Advances in Genomic Data and Biomarkers: Revolutionizing NSCLC Diagnosis and Treatment.

Non-small cell lung cancer (NSCLC) is a significant public health concern with high mortality rates. Recent advancements in genomic data, bioinformatics tools, and the utilization of biomarkers have improved the possibilities for early diagnosis, effective treatment, and follow-up in NSCLC. Biomarkers play a crucial role in precision medicine by providing measurable indicators of disease characteristics, enabling tailored treatment strategies. The integration of big data and artificial intelligence (AI) further enhances the potential for personalized medicine through advanced biomarker analysis. However, challenges remain in the impact of new biomarkers on mortality and treatment efficacy due to limited evidence. Data analysis, interpretation, and the adoption of precision medicine approaches in clinical practice pose additional challenges and emphasize the integration of biomarkers with advanced technologies such as genomic data analysis and artificial intelligence (AI), which enhance the potential of precision medicine in NSCLC. Despite these obstacles, the integration of biomarkers into precision medicine has shown promising results in NSCLC, improving patient outcomes and enabling targeted therapies. Continued research and advancements in biomarker discovery, utilization, and evidence generation are necessary to overcome these challenges and further enhance the efficacy of precision medicine. Addressing these obstacles will contribute to the continued improvement of patient outcomes in non-small cell lung cancer.

MELD 3.0 adequately predicts mortality and renal replacement therapy requirements in patients with alcohol-associated hepatitis.

Background & Aims: Model for End-Stage Liver Disease (MELD) score better predicts mortality in alcohol-associated hepatitis (AH) but could underestimate severity in women and malnourished patients. Using a global cohort, we assessed the ability of the MELD 3.0 score to predict short-term mortality in AH. Methods: This was a retrospective cohort study of patients admitted to hospital with AH from 2009 to 2019. The main outcome was all-cause 30-day mortality. We compared the AUC using DeLong's method and also performed a time-dependent AUC with competing risks analysis. Results: A total of 2,124 patients were included from 28 centres from 10 countries on three continents (median age 47.2 ± 11.2 years, 29.9% women, 71.3% with underlying cirrhosis). The median MELD 3.0 score at admission was 25 (20-33), with an estimated survival of 73.7% at 30 days. The MELD 3.0 score had a better performance in predicting 30-day mortality (AUC:0.761, 95%CI:0.732-0.791) compared with MELD sodium (MELD-Na; AUC: 0.744, 95% CI: 0.713-0.775; p = 0.042) and Maddrey's discriminant function (mDF) (AUC: 0.724, 95% CI: 0.691-0.757; p = 0.013). However, MELD 3.0 did not perform better than traditional MELD (AUC: 0.753, 95% CI: 0.723-0.783; p = 0.300) and Age-Bilirubin-International Normalised Ratio-Creatinine (ABIC) (AUC:0.757, 95% CI: 0.727-0.788; p = 0.765). These results were consistent in competing-risk analysis, where MELD 3.0 (AUC: 0.757, 95% CI: 0.724-0.790) predicted better 30-day mortality compared with MELD-Na (AUC: 0.739, 95% CI: 0.708-0.770; p = 0.028) and mDF (AUC:0.717, 95% CI: 0.687-0.748; p = 0.042). The MELD 3.0 score was significantly better in predicting renal replacement therapy requirements during admission compared with the other scores (AUC: 0.844, 95% CI: 0.805-0.883). Conclusions: MELD 3.0 demonstrated better performance compared with MELD-Na and mDF in predicting 30-day and 90-day mortality, and was the best predictor of renal replacement therapy requirements during admission for AH. However, further prospective studies are needed to validate its extensive use in AH. Impact and implications: Severe AH has high short-term mortality. The establishment of treatments and liver transplantation depends on mortality prediction. We evaluated the performance of the new MELD 3.0 score to predict short-term mortality in AH in a large global cohort. MELD 3.0 performed better in predicting 30- and 90-day mortality compared with MELD-Na and mDF, but was similar to MELD and ABIC scores. MELD 3.0 was the best predictor of renal replacement therapy requirements. Thus, further prospective studies are needed to support the wide use of MELD 3.0 in AH.

Impacto medioambiental y socioeconómico en la salud generado por la minería artesanal del oro en Colombia

Introducción: Este artículo de revisión sistemática describe el impacto medioambiental y socioeconómico en salud generado por la minería artesanal del oro en Colombia. Para el estudio se tuvieron en cuenta artículos publicados entre 2010 y 2019. El objetivo de esta revisión bibliográfica fue describir el impacto medioambiental y socioeconómico en la salud generado por la minería artesanal del oro en Colombia. Materiales y métodos: Trabajo construido mediante revisión sistemática, usando los siguientes descriptores: minería, sector informal, riesgo a la salud, condiciones de salud. Para esta búsqueda se utilizaron las bases de datos Scopus, Web of Science, ProQuest, Publindex, así como la normatividad colombiana. Resultados: Se desarrollan las categorías ambientales, socioeconómico y salud. En la categoría ambiental se detalla información sobre sostenibilidad ambiental, manejo de vertimientos, pruebas fisicoquímicas y control gubernamental; En la categoría socioeconómica se describen los dilemas entre minería y medio ambiente, el dilema entre pequeña minería o artesanal y minería a gran escala o industrializada, y el conflicto social y económico. En la categoría salud se analizan las afectaciones y la percepción de la población sobre los daños en la salud, la protección laboral, la innovación social y las oportunidades de cambio para una producción más limpia y saludable. Conclusiones: Los estudios realizados se concentran principalmente en el departamento de Antioquia evidenciando la necesidad de realizar investigaciones en otras zonas del país. A pesar de que en Colombia existe legislación minera, se requiere que el gobierno establezca medidas efectivas de control, capacite y socialice a los mineros sobre métodos adecuados de procesamiento del oro, garantizado el desarrollo ambiental, social y protección laboral.

Introduction: This systematic review article describes the environmental and socioeconomic impact on health generated by handmade gold mining in Colombia. For this study articles published between 2010 and 2019 were considered. The objective of this bibliographic review is to describe the environmental and socioeconomic impact on health generated by gold mining in Colombia. Materials and methods: Work constructed through systematic review, using the following descriptors: mining, informal sector, health risk, health conditions. For this search, Scopus, Web of Science, ProQuest, Publindex databases were used, as well as Colombian regulations. Results: The environmental, socioeconomic, and health categories were developed. In the environmental category, information on environmental sustainability, management of discharges, physicochemical tests, and government control is detailed. In the socioeconomic category, the dilemmas between mining and the environment are described, the dilemma between small or artisanal mining and large-scale or industrialized mining, and the social and economic conflict. In the third category, health, the effects and perception of the population regarding health damage, labor protection, social innovation, and opportunities for change for cleaner and healthier production are analyzed. Conclusions: The studies carried out are mainly concentrated in the department of Antioquia, showing the need to carry out research in other areas of the country. Although there is mining legislation in Colombia, the government is required to establish effective control measures, train, and socialize the miners on adequate gold processing methods, guaranteeing the environmental and social development and protection of its miners.

Genetic diversity of hepatitis C virus and resistance associated substitutions to direct-acting antiviral treatment in Colombia.

Hepatitis C virus (HCV) infection is one of the leading risk factors for end-stage liver disease development worldwide. This RNA virus displays high genetic diversity with 8 genotypes and 96 subgenotypes with heterogeneous geographical distribution around the world. In this study, we carried out an active case finding of individuals with a history of transfusion events before 1996 in three cities in Colombia. Then, the characterization of the HCV genotypes, subgenotypes, and resistance associate substitutions (RAS) was performed in samples positives for antibodies anti-HCV + from this study population. In addition, samples from PWID and patients with end-stage liver disease submitted to liver transplantation were included in the phylogenetic and RAS analysis. The 5'UTR, NS5A, and NS5B regions of the HCV genome were amplified in serum or liver explants samples. After the edition, assembly, and alignment of the sequences, genotyping through phylogenetic analysis was performed using IQTREE V2.0.5 based on the maximum likelihood approach. The identification of RAS was carried out by alignments based on the reference sequence (GenBank NC_004102). Two hundred sixty individuals with blood transfusion events before 1996 were recruited. The seroprevalence of antibodies anti-HCV was 2.69% in this population. The HCV genotypes 1, 2, and 4 and subgenotypes 1a, 1b, 2a, 4a and 4d were characterized in samples of the study populations. Three RAS (Q30R, C316N, and Y93H) were identified in samples obtained from 2 individuals who received blood transfusion before 1996 and without previous antiviral treatment and 6 samples obtained from patients with end-stage liver disease. Among the 20 samples analyzed, the HCV genotype 1, subgenotype 1b, was the most frequent (60%). We report the first characterization of HCV subgenotypes 4a and 4d and the first RAS identification in patients in Colombia.

The establishment of public health policies and the burden of non-alcoholic fatty liver disease in the Americas.

Non-alcoholic fatty liver disease (NAFLD) affects 20-25% of the general population and is associated with morbidity, increased mortality, and elevated health-care costs. Most NAFLD risk factors are modifiable and, therefore, potentially amenable to being reduced by public health policies. To date, there is no information about NAFLD-related public health policies in the Americas. In this study, we analysed data from 17 American countries and found that none have established national public health policies to decrease NAFLD-related burden. There is notable heterogeneity in the existence of public health policies to prevent NAFLD-related conditions. The most common public health policies were related to diabetes (15 [88%] countries), hypertension (14 [82%] countries), cardiovascular diseases (14 [82%] countries), obesity (nine [53%] countries), and dyslipidaemia (six [35%] of countries). Only seven (41%) countries had a registry of the burden of NAFLD, and efforts to raise awareness in the Americas were scarce. The implementation of public health policies are urgently needed in the Americas to decrease the burden of NAFLD.

Identification of optimal therapeutic window for steroid use in severe alcohol-associated hepatitis: A worldwide study.

BACKGROUND & AIMS: Corticosteroids are the only effective therapy for severe alcohol-associated hepatitis (AH), defined by a model for end-stage liver disease (MELD) score >20. However, there are patients who may be too sick to benefit from therapy. Herein, we aimed to identify the range of MELD scores within which steroids are effective for AH. METHODS: We performed a retrospective, international multicenter cohort study across 4 continents, including 3,380 adults with a clinical and/or histological diagnosis of AH. The main outcome was mortality at 30 days. We used a discrete-time survival analysis model, and MELD cut-offs were established using the transform-the-endpoints method. RESULTS: In our cohort, median age was 49 (40-56) years, 76.5% were male, and 79% had underlying cirrhosis. Median MELD at admission was 24 (19-29). Survival was 88% (87-89) at 30 days, 77% (76-78) at 90 days, and 72% (72-74) at 180 days. A total of 1,225 patients received corticosteroids. In an adjusted-survival-model, corticosteroid use decreased 30-day mortality by 41% (hazard ratio [HR] 0.59; 0.47-0.74; p <0.001). Steroids only improved survival in patients with MELD scores between 21 (HR 0.61; 0.39-0.95; p = 0.027) and 51 (HR 0.72; 0.52-0.99; p = 0.041). The maximum effect of corticosteroid treatment (21-30% survival benefit) was observed with MELD scores between 25 (HR 0.58; 0.42-0.77; p <0.001) and 39 (HR 0.57; 0.41-0.79; p <0.001). No corticosteroid benefit was seen in patients with MELD >51. The type of corticosteroids used (prednisone, prednisolone, or methylprednisolone) was not associated with survival benefit (p = 0.247). CONCLUSION: Corticosteroids improve 30-day survival only among patients with severe AH, especially with MELD scores between 25 and 39. LAY SUMMARY: Alcohol-associated hepatitis is a condition where the liver is severely inflamed as a result of excess alcohol use. It is associated with high mortality and it is not clear whether the most commonly used treatments (corticosteroids) are effective, particularly in patients with very severe liver disease. In this worldwide study, the use of corticosteroids was associated with increased 30-day, but not 90- or 180-day, survival. The maximal benefit was observed in patients with an MELD score (a marker of severity of liver disease; higher scores signify worse disease) between 25-39. However, this benefit was lost in patients with the most severe liver disease (MELD score higher than 51).

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

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

Mutación R249S TP53 en pacientes con cirrosis y carcinoma hepatocelular en un hospital de Medellín / TP53 R249S mutation in patients with cirrhosis and hepatocellular carcinoma in a hospital at Medellin

Resumen Introducción: la exposición dietaria a la aflatoxina es un factor de riesgo para carcinoma hepatocelular, el cáncer primario de hígado más frecuente. Esta asociación se estableció gracias a la evidencia in vitro e in vivo de la relación entre la exposición a la aflatoxina B1 y la transversión G→T en el codón 249 del gen TP53, así como evidencia de la sinergia entre la aflatoxina y la infección crónica por virus de la hepatitis B. Métodos: se determinó la frecuencia de la mutación R249S del gen TP53 en 30 pacientes con diagnóstico de cirrosis y/o carcinoma hepatocelular quienes fueron sometidos a trasplante hepático en un hospital en Medellín, Colombia. Se extrajo ADN a partir de las muestras de explante hepático, se amplificó el fragmento de interés y se detectó la mutación por polimorfismos de longitud de fragmentos de restricción. Resultados: se encontró la mutación R249S en una de las 30 muestras analizadas (3,33 %) y se determinó, por medio de marcadores serológicos, infección por el virus de la hepatitis B en dos casos (6,67 %). No se encontró simultáneamente la mutación y la presencia de los marcadores de infección por virus de la hepatitis B. Conclusión: los resultados sugieren una baja exposición dietaria con aflatoxina B1 en la población de estudio. Sin embargo, es importante tener en cuenta la regulación de los límites permisibles de aflatoxina B1 y la inclusión en el diagnóstico diferencial de carcinoma hepatocelular, dada la heterogeneidad de las condiciones de la población en diferentes regiones del país.

Abstract Introduction: The dietary exposure to aflatoxin is a risk factor of hepatocellular carcinoma, the most frequent primary liver cancer. This risk factor was identified after in vivo and in vitro evidence of the relation between exposure to aflatoxin B1 and transversion G → T at 249 codon of the TP53 gene; as well as evidence of the synergy between hepatitis B virus chronic infection. Methods: the frequency of the R249S mutation of the TP53 gene was determined in 30 cases of cirrhosis and/or hepatocellular carcinoma, with liver transplantation in the hepatology unit of a hospital in Medellín, Colombia. DNA was extracted from the liver explant samples; the sequence of interest was amplified, and the mutation was detected by restriction fragment length polymorphisms. Results: the R249S mutation was found in 1 of the 30 samples analyzed (3.33 %); and hepatitis B virus infection was detected by serological markers in 2 of the 30 cases (6.67 %). We did not find the mutation and the presence of hepatitis B virus infection markers at the same time in any of the samples. Conclusion: The results suggest a low dietary exposure with aflatoxin B1 in the study population. However, it is important to take into consideration the regulation of the permissible limits of aflatoxin B1 and the inclusion in the differential diagnosis of hepatocellular carcinoma, given the heterogeneity of the conditions of the population in different regions of the country.

Trasplante hepático en un centro de Colombia: comparación de dos períodos / Comparison of two periods in liver transplantation at Colombian medical center

Resumen Objetivo: el trasplante hepático es el tratamiento de elección para la falla hepática aguda y crónica. Los resultados en el trasplante hepático han mejorado en los últimos años, así que el objetivo de nuestro trabajo es comparar la experiencia de un centro en Colombia en dos períodos de tiempo diferentes. Pacientes y métodos: estudio descriptivo retrospectivo donde se analizaron pacientes adultos con primer trasplante hepático en dos períodos; serie 1, entre 2004-2010 (241 pacientes); y serie 2, entre 2011-2016 (142 pacientes). Resultados: la edad promedio fue de 54 años, el 57 % eran hombres y con un puntaje Model for End-stage Liver Disease (MELD) promedio de 20, sin cambios significativos en las características del donante y del receptor en los dos períodos. Las principales indicaciones de trasplante hepático fueron cirrosis por alcohol, cirrosis criptogénica y cirrosis por hepatitis autoinmune, con una disminución de los casos de hepatitis B y C en la serie 2. El 30 % de los pacientes tenía hepatocarcinoma. La supervivencia de los pacientes a 1 año fue de 81 % frente a 91 % y a 5 años fue de 71 % frente a 80 %, respectivamente. Las principales causas de muerte fueron: cáncer, enfermedad cardiovascular y sepsis. Existió un incremento significativo en las complicaciones biliares, sin diferencias en las complicaciones infecciosas, vasculares y el rechazo celular entre los dos períodos. Conclusión: el trasplante hepático en este centro en Colombia se relaciona con excelentes resultados a corto y mediano plazo, con una mejoría significativa en la supervivencia de los pacientes en los últimos años y con resultados similares a los reportados en otros centros del mundo.

Abstract Objective: Liver transplantation is the treatment of choice for acute and chronic liver failure. Liver transplantation results have improved in recent years, so the objective of our work was to compare results from two different periods of time at a center in Colombia. Patients and Methods: This is a retrospective descriptive study comparing first time adult liver transplant patients from 2004-2010 (Series 1: 241 patients) and from 2011-2016 (Series 2: 142 patients). Results: The average patient age was 54 years, 57% were men, and the average MELD score was 20. There were no significant differences between the characteristics of donors and recipients from one period to the next. The main indications for liver transplantation were alcoholic cirrhosis and cryptogenic and autoimmune hepatitis. Series 2 contained fewer hepatitis B and C cases than did Series 1. Thirty percent of the patients had hepatocellular carcinoma. The one-year survival rates were 81% in Series 1 and 91% in Series 2, whereas five-year survival rates were 71% and 80%, respectively. The main causes of death were cancer, cardiovascular disease and sepsis. From the first period to the second period, there was a significant increase in biliary complications but no differences in infectious complications, vascular complications or cellular rejection. Conclusion: Short and medium term liver transplantation results at this center in Colombia have been excellent, but there have been significant improvements in patient survival rates in recent years that are similar to those reported elsewhere in the world.

Alcohol-related liver disease: Clinical practice guidelines by the Latin American Association for the Study of the Liver (ALEH).

Alcohol-related liver disease (ALD) is a major cause of advanced chronic liver disease in Latin-America, although data on prevalence is limited. Public health policies aimed at reducing the alarming prevalence of alcohol use disorder in Latin-America should be implemented. ALD comprises a clinical-pathological spectrum that ranges from steatosis, steatohepatitis to advanced forms such as alcoholic hepatitis (AH), cirrhosis and hepatocellular carcinoma. Besides genetic factors, the amount of alcohol consumption is the most important risk factor for the development of ALD. Continuous consumption of more than 3 standard drinks per day in men and more than 2 drinks per day in women increases the risk of developing liver disease. The pathogenesis of ALD is only partially understood and recent translational studies have identified novel therapeutic targets. Early forms of ALD are often missed and most clinical attention is focused on AH, which is defined as an abrupt onset of jaundice and liver-related complications. In patients with potential confounding factors, a transjugular biopsy is recommended. The standard therapy for AH (i.e. prednisolone) has not evolved in the last decades yet promising new therapies (i.e. G-CSF, N-acetylcysteine) have been recently proposed. In both patients with early and severe ALD, prolonged abstinence is the most efficient therapeutic measure to decrease long-term morbidity and mortality. A multidisciplinary team including alcohol addiction specialists is recommended to manage patients with ALD. Liver transplantation should be considered in the management of patients with end-stage ALD that do not recover despite abstinence. In selected cases, increasing number of centers are proposing early transplantation for patients with severe AH not responding to medical therapy.

Polimorfismos en los genes de la enzima alcohol deshidrogenasa (ADH1) y la citocromo P450 2E1 (CYP2E1) en pacientes con cirrosis y carcinoma hepatocelular / Polymorphisms in alcohol dehydrogenase (ADH1) and cytochrome p450 2E1 (CYP2E1) genes in patients with cirrhosis and/or hepatocellular carcinoma

Introducción. Uno de los principales factores de riesgo del carcinoma hepatocelular es el consumo crónico de alcohol. En estudios en diferentes poblaciones, se sugiere que las variantes genéticas de las enzimas que participan en el metabolismo del alcohol, como la alcohol deshidrogenasa (ADH) y la citocromo P450 (CYP2E1), estarían asociadas con riesgo de enfermedades hepáticas terminales. Objetivo. Identificar y caracterizar las variantes alélicas de los genes ADH1B, ADH1C y CYP2E1 en pacientes colombianos con diagnóstico de cirrosis y carcinoma hepatocelular. Materiales y métodos. Se incluyeron muestras de pacientes atendidos entre el 2005 y el 2007, y entre el 2014 y el 2016, en la unidad de hepatología de un hospital de Medellín. La genotipificación de las muestras se hizo mediante reacción en cadena de la polimerasa (Polymerase Chain Reaction, PCR) con análisis de los polimorfismos en la longitud de los fragmentos de restricción (Restriction Fragment Length Polymorphism, RFLP). Los resultados se compararon con los de dos grupos de control y con lo reportado en la base de datos del 1000 Genomes Project. Resultados. Se recolectaron 97 muestras de pacientes con diagnóstico de cirrosis y carcinoma hepatocelular. Los dos factores de riesgo más frecuentes fueron el consumo crónico de alcohol (18,6 %) y las colangiopatías (17,5 %). Los genotipos más frecuentes en la población de estudio fueron el ADH1B*1/1 (82 %), el ADH1C*1/1 (59 %) y el CYP2E1*C/C (84 %). Conclusiones. En este primer estudio de los polimorfismos en pacientes colombianos con diagnóstico de cirrosis y carcinoma hepatocelular, los genotipos más frecuentes fueron el ADH1B*1/1, el ADH1C*1/1 y el CYP2E1*C/C. No se observaron diferencias estadísticamente significativas en la frecuencia de los genotipos entre los casos y los controles. Se requieren estudios adicionales en población colombiana para evaluar el riesgo de la enfermedad hepática terminal por consumo crónico de alcohol y la asociación con los polimorfismos.

Introduction: One of the most important risk factors for hepatocellular carcinoma (HCC) is alcohol consumption: Studies in different populations suggest that the risk of liver disease could be associated with genetic variants of the enzymes involved in alcohol metabolism, such as alcohol dehydrogenase (ADH) and cytochrome P450 CYP2E1. Objective: To identify and characterize the allelic variants of ADH1B, ADH1C and CYP2E1 genes in Colombian patients with cirrhosis and/or HCC. Materials and methods: We included samples from patients attending the hepatology unit between 2005-2007 and 2014-2016 of a hospital in Medellin. Samples were genotyped using PCR-RFLP. We compared the results with two control groups and the 1000 Genomes Project database. Results: We collected 97 samples from patients with a diagnosis of cirrhosis and/or HCC. The two main risk factors were chronic alcohol consumption (18.6%) and cholangiopathies (17.5%). The most frequent genotypes in the study population were ADH1B*1/1 (82%), ADH1C*1/1 (59%), and CYP2E1*C/C (84%). Conclusions: This first study of polymorphisms in Colombian patients diagnosed with cirrhosis and/or HCC showed genotypes ADH1B*1/1, ADH1C*1/1 and CYP2E1*C/C as the most frequent. We found no significant differences in the genotype frequency between cases and controls. Further studies are necessary to explore the association between polymorphisms and the risk of end-stage liver disease from alcohol consumption.

Efecto del consumo de alcohol al diagnóstico en la sobrevida de pacientes con cirrosis hepática en un hospital universitario de la ciudad de Medellín / Effect of alcohol consumption on diagnosis of liver cirrhosis patients' survival at a University Hospital in Medellín

Resumen El consumo de alcohol es un conocido factor de riesgo para muerte prematura, morbilidad y discapacidad a nivel mundial. Los registros de la mortalidad que se asocian con el consumo de alcohol están fraccionados. El objetivo de este estudio fue escribir la mortalidad relacionada con la ingesta de alcohol en pacientes con cirrosis atendidos en un hospital universitario de la ciudad de Medellín. Materiales y métodos: se incluyeron 163 pacientes con diagnóstico de cirrosis, evaluados en la consulta externa de hepatología de un hospital de referencia en la ciudad de Medellín con 277 camas y seguimiento hasta el 2016. Se midieron variables sociodemográficas, paraclínicas y clínicas. Se consideró el consumo de alcohol al inicio del seguimiento. Se describió la supervivencia y las complicaciones asociadas con la cirrosis según el estado de consumidores vs. no consumidores de alcohol. Resultados: se siguieron 163 pacientes hasta diciembre del 2016, encontrando una mortalidad en el 51% en consumidores de alcohol vs. 39% en no consumidores (P = 0,19). Las complicaciones de la cirrosis en consumidores de alcohol fueron ascitis en 68% vs. 43% (P = 0,01) en el grupo sin consumo de alcohol, encefalopatía 40,6% vs. 13,5% (P = 0,00) y carcinoma hepatocelular (HCC) en 29% vs. 17% (P = 0,08). En el análisis por subgrupos, los pacientes con hepatitis C con consumo de alcohol tuvieron una mortalidad más alta comparado con los pacientes que no consumieron alcohol (OR 33, IC 95%: 1,06 a 1023). Conclusiones: a pesar que el consumo de alcohol no se relaciona con aumento de la mortalidad en pacientes con cirrosis en este estudio, sí se observa incremento de esta en ciertas poblaciones, como en el subgrupo de pacientes con hepatitis C.

Abstract Worldwide, alcohol consumption is a well-known risk factor for premature death, morbidity and disability. Records of mortality associated with alcohol consumption are not centralized. The aim of this study was to record the mortality rate associated with alcohol intake in patients with cirrhosis who were treated at a university hospital in the city of Medellin. Materials and methods: We included 163 patients who had been diagnosed with cirrhosis in the outpatient hepatology clinic of a 277 bed referral hospital in Medellín. Patients were monitored until 2016. Sociodemographic, paraclinical and clinical variables were measured. Alcohol consumption was considered at the beginning of the follow-up. Survival and complications associated with cirrhosis were described and recorded for patients who consumed alcohol as well as for those who did not, and then the two groups were compared. Results: One hundred sixty-three patients were followed until December 2016. The mortality rate among those who consumed alcohol was 51% while it was only 39% for those who did not consume alcohol (P = 0.19). Comparison of complications of cirrhosis showed that 68% of alcohol users developed ascites vs. 43% of non-consumers (P = 0.01); 40.6% of alcohol users developed encephalopathy vs. 13.5% of non-consumers (P = 0.00); and 29% of alcohol users developed hepatocellular carcinoma (HCC) vs. 17% of non-consumers (P = 0.08). In the subgroup analysis, patients with hepatitis C who consumed alcohol had a higher mortality rate than patients who did not consume alcohol (OR: 33, 95% CI: 1.06 to 1023). Conclusions: Although alcohol consumption was not related to increased mortality among patients with cirrhosis in this study, increased mortality was observed in the subgroup of patients with hepatitis C.

Current controversies in cholangiocarcinoma.

Cholangiocarcinoma represents 10% of primary liver malignancies and accounts for less than 3% of all gastrointestinal malignant tumors, with an enormous geographical variation. This neoplasia can arise from the biliary tract epithelium or hepatic progenitor cells. Depending on the anatomic localization, it is classified into three subtypes: intrahepatic, perihilar and distal. This fact is one of the main difficulties, because there are many studies that indistinctly include the results in the management of these different types of cholangiocarcinoma, without differentiating its location and even including gallbladder cancer. There are many controversial points in epidemiology, liver transplantation as a treatment, limitations of different results by group and type of treatment, histological testing and chemotherapy. This is a narrative review about topics in cholangiocarcinoma. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

Polymorphisms in alcohol dehydrogenase (ADH1) and cytochrome p450 2E1 (CYP2E1) genes in patients with cirrhosis and/or hepatocellular carcinoma / Polimorfismos en los genes de la enzima alcohol deshidrogenasa (ADH1) y la citocromo P450 2E1 (CYP2E1) en pacientes con cirrosis y carcinoma hepatocelular

Introduction: One of the most important risk factors for hepatocellular carcinoma (HCC) is alcohol consumption: Studies in different populations suggest that the risk of liver disease could be associated with genetic variants of the enzymes involved in alcohol metabolism, such as alcohol dehydrogenase (ADH) and cytochrome P450 CYP2E1. Objective: To identify and characterize the allelic variants of ADH1B, ADH1C and CYP2E1 genes in Colombian patients with cirrhosis and/or HCC. Materials and methods: We included samples from patients attending the hepatology unit between 2005-2007 and 2014-2016 of a hospital in Medellin. Samples were genotyped using PCR-RFLP. We compared the results with two control groups and the 1000 Genomes Project database. Results: We collected 97 samples from patients with a diagnosis of cirrhosis and/or HCC. The two main risk factors were chronic alcohol consumption (18.6%) and cholangiopathies (17.5%). The most frequent genotypes in the study population were ADH1B*1/1 (82%), ADH1C*1/1 (59%), and CYP2E1*C/C (84%). Conclusions: This first study of polymorphisms in Colombian patients diagnosed with cirrhosis and/or HCC showed genotypes ADH1B*1/1, ADH1C*1/1 and CYP2E1*C/C as the most frequent. We found no significant differences in the genotype frequency between cases and controls. Further studies are necessary to explore the association between polymorphisms and the risk of end-stage liver disease from alcohol consumption.

Introducción. Uno de los principales factores de riesgo del carcinoma hepatocelular es el consumo crónico de alcohol. En estudios en diferentes poblaciones, se sugiere que las variantes genéticas de las enzimas que participan en el metabolismo del alcohol, como la alcohol deshidrogenasa (ADH) y la citocromo P450 (CYP2E1), estarían asociadas con riesgo de enfermedades hepáticas terminales.Objetivo. Identificar y caracterizar las variantes alélicas de los genes ADH1B, ADH1C y CYP2E1 en pacientes colombianos con diagnóstico de cirrosis y carcinoma hepatocelular.Materiales y métodos. Se incluyeron muestras de pacientes atendidos entre el 2005 y el 2007, y entre el 2014 y el 2016, en la unidad de hepatología de un hospital de Medellín. La genotipificación de las muestras se hizo mediante reacción en cadena de la polimerasa (Polymerase Chain Reaction, PCR) con análisis de los polimorfismos en la longitud de los fragmentos de restricción (Restriction Fragment Length Polymorphism, RFLP). Los resultados se compararon con los de dos grupos de control y con lo reportado en la base de datos del 1000 Genomes Project.Resultados. Se recolectaron 97 muestras de pacientes con diagnóstico de cirrosis y carcinoma hepatocelular. Los dos factores de riesgo más frecuentes fueron el consumo crónico de alcohol (18,6 %) y las colangiopatías (17,5 %). Los genotipos más frecuentes en la población de estudio fueron el ADH1B*1/1 (82 %), el ADH1C*1/1 (59 %) y el CYP2E1*C/C (84 %).Conclusiones. En este primer estudio de los polimorfismos en pacientes colombianos con diagnóstico de cirrosis y carcinoma hepatocelular, los genotipos más frecuentes fueron el ADH1B*1/1, el ADH1C*1/1 y el CYP2E1*C/C. No se observaron diferencias estadísticamente significativas en la frecuencia de los genotipos entre los casos y los controles. Se requieren estudios adicionales en población colombiana para evaluar el riesgo de la enfermedad hepática terminal por consumo crónico de alcohol y laasociación con los polimorfismos.

Prevención de recurrencia de infección por hepatitis B en receptores de trasplante hepático utilizando dosis bajas de inmunoglobulina antihepatitis B y análogo de nucleósido / Prevention of Hepatitis B Recurrence in Liver Transplant Recipients Using Low Doses of Anti-Hepatitis B Immunoglobulin and Nucleoside Analogue

Introducción: la hepatitis B es una causa importante de trasplante hepático; produce 1 millón de muertes anuales. El uso de inmunoglobulina antihepatitis B en dosis altas y análogos de nucleósidos redujeron en un 90% la reinfección del injerto. Objetivo: evaluar la eficacia de dosis bajas de inmunoglobulina postrasplante para prevenir la reinfección del injerto. Metodología: serie de casos retrospectiva de pacientes trasplantados en el Hospital “Pablo Tobón Uribe”, entre enero de 2004 y septiembre de 2014, que recibieron inmunoglobulina después del trasplante. Se evaluaron la carga viral de hepatitis B, las transaminasas y los marcadores serológicos para documentar recaída, además de variables como mortalidad, complicaciones, disfunción del injerto, reacciones adversas y costos. Resultados: fueron 18 pacientes trasplantados con hepatitis B; 50% tenía hepatocarcinoma; 22%, cirrosis; y 22%, insuficiencia hepática aguda. La mediana de seguimiento fue de 43,27 meses (14,7-65,2). De los pacientes, 2 tuvieron antígeno de superficie positivo en el postrasplante y en 1 hubo recaída con carga viral positiva a los 41 meses. La tasa de reinfección del injerto fue del 5,5%. No hubo muertes. Se estimó que el costo de usar dosis bajas de inmunoglobulina fue menor comparado con las dosis altas a 6 meses de terapia; sin embargo, no se hizo estudio de costo-efectividad. La disfunción del injerto fue del 10% a 33 meses. Conclusión: con dosis bajas de inmunoglobulina se previno la reinfección del injerto, similar a lo reportado en otras series. Mientras los esquemas libres de inmunoglobulina logran demostrar su utilidad a largo plazo, usar dosis bajas de inmunoglobulina sigue siendo útil.

Introduction: Hepatitis B results in one million deaths every year and is is an important reason for liver transplantation. The use of anti-hepatitis B immunoglobulin at high doses and nucleoside analogues have reduced reinfection of the graft by 90%. Objective: This study evaluated the efficacy of low doses of immunoglobulin to prevent reinfection of grafts after transplantation. Methodology: This is a retrospective study of a series of patients who had been transplanted and who received immunoglobulin after transplantation at the Hospital Pablo Tobón Uribe between January 2004 and September 2014. Hepatitis B viral load, transaminase and serological markers were used to document relapses. Other variables studied included mortality, complications, graft dysfunction, adverse reactions and costs. Results: There were 18 patients with hepatitis B who had transplants: 50% had hepatocarcinoma, 22% had cirrhosis, and 22% had acute liver failure. The median follow-up time was 43.27 months with a range of 14.7 to 65.2 months. Two patients tested positive for surface antigen in the post-transplant period and one relapsed and had a positive viral load at 41 months. The graft reinfection rate was 5.5%. There were no deaths. It was estimated that the cost of using low doses of immunoglobulin was lower than that of using high doses at 6 months of therapy, but no cost-effectiveness study was done. Graft dysfunction was 10% to 33 months. Conclusion: Low doses of immunoglobulin prevented reinfection of grafts in a way that is similar to that reported in other series. While immunoglobulin free schemes have proven to be useful for the long term, low doses of immunoglobulin remain useful.

Primer trasplante hepático en paciente con infección por VIH en Colombia: reporte de caso y revisión de la literatura / First Liver Transplant in an HIV Patient in Colombia: Case Report and Literature Review

Resumen El tratamiento antirretroviral y el manejo adecuados convirtieron a la infección por VIH en una enfermedad crónica con buena sobrevida a largo plazo. Actualmente, más de la mitad de las muertes en estos pacientes se debe a causas no relacionadas con el VIH, y la enfermedad hepática terminal de diversas etiologías es la segunda causa de muerte en estos pacientes, por lo que el trasplante de hígado se ha convertido en una opción de tratamiento para pacientes seleccionados que tengan buen control de la infección por VIH, con una sobrevida postrasplante similar a otras indicaciones. En este reporte, presentamos el caso del primer paciente en Colombia trasplantado de hígado con infección por VIH, con coinfección por virus B, cirrosis hepática y hepatocarcinoma en el Hospital Pablo Tobón Uribe en el año 2010.

Abstract Appropriate antiretroviral treatment and management has transformed HIV into a chronic disease with good long-term survival rates. Currently more than half of the deaths of these patients are due to non-HIV-related causes among which terminal liver disease resulting from various etiologies is the second most frequent cause of death. Consequently, liver transplantation has become a treatment option for selected patients whose HIV infections have been controlled. Post-transplant survival rates are similar to those of other liver transplant patients. This report presents the first liver transplant in Colombia of an HIV infected patient. This patient had a coinfection with Hepatitis B virus as well as cirrhosis of the liver and hepatocellular carcinoma. The procedure was performed in the Hospital Pablo Tobón Uribe in 2010.

Infección oculta por el virus de la hepatitis B en pacientes sometidos a trasplante hepático / Occult Hepatitis B Virus Infection in Liver Transplant Patients

Introducción: la infección oculta por el virus de la hepatitis B (VHB) se caracteriza por la presencia del genoma viral en suero y/o tejido hepático de individuos negativos para el antígeno de superficie HBsAg. La infección oculta se ha asociado con el desarrollo de cirrosis y carcinoma hepatocelular. Objetivo: identificar casos de infección oculta por el VHB en pacientes con diagnóstico de cirrosis y carcinoma hepatocelular, sometidos a trasplante hepático. Materiales y métodos: entre febrero de 2013 y marzo de 2014 fueron obtenidas muestras de explante hepático provenientes de pacientes con diagnóstico de cirrosis y/o carcinoma hepatocelular. Se detectó el genoma del VHB mediante amplificación de tres regiones del genoma viral (S, Core y X). Las muestras positivas se confirmaron por reacción en cadena de la polimerasa (PCR) en tiempo real para la región S. Resultados: se analizaron 15 muestras de tejido hepático, y en dos (13,3%) se detectó el genoma del VHB mediante PCR anidada para la región S y por PCR semianidada para la región X, resultado confirmado por PCR en tiempo real. Estas muestras provenían de pacientes negativos para los marcadores serológicos de infección por el VHB, anti-HBc y anti-HBs. Conclusión: la frecuencia de infección oculta reportada en este estudio es similar a lo reportado en Brasil en muestras de biopsias obtenidas de pacientes con hepatitis crónica. Estudios adicionales son necesarios para estimar la frecuencia de infección oculta por VHB (OBI) en pacientes con hepatopatías terminales en Colombia

Introduction: Occult hepatitis B virus infection is characterized by the presence of the viral genome in serum and/or liver tissue from individuals who test negative for the HBsAg surface antigen. Occult infection has been associated with the development of cirrhosis and hepatocellular carcinoma. Objective: The objective of this study was to identify cases of occult hepatitis B virus infection in patients with cirrhosis and/or hepatocellular carcinoma undergoing liver transplantation. Materials and methods: Between February 2013 and March 2014 hepatic explant samples were obtained from patients with cirrhosis and/or hepatocellular carcinoma. The hepatitis B virus genome was detected by amplification of three regions of the viral genome (S, Core and X). Positive samples were confirmed by real-time PCR for the S region. Results: Fifteen hepatic tissue samples were analyzed. The genome of the hepatitis B virus was detected in two (13.3%) samples by nested PCR for the S region and by semi-nested PCR for region X. The results were confirmed by real-time PCR. These samples came from patients who had tested negative for anti-HBc and anti-HBs serological markers for hepatitis B virus infection. Conclusion: The frequency of occult infection reported in this study is similar to that reported in Brazil in biopsy specimens obtained from patients with chronic hepatitis. Additional studies are needed to estimate the frequency of occult hepatitis B in patients with end-stage liver disease in Colombia

Hepatitis E Virus Genotype 3 in Colombia: Survey in Patients with Clinical Diagnosis of Viral Hepatitis.

BACKGROUND: Hepatitis E virus is a major cause of outbreaks as well as sporadic hepatitis cases worldwide. The epidemiology of this enterically transmitted infection differs between developing and developed countries. The aims of this study were to describe HEV infection in Colombian patients and to characterize the genotype. METHODS: A prospective study was carried out on 40 patients aged over 15 with a clinical diagnosis of viral hepatitis, recruited from five primary health units in the city of Medellin, Colombia. Fecal samples obtained from the 40 consecutives cases were analyzed for HEV RNA using nested reverse transcription PCR for both ORF1 and ORF2-3. The amplicons were sequenced for phylogenetic analyses. RESULTS: Nine (22.5%) cases of HEV infection were identified in the study population. Three HEV strains obtained from patients were classified as genotype 3. No significant association was found between cases of Hepatitis E and the variables water drinking source, garbage collection system and contact with pigs. CONCLUSIONS: This is the first prospective study of hepatitis E in Colombian patients. The circulation of the genotype 3 in this population is predictable considering the reports of the region and the identification of this genotype from pigs in the state of Antioquia, of which Medellin is the capital. Further studies are necessary to establish whether zoonotic transmission of HEV is important in Colombia.

Enfermedad renal crónica en pacientes trasplantados de hígado en el Hospital Pablo Tobón Uribe 2005-2013 / Chronic Kidney Disease in Liver Transplant Patients in the Hospital Pablo Tobón Uribe 2005-2013

Avances en la terapia inmunosupresora han revolucionado los resultados a largo plazo del trasplante de hígado, sin embargo esto ha incrementado la prevalencia de enfermedad renal crónica (ERC); existen algunos factores de riesgo asociados como el uso de inhibidores de calcineurínicos, la presencia de diabetes e hipertensión. El objetivo de este estudio es determinar la incidencia de ERC en los pacientes trasplantados de hígado del hospital Pablo Tobón Uribe durante los años 2005-2013 y evaluar las complicaciones asociadas. Metodología: cohorte retrospectiva. Resultados: se evaluaron 215 pacientes trasplantados de hígado, la edad mediana fue de 50,37 años (DE ± 12,6), el 42,8% mujeres; 3,3% de los pacientes necesitaron terapia de reemplazo renal al primer mes del trasplante; la terapia inmunosupresora más utilizada fue ciclosporina en el 90,7%. Durante el seguimiento la tasa de filtración disminuye con el tiempo, con una mediana de 86,2 mL/min/1,73 (DE ± 25,9) al momento del trasplante y llegando a 74,2 mL/min/1,73 (DE ± 24,5) a 3 años de seguimiento. La velocidad de deterioro de la función renal por medio del modelo de ecuaciones generalizadas estimadas fue de 3,5 mL/año (IC: 95% 2,44-4,74, p= 0,000). Al momento del trasplante de hígado el 16,3% de los pacientes presentaban una TFG menor a 60 mL/min; a tres años de seguimiento fue de 29,6%; al agrupar las complicaciones encontradas, según presencia o no de disfunción renal al final del seguimiento, encontramos que a excepción de la muerte, la presencia de enfermedad cerebrovascular y enfermedad coronaria fue similar en ambos grupos. Conclusión: la ERC es una complicación frecuente en los pacientes trasplantados de hígado, nuestra recomendación es el control frecuente de los marcadores de daño renal.

Advances in immunosuppressive therapy have revolutionized long-term results of liver transplantation, but this has increased the prevalence of chronic kidney disease (CKD). Some risk factors including diabetes and hypertension are associated with the use of calcineurin inhibitors. The objective of this study is to determine the incidence of CKD in liver transplant patients at the Hospital Pablo Tobon Uribe from 2005 to 2013 and then assess associated complications. Methods: This is a retrospective cohort study. Results: This study evaluated 215 patients with liver transplants. Average patient age at transplant was 50.37 years (SD +/- 12.6), and 42.8% of the patients were women. Kidney replacements were required by 3.3% of the patients within the first month after liver transplantation. The most frequently used immunosuppressive therapy was cyclosporine which was used for 90.7% of the patients. During follow-up, the filtration rate decreased over time with a median of 86.2ml/min/1.73 (SD +/- 25.9) at transplant. This reached 74.2ml/min/1.73 (SD +/- 24.5) at 3 years follow-up. The rate of deterioration of renal function determined by generalized estimated equations was 3.5ml/year (95% CI 2.44 to 4.74, p = 0.000). At the time of liver transplantation 16.3% of patients had glomerular filtration rates of less than 60ml/min. After three years of follow-up, 29.6% of patients had glomerular filtration rates of less than 60ml/min. By grouping complications such as the presence or absence of renal dysfunction at follow-up, we found that, except for death, the presence of cerebrovascular disease and coronary heart disease was similar in both groups. Conclusion: CKD is a frequent complication in liver transplant patients. Our recommendation is frequent monitoring of kidney damage markers.