Twenty-year follow-up of an outbreak of hepatitis C in a small rural town of Argentina: The O'Brien Project.

INTRODUCTION AND OBJECTIVES: In 1999, a population-based survey showed a 5.6 % (102/1832) prevalence of HCV infection in O'Brien, a small rural town of Argentina. The aim of this study was to assess the impact of screening, clinical evaluation and antiviral therapy on elimination of HCV after 20 years of follow-up. PATIENTS AND METHODS: HCV+ subjects (n=102) underwent clinical, biochemical and histological evaluation to assess the presence and severity of liver disease. Antiviral therapy included pegylated interferon + ribavirin in 2005 and direct antiviral agents from 2017. RESULTS: All viremic subjects (n=84) had genotype 1b with 90%-97.5% sequence homology scores, suggesting the existence of a common source of infection (use of unsafe injections administered by the same health professional). Liver biopsy (n=55) showed chronic hepatitis in all patients. The prevalence of cirrhosis was 28% overall (29/102) and 34.5% among viremic patients. Sustained virological response (SVR) was obtained in 20/34 (59%) patients treated with interferon. From 2005 to 2017, when oral antivirals became available 37/50 untreated patients died. Median age of this group in 2005 was 67 years. Six interferon non-responders and five naive subjects received direct antiviral agents and all developed SVR. Only 1/31 patient (3.2%) with SVR died and none developed decompensated cirrhosis or HCC. In 2019, a new population-based study showed that the prevalence of HCV in O'Brien decreased 20-fold, from 5.6% to 0.28% (3/1070). CONCLUSIONS: Despite the high mortality rate precluding timely access to direct antiviral agents, the O'Brien Project is a good example of HCV micro-elimination studies.

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).

Argentinian clinical practice guideline for surveillance, diagnosis, staging and treatment of hepatocellular carcinoma.

The A.A.E.E.H has developed this guideline for the best care of patients with hepatocellular carcinoma (HCC) from Argentina. It was done from May 2018 to March 2020. Specific clinical research questions were systematically searched. The quality of evidence and level of recommendations were organized according to GRADE. HCC surveillance is strongly recommended with abdominal ultrasound (US) every six months in the population at risk for HCC (cirrhosis, hepatitis B or hepatitis C); it is suggested to add alpha-feto protein (AFP) levels in case of inexeperienced sonographers. Imaging diagnosis in patients at risk for HCC has high specificity and tumor biopsy is not mandatory. The Barcelona Clinic Liver Cancer algorithm is strongly recommended for HCC staging and treatment-decision processes. Liver resection is strongly recommended for patients without portal hypertension and preserved liver function. Composite models are suggested for liver transplant selection criteria. Therapies for HCC with robust clinical evidence include transarterial chemoembolization (TACE) and first to second line systemic treatment options (sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab). Immunotherapy with nivolumab and pembrolizumab has failed to show statistical benefit but the novel combination of atezolizumab plus bevacizumab has recently shown survival benefit over sorafenib in frontline.

Calibración y validación de la Razón Internacional Normatizada (RIN) en pacientes cirróticos / Calibration and Validation of the International Normalized Ratio (INR) in Cirrhotic Patients

El MELD es un modelo pronóstico de score matemático usado para priorizar los pacientes en lista de espera para trasplante hepático, incluye resultados de creatinina, bilirrubina y tiempo de protrombina expresado como RIN. La disparidad en el score MELD como resultado de la variabilidad interlaboratorio de los componentes de la formula nos lleva a cuestionar la validez del mismo como herramienta de medición objetiva para la locación del órgano. El motivo de utilizar el MELD se basa en la presunción que el score debería ser igual en distintos lugares, si los métodos utilizados para medir las distintas variables llegaran al mismo resultado numérico. La evidencia muestra que la metodología utilizada para las mediciones puede influenciar en el cálculo del MELD identificando al RIN como la variable más importante. Esta variabilidad está dada por la distinta procedencia biológica de las tromboplastinas y de su ISI el cual refleja la capacidad de respuesta de la tromboplastina a la disminución de los factores de coagulación dependientes de la vitamina k. El RIN estandariza el tiempo de protrombina durante la anticoagulación oral, su uso se extendió para estandarizar el tiempo de protrombina en la enfermedad hepática y se incluyó en los modelos pronósticos como el MELD. Sin embrago los mecanismos de prolongación del tiempo de protrombina en la enfermedad hepática difieren de aquellos implicados en la anticoagulación oral y las tromboplastinas difieren en su sensibilidad para detectar las variaciones en los diferentes mecanismos. Tripodi y Velez han propuesto que los valores de ISI para las distintas tromboplastinas deberían ser calculados con plasmas de pacientes cirróticos y así calcular el RIN hepático lo que resolvería la variabilidad relacionada al RIN en el cálculo del MELD.

MELD is a prognostic model from amathematical score used to prioritize patients on a waiting list for liver transplantation and includes creatinine, bilirubin and prothrombin time expressed as an INR. The disparity in the MELD score, as a result of interlaboratory variability of the formula components, has lead us to question its validity as an objective measuring tool to localize the organ. The reason to use the MELD is based on the assumption that the score should be the same through different places, if methods used to measure the different variables reached the same numerical results. The evidence shows that the methods used in measuring can affect the MELD assessment by identifying the INR as the most important variable. This variability is caused by the different biological origin of the thromboplastins and their ISI, which reflects the thromboplastin's capacity of response to the decrease of vitamin K-dependent coagulation factors. The INR standardizes the prothrombin time during oral coagulation; its use was extended to standardize the prothrombin time in liver disease and was included in prognostic models like MELD. However, the mechanisms to extend the prothrombin time in liver disease are different from those involved in oral anticoagulation and the sensitivity of thromboplastins differ when detecting the variations in the different mechanisms. Tripodi and Velez have proposed that the ISI values for the different thromboplastins should be calculated on the basis of plasma from cirrhotic patients and thus the liver IRN should be calculated as well, which would resolve the variability associated to the IRN in calculating the MELD.

Hepatitis C virus infection in Argentina: Burden of chronic disease.

AIM: To estimate the progression of the hepatitis C virus (HCV) epidemic and measure the burden of HCV-related morbidity and mortality. METHODS: Age- and gender-defined cohorts were used to follow the viremic population in Argentina and estimate HCV incidence, prevalence, hepatic complications, and mortality. The relative impact of two scenarios on HCV-related outcomes was assessed: (1) increased sustained virologic response (SVR); and (2) increased SVR and treatment. RESULTS: Under scenario 1, SVR raised to 85%-95% in 2016. Compared to the base case scenario, there was a 0.3% reduction in prevalent cases and liver-related deaths by 2030. Given low treatment rates, cases of hepatocellular carcinoma and decompensated cirrhosis decreased < 1%, in contrast to the base case in 2030. Under scenario 2, the same increases in SVR were modeled, with gradual increases in the annual diagnosed and treated populations. This scenario decreased prevalent infections 45%, liver-related deaths 55%, liver cancer cases 60%, and decompensated cirrhosis 55%, as compared to the base case by 2030. CONCLUSION: In Argentina, cases of end stage liver disease and liver-related deaths due to HCV are still growing, while its prevalence is decreasing. Increasing in SVR rates is not enough, and increasing in the number of patients diagnosed and candidates for treatment is needed to reduce the HCV disease burden. Based on this scenario, strategies to increase diagnosis and treatment uptake must be developed to reduce HCV burden in Argentina.

Fibrosis progression in maintenance liver transplant patients with hepatitis C recurrence: a randomised study of everolimus vs. calcineurin inhibitors.

BACKGROUND & AIMS: Robust clinical data evaluating fibrosis progression in hepatitis C virus (HCV) liver transplant patients receiving an mTOR inhibitor vs. calcineurin inhibitor (CNI) are lacking. To evaluate fibrosis progression in maintenance liver transplant patients receiving everolimus- or CNI-based immunosuppression. METHODS: In a randomised, multicentre, open-label study, 43 maintenance liver transplant patients with recurrent HCV infection were randomised to continue CNI-based immunosuppression or switch to everolimus. RESULTS: For patients with biopsy data at month 12, mean Ishak-Knodell fibrosis score at baseline was 2.6 ± 0.9 (n = 14) with everolimus vs. 1.9 ± 1.1 (n = 18) with CNI (P = 0.043), and 1.9 ± 1.2 vs. 2.2 ± 1.3 at month 12. Ishak-Knodell fibrosis score decreased from baseline to month 12 by a mean of -0.7 ± 1.1 with everolimus, but increased by 0.2 ± 1.2 with CNI (P = 0.046). No acute rejection or graft losses occurred up to month 12. Estimated GFR at month 12 was 65.6 ml/min/1.73 m² with everolimus and 62.2 ml/min/1.73 m² with CNI [mean difference 3.4 ml/min/1.73 m² compared to CNI control group, 95% CI -4.9, 11.8 ml/min/1.73 m², P = 0.411 (analysis of covariance adjusting for baseline GFR)]. Adverse events occurred in 95.5% of everolimus patients and 71.4% of CNI patients (serious adverse events 31.8% and 0.0%, respectively). Adverse events led to everolimus discontinuation in five patients (22.7%). CONCLUSIONS: This exploratory study suggests that conversion from CNI to everolimus reduces progression of liver fibrosis, and preserves renal function without jeopardising efficacy in liver transplant recipients with recurrent HCV, but is associated with a higher incidence of adverse events and serious adverse events. These preliminary findings merit examination in a larger trial.

Improved waiting-list outcomes in Argentina after the adoption of a model for end-stage liver disease-based liver allocation policy.

In July 2005, Argentina became the first country after the United States to introduce the Model for End-Stage Liver Disease (MELD) for organ allocation. In this study, we investigated waiting-list (WL) outcomes (n = 3272) and post-liver transplantation (LT) survival in 2 consecutive periods of 5 years before and after the implementation of a MELD-based allocation policy. Data were obtained from the database of the national institute for organ allocation in Argentina. After the adoption of the MELD system, there were significant reductions in WL mortality [28.5% versus 21.9%, P < 0.001, hazard ratio (HR) = 1.57, 95% confidence interval (CI) = 1.37-1.81] and total dropout rates (38.6% versus 29.1%, P < 0.001, HR = 1.31, 95% CI = 1.16-1.48) despite significantly less LT accessibility (57.4% versus 50.7%, P < 0.001, HR = 1.53, 95% CI = 1.39-1.68). The annual number of deaths per 1000 patient-years at risk decreased from 273 in 2005 to 173 in 2010, and the number of LT procedures per 1000 patient-years at risk decreased from 564 to 422. MELD and Model for End-Stage Liver Disease-Sodium scores were excellent predictors of 3-month WL mortality with c statistics of 0.828 and 0.857, respectively (P < 0.001). No difference was observed in 1-year posttransplant survival between the 2 periods (81.1% versus 81.3%). Although patients with a MELD score > 30 had lower posttransplant survival, the global accuracy of the score for predicting outcomes was poor, as indicated by a c statistic of only 0.523. Patients with granted MELD exceptions (158 for hepatocellular carcinoma and 52 for other reasons) had significantly higher access to LT (80.4%) in comparison with nonexception patients with equivalent listing priority (MELD score = 18-25; 54.6%, P < 0.001, HR = 0.49, 95% CI = 0.40-0.61). In conclusion, the adoption of the MELD model in Argentina has resulted in improved liver organ allocation without compromising posttransplant survival.

Hepatitis C virus diversification in Argentina: comparative analysis between the large city of Buenos Aires and the small rural town of O'Brien.

BACKGROUND: The estimated prevalence of HCV infection in Argentina is around 2%. However, higher rates of infection have been described in population studies of small urban and rural communities. The aim of this work was to compare the origin and diversification of HCV-1b in samples from two different epidemiological scenarios: Buenos Aires, a large cosmopolitan city, and O'Brien, a small rural town with a high prevalence of HCV infection. PATIENTS AND METHODS: The E1/E2 and NS5B regions of the viral genome from 83 patients infected with HCV-1b were sequenced. Phylogenetic analysis and Bayesian Coalescent methods were used to study the origin and diversification of HCV-1b in both patient populations. RESULTS: Samples from Buenos Aires showed a polyphyletic behavior with a tMRCA around 1887-1900 and a time of spread of infection approximately 60 years ago. In contrast, samples from ÓBrien showed a monophyletic behavior with a tMRCA around 1950-1960 and a time of spread of infection more recent than in Buenos Aires, around 20-30 years ago. CONCLUSION: Phylogenetic and coalescence analysis revealed a different behavior in the epidemiological histories of Buenos Aires and ÓBrien. HCV infection in Buenos Aires shows a polyphyletic behavior and an exponential growth in two phases, whereas that in O'Brien shows a monophyletic cluster and an exponential growth in one single step with a more recent tMRCA. The polyphyletic origin and the probability of encountering susceptible individuals in a large cosmopolitan city like Buenos Aires are in agreement with a longer period of expansion. In contrast, in less populated areas such as O'Brien, the chances of HCV transmission are strongly restricted. Furthermore, the monophyletic character and the most recent time of emergence suggest that different HCV-1b ancestors (variants) that were in expansion in Buenos Aires had the opportunity to colonize and expand in O'Brien.

Cuantificación de hierro hepático por espectrometría de absorción atómica con vaporización electrotérmica / Iron liver quantification using electrothermal atomic absorption spectrometry / Quantificação de ferro hepático por espectrometria de absorção atômica com vaporização eletrotérmica

Se estudió el depósito de hierro (Fe) en tejido hepático de individuos sanos y de individuos con enfermedades crónicas del hígado, siendo todos adultos entre 46 y 70 años. La cuantificación de hierro se realizó mediante la técnica de Espectrometría de Absorción Atómica con Vaporización Electrotérmica (ET AAS). Las muestras de hígado obtenidas por biopsia hepática fueron pesadas y sometidas a digestión ácida. Simultáneamente se realizaron ensayos de recuperación del analito fortificando las muestras y el blanco de reactivo con el agregado de un estándar de Fe. La cuantificación se realizó mediante una curva de calibración (con estándares entre 10 y 50 µg/L). Se midieron áreas de pico a 248,3 nm usando como fuente una lámpara de cátodo hueco. Los resultados obtenidos de las muestras correspondientes a individuos sanos fueron inferiores a 1.000 µg/g de tejido seco, mientras que los valores correspondientes a individuos con enfermedades crónicas del hígado resultaron superiores, entre 1.800 y 7.835 µg/g de tejido seco. Se observó una relación directa entre la concentración de hierro en tejido hepático y el grado de depósito de este metal, por lo que el desarrollo de la metodología ET AAS permitió cuantificar la sobrecarga de hierro y estimar los valores obtenidos asociados a diferentes hepatopatías.

The iron (Fe) deposit was studied in the liver tissue of healthy and chronic liver disease subjects, all of them adults aged 46 to 70. The iron quantification was made by electrothermal atomic absorption spectrometry (ET AAS). Biopsy liver samples were weighed, measured, and put under acid digestion. Simultaneously a test was performed to analyze recovery in both strong samples and bound reagents with the addition of a standard of iron. Quantification was carried out using a calibration curve (from 10 to 50 mg/L): Peak areas of 248.3 nm were measured through a hollow cathode lamp. The results of the samples for healthy individuals were less than 1,000 µg/g of dry tissue, while the range in subjects with chronic liver disease was higher, (range from 800 to 7,835 µg/g dry tissue). There is a direct relationship between concentrations of iron in liver tissue and the range of the metal deposit for which reason development of the ET AAS methodology made it possible to quantify the iron overload and estimate the values associated to the different hepatopathies.

Foi estudado o depósito de ferro (Fe) em tecido hepático de indivíduos saudáveis e de indivíduos com doenças crônicas do fígado, sendo todos adultos entre 46 e 70 anos. A quantificação de ferro foi realizada através da Técnica de Espectrometria de Absorção Atômica com Vaporização Eletrotérmica (ET AAS). As amostras de fígado obtidas por biópsia hepática foram pesadas e submetidas à digestão ácida. Simultaneamente foram realizados testes de recuperação do analito fortificando as amostras e o branco de reagente com o acréscimo de um padrão de Fe. A quantificação foi realizada através de uma curva de calibragem (com padrões entre 10 e 50 mg/L). Mediram-se áreas de pico a 248,3 nm usando como fonte uma lâmpada de cátodo oco. Os resultados obtidos das amostras correspondentes a indivíduos sadios foram inferiores a 1.000 µg/g de tecido seco, e os valores correspondentes a indivíduos com doenças crônicas do fígado resultaram superiores, entre 1.800 a 7.835 µg/g de tecido seco. Foi observada uma relação direta entre a concentração de ferro em tecido hepático com o grau de depósito deste metal, pelo qual o desenvolvimento da metodologia ET AAS permitiu quantificar a sobrecarga de ferro e calcular os valores obtidos associados a diferentes hepatopatias.

Transcriptome at the time of hepatitis C virus recurrence may predict the severity of fibrosis progression after liver transplantation.

Allograft gene expression analysis may provide insights into the mechanisms involved in liver damage during hepatitis C virus recurrence (HCVrec) after orthotopic liver transplantation (OLT) and allow the identification of patients who have a higher risk of developing severe disease. Forty-three OLT recipients with hepatitis C virus (HCV) were evaluated. Genomewide gene expression analysis was performed with formalin-fixed, paraffin-embedded (FFPE) liver biopsy samples obtained from 21 OLT recipients with HCV at the time of clinical HCVrec, which was defined as increased alanine aminotransferase levels and detectable HCV RNA levels in serum. Patients were classified into 3 groups according to the severity of the fibrosis in the liver biopsies at 36 months post-OLT : group 1 (G1) for mild fibrosis (F0-F1), group 2 for moderate fibrosis (F2), and group 3 (G3) for severe fibrosis (F3-F4). No significant differences were observed between the groups with respect to donor age, histology during HCVrec, treated episodes of acute cellular rejection, or immunosuppression therapy. The results were validated in the remaining 22 OLT recipients with HCV using quantitative real-time polymerase chain reaction. Fifty-seven beadtypes showed significantly different expression (P < 0.001) between the groups during HCVrec. In G3, the gene expression of interleukin-28RA (IL-28RA), IL-28, and angiotensin-converting enzyme was up-regulated. Samples from G1 and G3 were used to determine whether a multigenetic classifier could be derived to predict the group class. The final model included the intercept and 9 bead types. Pairwise scatter plots of these 9 bead types revealed that G1 and G3 were well separated with respect to each gene. Our analysis has demonstrated the utility of a set of molecular markers indicating HCVrec severity early after OLT.

[Indications and timing of liver transplantation]. / Indicaciones y oportunidad del trasplante hepático.

Liver transplantation (OLT) is indicated in patients with severe and irreversible acute or chronic liver disease without alternative therapy and in the absence of contraindications. Indications for OLT can be grouped in four categories, namely cirrhosis, fulminant hepatitis, malignant hepatic tumors and liver-based genetic defects that trigger damage of other organs. Patients with cirrhosis should be referred for OLT after the onset of any of the major complications or coagulopathy. Early referral is crucial in fulminant hepatitis due to the high mortality with medical therapy and the unpredictable nature of this condition. Ideal timing for OLT is the moment in the natural history of the disease when the expected survival of patients on the waiting list is higher with than without OLT. Recent data suggest that maximal benefit of OLT is obtained in patients with a MELD score >15. However, in some cases with no imminent risk of death, OLT is indicated to improve quality of life or to prevent contraindications such as progression of hepatocellular carcinoma. At present, there is a marked disproportion between the number of donors available and the growing number of patients listed worldwide, which in turn has resulted in prolongation of the time-interval to OLT and waitlist mortality. The rationale of allocation systems utilizing the MELD score is to prioritize on the waiting list patients with severe liver dysfunction ("the sickest first") and those with hepatocellular carcinoma who may loose the benefits of OLT when waitlist time exceeds eight months.

Indicaciones y oportunidad del trasplante hepático / Indications and timing of liver transplantation

El trasplante hepático (TH) está indicado en pacientes con enfermedades hepáticas agudas o crónicas severas e irreversibles para las cuales no exista un tratamiento alternativo y en ausencia de contraindicaciones. Las indicaciones de TH pueden ser agrupadas en cuatro categorías: cirrosis hepática, hepatitis fulminante, tumores hepáticos y defectos genéticos de origen hepático que producen daño en otros órganos. Deben ser derivados para TH los pacientes con cirrosis que desarrollen cualquier complicación mayor o coagulopatía. La derivación precoz es "la clave del éxito" en la hepatitis fulminante por el alto riesgo de muerte y por tener una evolución mayormente impredecible. La oportunidad del TH es el momento en la historia natural de la hepatopatía cuando la sobrevida esperada es mayor con TH que en lista de espera. Estudios recientes han sugerido que el máximo beneficio del TH se obtiene en pacientes con MELD >15. Sin embargo, en algunos casos sin riesgo de muerte inminente, el objetivo del TH es mejorar la calidad de vida o prevenir contraindicaciones como la progresión del hepatocarcinoma cuando el tiempo de espera excede los 8 meses. Actualmente existe una marcada desproporción entre el número de donantes disponibles y el número creciente de potenciales receptores, lo que ha determinado un incremento progresivo del tiempo y mortalidad en lista. La racionalidad de distribuir los órganos en base al score de MELD es otorgar prioridad en la lista a los candidatos más enfermos y a aquellos que no pueden esperar como los pacientes con hepatocarcinoma.

Liver transplantation (OLT) is indicated in patients with severe and irreversible acute or chronic liver disease without alternative therapy and in the absence of contraindications. Indications for OLT can be grouped in four categories, namely cirrhosis, fulminant hepatitis, malignant hepatic tumors and liver-based genetic defects that trigger damage of other organs. Patients with cirrhosis should be referred for OLT after the onset of any of the major complications or coagulopathy. Early referral is crucial in fulminant hepatitis due to the high mortality with medical therapy and the unpredictable nature of this condition. Ideal timing for OLT is the moment in the natural history of the disease when the expected survival of patients on the waiting list is higher with than without OLT. Recent data suggest that maximal benefit of OLT is obtained in patients with a MELD score >15. However, in some cases with no imminent risk of death, OLT is indicated to improve quality of life or to prevent contraindications such as progression of hepatocellular carcinoma. At present, there is a marked disproportion between the number of donors available and the growing number of patients listed worldwide, which in turn has resulted in prolongation of the time-interval to OLT and waitlist mortality. The rationale of allocation systems utilizing the MELD score is to prioritize on the waiting list patients with severe liver dysfunction ("the sickest first") and those with hepatocellular carcinoma who may loose the benefits of OLT when waitlist time exceeds eight months.

Prevalencia de enfermedades hepáticas en una población rural de alta montaña: estudio clínico, bioquímico y ecográfico / Prevalence of liver diseases in a small rural community isolated in tne mountain heights: clinical, biochemical and ultrasonographic study

En este estudio clínico, bioquímico y ecográfico se evaluó la prevalencia de hepatopatías en Lara, una comunidad rural aislada de alta montaña en Tucumán, provincia con la máxima prevalencia de infección por HAV en niños de Argentina. Lara carece de agua potable, electricidad y cloacas. Se estudiaron 102 habitantes, lo que representa el 41% de la población. El anti-HBc y anti-HCV fueron negativos en todos los casos. Ningún niño presentó anormalidades hepáticas. El 41% de los adultos refirió ingesta alcohólica y el 12% transfusiones. Se observó incremento leve de ALT en 3 casos (6%). La ecografía demostró esteatosis en 8 individuos (16%), litiasis vesicular en 7 (14%), microcalcificaciones en 5 (10%) y quistes de aspecto parasitario en 4 (8%). La prevalencia de infección por HAV en Lara fue de 89% en adultos y 35% en niños, siendo significativamente menor que la de los niños de la ciudad de Tucumán con nivel socioeconómico medio / alto (53%, p = 0.05) o bajo (74%, p = 0.0006). La diferencia fue más evidente en niños menores de 5 años (0%, 53% y 75% respectivamente). La serología para hidatidosis fue positiva en 3/4 individuos con quistes, 2/5 con microcalcificaciones y 17/85 (20%) con ecografía normal, lo que sugiere que la técnica de Elisa utilizada se asocia a frecuentes resultados falsos positivos. El estudio poblacional de Lara demostró una elevada prevalencia de esteatosis, litiasis vesicular e hidatidosis en adultos, ausencia de infección por HBV y HCV, y una baja exposición al HAV en niños, especialmente en menores de 5 años.

The goal of this population-based clinical, biochemical and ultrasonographic study was to assess the prevalence of liver diseases in Lara, a small rural community isolated in the mountain heights of Tucumán, a Province of Argentina with the highest reported rates of HAV infection in children. Inhabitants of Lara lack electricity, potable water and a sewer system. The study included 102 individuals representing 41% of the total population. Anti-HBc and anti-HCV were negative in all cases. No children showed clinical, biochemical or ecographic abnormalities. Among adults, 41% referred alcohol consumption and 12% blood transfusions. Only 3 adults (6%) had mildly elevated ALT. Ultrasound showed steatosis in 8 individuals (16%), gallstones in 7 (14%), parenchymal micro-calcifications in 5 (10%) and parasitic cysts in 4 (8%). Prevalence of HAV infection in Lara was 89% in adults and 35% in children, being significantly lower than that of children of medium/high (53%, p=0.05) and low (74%, p=0.0006) socioeconomic level from the city of Tucumán (control groups). These differences were more marked in children aged <5 years (anti-HAV in 0%, 53% y 75% respectively). Serologic tests for echinoccocal disease were positive in 3/4 individuals with parasitic cysts, 2/5 with micro-calcifications and 17/85 (20%) with normal ultrasound, thus suggesting a high rate of false-positive results of the Elisa test utilized. This study showed that in Lara there is a high prevalence of steatosis, gallstones and equinoccocal disease in adults, absenceof HBV and HCV infection and low exposure to HAV in children especially in those aged <5 years.

Protocol liver biopsies in long-term management of patients transplanted for hepatitis B-related liver disease.

AIM: To evaluate the long-term histological outcome of patients transplanted for HBV-related liver disease and given HBIg prophylaxis indefinitely after LT. METHODS: Forty-two consecutive patients transplanted for hepatitis B were prospectively studied. HBsAg, HBV-DNA and liver function tests were evaluated in the serum 3, 6 and 12 mo after LT and then yearly. LB was obtained 6 and 12 mo after LT and yearly thereafter. Chronic hepatitis (CH) B after LT was classified as minimal, mild, moderate or severe. RESULTS: HBV recurred in 7/42 (16.6%) patients after 6-96 mo of follow-up. A hundred and eighty-seven LB were evaluated. Four of 7 patients with graft reinfection, all with unknown HBV DNA status before LT, developed cirrhosis at 12-36 mo of follow-up. Of the 122 LB obtained from 28 HBsAg+/HCV- recipients with no HBV recurrence after LT, all biopsies were completely normal in only 2 patients (7.1%), minimal/non-specific changes were observed in 18 (64.2%), and at least 1 biopsy showed CH in the remaining 8 (28.5%). Twenty-nine LB obtained from 7 patients transplanted for HBV-HCV cirrhosis and remaining HBsAg- after LT revealed recurrent CH-C. Actuarial survival was similar in patients with HBsAg+ or HBsAg- liver diseases. CONCLUSION: Though protocol biopsies may enable the detection of graft dysfunction at an early stage, the risk of progression and the clinical significance of these findings remains to be determined.

[Prevalence of liver diseases in a small rural community isolated in the mountain heights: clinical, biochemical and ultrasonographic study]. / Prevalencia de enfermedades hepáticas en una población rural de alta montaña: estudio clínico, bioquímico y ecográfico.

The goal of this population-based clinical, biochemical and ultrasonographic study was to assess the prevalence of liver diseases in Lara, a small rural community isolated in the mountain heights of Tucumán, a Province of Argentina with the highest reported rates of HAV infection in children. Inhabitants of Lara lack electricity, potable water and a sewer system. The study included 102 individuals representing 41% of the total population. Anti-HBc and anti-HCV were negative in all cases. No children showed clinical, biochemical or ecographic abnormalities. Among adults, 41% referred alcohol consumption and 12% blood transfusions. Only 3 adults (6%) had mildly elevated ALT. Ultrasound showed steatosis in 8 individuals (16%), gallstones in 7 (14%), parenchymal micro-calcifications in 5 (10%) and parasitic cysts in 4 (8%). Prevalence of HAV infection in Lara was 89% in adults and 35% in children, being significantly lower than that of children of medium/high (53%, p = 0.05) and low (74%, p = 0.0006) socioeconomic level from the city of Tucumán (control groups). These differences were more marked in children aged < 5 years (anti-HAV in 0%, 53% and 75% respectively). Serologic tests for echinoccocal disease were positive in 3/4 individuals with parasitic cysts, 2/5 with micro-calcifications and 17/85 (20%) with normal ultrasound, thus suggesting a high rate of false-positive results of the Elisa test utilized. This study showed that in Lara there is a high prevalence of steatosis, gallstones and equinoccocal disease in adults, absence of HBVand HCV infection and low exposure to HAV in children especially in those aged < 5 years.

Comparison of cyclosporine microemulsion and tacrolimus in 39 recipients of living donor liver transplantation.

New immunosuppressive agents and regimens should be evaluated specifically in living donor liver transplant patients due to potential clinical and pharmacokinetic differences between deceased donor and living donor transplant recipients. The analysis presented here is the first direct comparison of clinical outcomes using cyclosporine microemulsion (CsA-ME) with monitoring of blood concentration at 2 hours postdose (C2) and tacrolimus-based immunosuppression in living donor liver transplantation. The analysis was conducted on the data provided by the 39 recipients of a living donor transplant out of the 495 patients enrolled in a 6-month, randomized, prospective, multicenter, open-label study (LIS2T). Patients were randomized to CsA-ME (C2 monitoring) or tacrolimus (monitoring of predose trough drug blood level [C0)]) and were administered corticosteroids with or without azathioprine. Twenty-three living-donor patients received CsA-ME and 16 received tacrolimus. By month 6, 9% of patients receiving CsA-ME and 19% of those receiving tacrolimus had lost their graft or died (not significant [NS]). Nine episodes of biopsy-proven acute rejection were reported: 4 in the CsA-ME group (17%) and 5 in the tacrolimus cohort (31%, NS). There were no significant differences in any safety parameter between groups. The most frequently reported serious adverse events were infections, which occurred in 14 patients in the CsA-ME group (61%) and 13 patients in the tacrolimus arm (81%, NS). Twelve patients in the CsA-ME arm (52%) and 5 in the tacrolimus arm (31%, NS) discontinued the study prematurely. In conclusion, CsA-ME C2 monitoring or tacrolimus both offer effective protection against rejection in living donor liver transplants while maintaining a good safety profile.