones sanguíneas representa la segundalínea de infección después de la vectorial, lo que hace necesario identificar algunas particularidadessocioepidemiológicas en los donantes que permitan predecir la infección por Trypanosoma cruzi. Objetivo: Determinar la prevalencia de anticuerpos anti-Trypanosoma cruzi y los factores de riesgo de seropositividad en donantes de sangre voluntarios del Hemocentro y Unidad de Aféresis de Valledupar, Colombia. Materiales y métodos: Se realizó un estudio descriptivo de corte transversal en 170 donantes de sangre voluntarios reclutados entre 2013 y 2014. La detección de anticuerpos IgG anti-Trypanosoma cruzi se realizó mediante pruebas serológicas. Las variables que predicen la seropositividadpara Trypanosoma cruzi se indagaron mediante un cuestionario socioepidemiológico y un posterioranálisis bivariado y de regresión logística...

Introduction: Transmission of Trypanosoma cruzi through blood transfusions represents the second most frequent mechanism after the vectorial transmission. Therefore, it is necessary to identify some socioepidemiological characteristics that allow predicting the Trypanosoma cruzi infection on the donors. Objective: To determine the prevalence of anti-Trypanosoma cruzi and risk factors for seropositivity in voluntary blood donors at the Hemocentro y Unidad de Aferesis de Valledupar, Colombia. Materialsand methods: A descriptive cross-sectional study was conducted in 170 volunteer blood donors recruited between 2013 and 2014. Detection of IgG antibodies anti-Trypanosoma cruzi was performed by serological tests. The inquiry about the predictors of seropositivity for Trypanosoma cruzi was made through a socioepidemiological questionnaire, followed by a bivariate analysis and logistic regression...

Trasplante hepático ortotópico. Experiencia en Monterrey, N. L. [simposio] / Orthotopic liver transplantation. Experience in Monterrey, NL, Mexico [symposium]

Objetivo. Estudiar el curso clínico y la supervivencia de 4 pacientes con trasplante hepático ortotópico (THO) realizados en Monterrey, N.L. Antecedentes. El programa de THO en humanos se inicio en 1991 en el Hospital Universitario de la UANL en Monterrey. Resultados. Tres pacientes pediátricos con diagnóstico de cirrosis hepáticos por atresia de vías biliares y un paciente adulto con cirrosis hepática alcohólica, todos con clasificación C Child-Pugh. El trasplante realizado fue completo en dos pacientes. Uno pediátrico y un adulto, reducido en dos pacientes pediátricos, uno de éstos con injerto de donador vivo relacionado. El esquema de inmunosupresión fue a base de ciclosporina, esteroides y azatriopina. Complicaciones: hemorragia abdominal; hipertensión arterial; colangitis y colestasis; insuficiencia renal aguda; neumonía, datos de rechazo, sepsis y fuga biliar en dos casos, respectivamente y pancreatitis aguda en un caso. Sobrevida: límites de 16 horas a 3 años con 5 meses. Conclusiones. El THO en pacientes con enfermedades terminales del hígado es una terapéutica quirúrgica moderna capaz de rehabilitar y prolongar la sobrevida de estos pacientes. La factibilidad de THO reducido con donadores vivos constituye una opción ante la escasez de órganos