Resumen ejecutivo: Enfermedad por hígado graso no alcohólico en sujetos con diabetes mellitus tipo 2: Postura conjunta de la Asociación Chilena de Hepatología (ACHHEP) y la Sociedad Chilena de Diabetología (SOCHIDIAB) / Non-alcoholic fatty liver disease in type 2 diabetes: a joint statement of the Chilean Hepatology and Diabetology Societies

Non-alcoholic fatty liver disease (NAFLD) has a high prevalence and risk of progression to cirrhosis and other complications in patients with type 2 diabetes mellitus (T2DM). Likewise, the presence of NAFLD implies a high risk of developing T2DM, determining a bidirectional relationship between them. The diabetology and hepatology societies, developed a joint initiative aiming to unify criteria, reviewing the definitions, diagnostic criteria, risk stratification, treatment, and follow-up of patients with NAFLD and T2DM. The key questions to be discussed were defined by a panel of specialists in diabetology and hepatology. The Delphi methodology was used to reach consensus on the respective recommendations. Based on the discussion generated among the experts, diagnostic and treatment algorithms were proposed, as well as an indication for referral and the role of the different specialists involved in the management of these patients. Strengthening multidisciplinary work with patients with NAFLD and T2DM will allow the early recognition of the disease, the prevention of the progression to cirrhosis, and reducing the associated complications.

Trasplante hepático: evolución, curva de aprendizaje y resultados después de los primeros 300 casos / Liver transplantation: development, learning curve and results after the first 300 cases

Background: Liver transplantation (LT) is an option for people with liver failure who cannot be cured with other therapies and for some people with liver cancer. Aim: To describe, and analyze the first 300 LT clinical results, and to establish our learning curve. Material and Methods: Retrospective cohort study with data obtained from a prospectively collected LT Program database. We included all LT performed at a single center from March 1994 to September 2017. The database gathered demographics, diagnosis, indications for LT, surgical aspects and postoperative courses. We constructed a cumulative summation test for learning curve (LC-CUSUM) using 30-day post-LT mortality. Mortality at 30 days, and actuarial 1-, and 5-year survival rate were analyzed. Results: A total of 281 patients aged 54 (0-71) years (129 women) underwent 300 LT. Ten percent of patients were younger than 18 years old. The first, second and third indications for LT were non-alcoholic steatohepatitis, chronic autoimmune hepatitis and alcoholic liver cirrhosis, respectively. Acute liver failure was the LT indication in 51 cases (17%). The overall complication rate was 71%. Infectious and biliary complications were the most common of them (47 and 31% respectively). The LC-CUSUM curve shows that the first 30 patients corresponded to the learning curve. The peri-operative mortality was 8%. Actuarial 1 and 5-year survival rates were 82 and 71.4%, respectively. Conclusions: Outcome improvement of a LT program depends on the accumulation of experience after the first 30 transplants and the peri-operative mortality directly impacted long-term survival.

Trasplante hepático exitoso en un paciente portador del Virus de la Inmunodeficiencia Humana (VIH) / Liver transplantation in a patient with human immunodeficiency virus (HIV): case report

Abstrac: Before the advent of highly active antiretroviral therapy (HAART), patients infected with human immunodeficiency virus (HIV) were considered as having an absolute contraindication for liver transplantation (LT). Considering the increased life expectancy in HIV positive patients under HAART and the improvements in the management of graft recipients, these patients are now suitable for carrying out transplants in selected cases. We report a 26 years old HIV positive male who developed acute liver failure possibly caused by drug induced liver injury who underwent a successful liver transplantation.

Nuevas terapias orales de acción directa para tratamiento de virus de hepatitis C (VHC) / Direct antivirals for the treatment of chronic hepatitis C virus infection: experience in 106 patients

Background: The availability of direct-acting antivirals (DAA) for the treatment of chronic hepatitis C virus (HCV) infection is just starting to expand in Chile. Aim: To report the initial experience of patients treated with DAA and their evolution after treatment. Material and Methods: Prospective cohort study, from June 2013 to August 2016 of patients treated with DAA for HCV in three clinical centers. The presence of cirrhosis, clinical and laboratory features; adverse events (AE) and post-treatment changes in liver function were evaluated. Sustained viral response at 12 weeks post-treatment (SVR12) was determined. Results: One hundred six patients aged 58 ± 13 years, 54% males, were included. HCV genotype 1b was present in 88% and 47% had cirrhosis. Treatment regimens were asunaprevir + daclatasvir (DCV) in 17% of patients, paritaprevir / ritonavir / ombitasvir + dasabuvir in 33%, sofosbuvir (SOF) + DCV in 19%, and SOF + ledipasvir in 30%. Twenty five percent of patients used generic drugs. SVR12 was 92.1%, with no differences between generic and brand-name drugs. Serious AE were recorded in 22% of patients, being more common in those with cirrhosis (34% vs 11.5%, p < 0.01). At 12 weeks post-treatment follow-up, there was a decrease in aminotransferase values (p < 0.01), improvement in Child-Pugh score (5.9 vs. 5.5, p = 0.03) and decreased presence of ascites (p = 0.02). Conclusions: In our setting, DAA for HCV was highly effective and safe in non-cirrhotic patients. Hepatic function and inflammation improved at 12 weeks of follow-up. AE were common in patients with cirrhosis, suggesting that these patients should be treated by experienced teams. Generic drugs had similar effectiveness compared to originals.

Diarrea poscolecistectomía: ¿un problema frecuente? / Postcholecystectomy diarrhea is a frequent problem?

Resumen Introducción: La colecistectomía laparoscópica es una de las intervenciones quirúrgicas más frecuentes en nuestro país. La diarrea poscolecistectomía es una entidad poco reconocida, con una prevalencia descrita entre el 0,9 y 35,6%, sin embargo, en Chile esto no ha sido claramente definido. Objetivo: Determinar la prevalencia y características de la diarrea poscolecistectomía laparoscópica electiva en una muestra de pacientes chilenos. Material y métodos: Se aplicó una encuesta telefónica estructurada sobre consistencia y frecuencia de deposiciones, entre 4 y 6 meses después de la intervención, a los pacientes adultos operados de colecistectomía laparoscópica electivamente entre diciembre de 2014 y marzo de 2015. Se definió como «diarrea poscolecistectomía¼ la presencia de deposiciones líquidas o inusualmente disgregadas que hubiesen comenzado posteriormente a la intervención y se estableció el término de «diarrea prolongada¼ como la duración de síntomas mayor de 4 semanas. Resultados: Se encuestó a 100 pacientes (73% de mujeres). La prevalencia global de diarrea poscolecistectomía fue del 35% (n = 35). La prevalencia de pacientes con diarrea prolongada fue del 15% (n = 15). En el grupo con diarrea prolongada, se observó resolución completa de esta en el 57% de los pacientes (n = 8) en un plazo medio de 99 ± 29 días. Conclusión: La diarrea poscolecistectomía es una entidad frecuente en nuestra población, con una alta prevalencia dentro de los primeros 28 días posteriores a la intervención. En la mayoría de los pacientes se resuelve en los primeros 6 meses.

Abstract Introduction: Laparoscopic cholecystectomy (LC) is one of the most common surgical procedures in our country. Postcholecystectomy diarrhea is an unrecognized entity, with a reported prevalence between 0.9 and 35.6%, nonetheless in Chile this has not been clearly defined. Objective: To determine the prevalence and characteristics of diarrhea following elective laparoscopic cholecystectomy in our institution. Material and methods: A structured questionnaire about consistency and defecation frequency was applied to adult patients summited to an elective LC between December 2014 and February 2015, by a telephone survey within 4 and 6 months after the surgical procedure. Postcholecystectomy diarrhea was defined as the presence of liquid or unusually disrupted faecal material beginning after LC. Persistent diarrhea was established when diarrhea continued for a period longer than four weeks. Results: One hundred patients were included (73% women). The overall prevalence of postcholecystectomy diarrhea was 35% (n = 35). The prevalence of patients with persistent diarrhea was 15% (n = 15). In the group of patients with persistent diarrhea, complete resolution was observed on 57% of the cases (n = 8) within an average period of 99 ± 29 days. Conclusion: Post cholecystectomy diarrhea is a frequent condition in our population, with a high prevalence within the first 28 days after LC. In most patients it resolved within 6 months.

Conversion to Mycophenolate Mofetil Monotherapy in Liver Recipients: Calcineurin Inhibitor Levels are Key

Abstract: The use of calcineurin inhibitors (CNI) after liver transplantation is associated with post-transplant nephrotoxicity. Conversion to mycophenolate mofetil (MMF) monotherapy improves renal function, but is related to graft rejection in some recipients. Our aim was to identify variables associated with rejection after conversion to MMF monotherapy. Conversion was attempted in 40 liver transplant recipients. Clinical variables were determined and peripheral mononuclear blood cells were immunophenotyped during a 12-month follow- up. Conversion was classified as successful (SC) if rejection did not occur during the follow-up. MMF conversion was successful with 28 patients (70%) and was associated with higher glomerular filtration rates at the end of study. It also correlated with increased time elapsed since transplantation, low baseline CNI levels (Tacrolimus ≤ 6.5 ng/mL or Cyclosporine ≤ 635 ng/mL) and lower frequency of tacrolimus use. The only clinical variable independently related to SC in multivariate analysis was low baseline CNI levels (p = 0.02, OR: 6.93, 95%, CI: 1.3-29.7). Mean baseline fluorescent intensity of FOXP3+ T cells was significantly higher among recipients with SC. In conclusion, this study suggests that baseline CNI levels can be used to identify recipients with higher probability of SC to MMF monotherapy. Clinicaltrials.gov identification: NCT01321112.

Aumento aislado y sostenido de aspartato aminotransferasa por presencia de macroenzimas: caso clínico / Persistent elevation of aspartate aminotransferase (AST) due to the presence of macro-AST: report of one case

We report an asymptomatic 23-year-old woman with an isolated and persistent increase in serum levels of aspartate aminotransferase (AST). An extensive work up including laboratory and image testing revealed no abnormalities thus suggesting the presence of macro-AST. A polyethylene glycol (PEG) precipitation assay was performed and confirmed the presence of macro-AST.

II Consenso de la Sociedad Chilena de Endocrinología y Diabetes sobre resistencia a la insulina

Insulin resistance is a prevalent condition commonly associated with unhealthy lifestyles. It affects several metabolic pathways, increasing risk of abnormalities at different organ levels. Thus, diverse medical specialties should be involved in its diagnosis and treatment. With the purpose of unifying criteria about this condition, a scientific-based consensus was elaborated. A questionnaire including the most important topics such as cardio-metabolic risk, non-alcoholic fatty liver disease and polycystic ovary syndrome, was designed and sent to national experts. When no agreement among them was achieved, the Delphi methodology was applied. The main conclusions reached are that clinical findings are critical for the diagnosis of insulin resistance, not being necessary blood testing. Acquisition of a healthy lifestyle is the most important therapeutic tool. Insulin-sensitizing drugs should be prescribed to individuals at high risk of disease according to clinically validated outcomes. There are specific recommendations for pregnant women, children, adolescents and older people.

Evaluación para el aprendizaje: experiencia en un curso teórico de pregrado en medicina / Assessment for learning: experience in an undergraduate medical theoretical course

Background: Assessment for learning is a paradigm that is taking shape in the field of medical education. This approach aims to embed the assessment process within the educational and learning process. Aim: To evaluate the impact of curricular changes, from a focus of assessment of learning to one of assessment for learning, in the perception of undergraduate students of medicine and their final grades obtained in a theoretical course (TCG). Material and Methods: In the year 2011 lectures were reduced and intermediate assessments followed by a feedback session were introduced. The activities of each program course, surveys about student perceptions of the course and the final grades of students (assessments with multiple choice questions) were compared between the periods prior and after curricular changes (2005-2010 and 2011-2013). Results: As a consequence of curricular changes, time for lectures was reduced by 19.5%, time for summative assessments was increased by 8.5%, and feedback activity, occupying 7.3% of the course time was added. There were significant improvements in student is perceptions in all areas assessed by surveys, emphasizing feedback and assessments. The overall grade assigned to the course dictated after implementing the changes increased from 6.18 to 6.59 (p < 0.001, 1-7 scale). The grades of students also improved from an average of 5.78 to 6.43 (p < 0.001, 1-7 scale). Conclusions: Assessment for learning achieved the desired educational impact without increasing the assigned curricular time. Programmatic assessment is favorably perceived by students.

¿Influye el medio de preservación del injerto en los resultados y costos del trasplante hepático de donante fallecido?: Comparación de dos soluciones de preservación / Outcomes using two preservation solutions (UW/HTK) in liver transplantation from brain death donors

Background: Preservation solutions are critical for organ transplantation. In liver transplant (LT), the solution developed by the University Of Wisconsin (UW) is the gold-standard to perfuse deceased brain death donor (DBD) grafts. Histidine-Tryptophan-Ketoglutarate (HTK), formerly a cardioplegic infusion, has been also used in solid organ transplantation. Aim: To compare the outcomes of LT in our center using either HTK or UW solution. Patients and Methods: Retrospective study including 93 LT DBD liver grafts in 89 patients transplanted between March 1994 and July 2010. Forty-eight grafts were preserved with UW and 45 with HTK. Donor and recipient demographics, total infused volume, cold ischemia time, post-reperfusion biopsy, liver function tests, incidence of biliary complications, acute rejection and 12-month graft and patient survival were assessed. Preservation solution costs per liver graft were also recorded. Results: Donor and recipient demographics were similar. When comparing UW and HTK, no differences were observed in cold ischemia time (9.6 ± 3 and 8.7 ± 2 h respectively, p = 0.23), biliary complications, the incidence of acute rejection, primary or delayed graft dysfunction. Histology on post-reperfusion biopsies revealed no differences between groups. The infused volume was significantly higher with HTK than with UW (9 (5-16) and 6 (3-11) l, p < 0.001). The cost per procurement was remarkably lower using HTK. Conclusions: Perfusion of DBD liver grafts with HTK is clinically equivalent to UW, with a significant cost reduction.

Prevalencia de síndrome de Gilbert y sus determinantes genéticas en población chilena / Prevalence of Gilbert syndrome and its genetic determinants in Chile

Background: In Europeans the TATA box TA7 repeat promoter variant in the UGT1A1 gene (UGT1A1*28) is the major determinant of bilirubin levels. Aim: To study the prevalence of Gilbert Syndrome (GS) and its genetic determinants in Chile. Material and Methods: Three different studies were conducted. The prevalence of GS in Chile was assessed in 991 subjects with normal liver tests (ALT and GGT) from the 2nd National Health Survey. We defined GS as a total bilirubin (TB) between 1.4-5mg/dL. The second study assessed the genotype prevalence of SNP rs6742078 (in LD with UGT1A1*28) and rs4149056 in 500 DNA samples of non-related Hispanics. Finally, a case-control study was designed to assess the phenotype-genotype correlation. UGT1A1*28 and rs4149056 variants were determined by direct sequencing and allelic discrimination assays (TaqMan), respectively. Results: Prevalence of GS in the general Chilean population was 2.6% (4.5% in males and 0.5% in female). No correlation with age, educational level or home location was found. Genotypes for UGT1A1*28 (TA6/6 50.5%, TA6/7 37.8%, TA7/7 11.7%) and rs4149056 (TT 74.1%, CT 22.8%, and CC 3.1%) variants were similar to Europeans. In the case-control study, most patients with GS were homozygotes for UGT1A1*28 (TA7/7, 74%). Of note, 44% of patients with intermediate TB levels were also TA7/7, compared to 7% in normal subjects. SLCO1B1 genotype was not correlated with TB levels. Conclusions: While the prevalence of GS was lower in Chile compared to Europeans (~5%), the prevalence of UGT1A1*28 homozygotes was similar (~12%). In Chilean Hispanics, the UGT1A1*28 variant explain 75% of GS phenotype.

Niveles séricos de alanino-aminotransferasa en población chilena: análisis de los resultados de la encuesta nacional de salud 2009-2010 / Serum levels of alanine aminotransferase in Chilean population: analysis of results of the national health survey 2009-2010

Background: Determination of Alanine aminotransferase serum levels ([ALT]s) is a sensitive ana reliable test for liver diseases. Aim: To report the prevalence of abnormal [ALT]s in Chilean population and to identify associated variables. Methods: We analyzed data from a random sub-sample of 2,794 adults surveyed during the second Chilean National Health Survey. Abnormal [ALT]s were defined by using three different cut-off values (COV), two fixed COV (COV1: > 30 IU/L in men and > 19 IU/L in women and COV2 pre-defined by the performing laboratory) and a COV adjusted by age, weight and sex (COV3 > 31 IU/L for women and > 44 IU/L and men > 42 IU/L and > 66 IU/L with a BMI > 23). Logistic regression analysis was performed to determine risk factors for elevated [ALT]s Results: Mean [ALT]s values were 30.14 I U/L in men and 22.03 IU/L in women. The observed prevalence of abnormal [ALT]s defined by different COV were 38%, 11.5%, and 8.1% for COV1, COV2 and COV3 respectively. Variables independently associated to abnormal [ALT]s in a multivariate analysis were the following: serum gamma-glutamyl-transpeptidase (OR: 1.055 [95% CI 1.033-1.078]) and body mass index (OR:1.13 [95% CI 1.09-1.17]). Variables inversely associated with abnormal [ALT]s (COV1) were mole gender (OR-.0.976 [95% CI 0.96-0.99) and HDL-cholesterol (OR:0979 [95% CI 0.96-0.99]). Conclusions: Independently of the COV used, Chilean population exhibits a high prevalence of abnormal [ALT]s which may reflect a significant burden of liver disease. Non-alcoholic fatty liver disease could be a major contributor to elevated [ALT]s considering the association of abnormal [ALT]s and metabolic variables.

Medición volumétrica de grasa visceral abdominal con resonancia magnética y su relación con antropometría, en una población diabética / Quantification of visceral adipose tissue using magnetic resonance imaging compared with anthropometry, in type 2 diabetic patients

Background: Visceral fat accumulation is associated with the development of metabolic diseases. Anthropometry is one of the methods used to quantify it. aim: to evaluate the relationship between visceral adipose tissue volume (VAT), measured with magnetic resonance imaging (MRI), and anthropometric indexes, such as body mass index (BMI) and waist circumference (WC), in type 2 diabetic patients (DM2). Patients and Methods: Twenty four type 2 diabetic patients aged 55 to 78 years (15 females) and weighting 61.5 to 97 kg, were included. The patients underwent MRI examination on a Philips Intera® 1.5T MR scanner. The MRI protocol included a spectral excitation sequence centered at the fat peak. The field of view included from L4-L5 to the diaphragmatic border. VAT was measured using the software Image J®. Weight, height, BMI, WC and body fat percentage (BF%), derived from the measurement offour skinfolds with the equation of Durnin and Womersley, were also measured. The association between MRIVAT measurement and anthropometry was evaluated using the Pearson's correlation coefficient. Results: Mean VAT was 2478 ± 758 ml, mean BMI29.5 ± 4.7 kg/m², and mean WC was 100 ± 9.7 cm. There was a poor correlation between VAT, BMI (r = 0.18) and WC (r = 0.56). Conclusions: BMI and WC are inaccurate predictors of VAT volume in type 2 diabetic patients.

El síndrome metabólico: De factor agravante a principal factor de riesgo patogénico en diversas enfermedades crónicas / The metabolic syndrome: From an aggravating condition to a pathogenic risk factor for chronic diseases

In recent years, a rapidly increasing number of studies have focused on the association between metabolic syndrome and several chronic diseases. However, it is difficult to determine a well defined pathogenic relationship, due to the etiological heterogeneity and comorbidities of these diseases. Research efforts are aiming to identify the convergent biological mechanisms that mediate the effects of hyperinsulinemia, hyperglycemia, dyslipidemia, and hypertension. All these conditions define the metabolic syndrome, that increases the risk for several diseases. The knowledge of these biological mechanisms associated with this syndrome will elucidate the pathogenic association between a variety of chronic diseases, including its pathogenic link with cardiovascular diseases and the most common forms of dementia. The development of new therapeutic and preventive strategies for these diseases will be a corollary of this research.

Complicaciones neurológicas en pacientes adultos sometidos a trasplante hepático ortotópico: experiencia de un centro universitario / Neurological complications following a liver transplantation: experience from a Chilean center

Background: Orthotopic liver transplantation (OLT) is the treatment of choice for multiple acute and chronic end-stage liver diseases as well as for selected cases of liver malignancy and ¡iver-site metabolic disorders. Neurological impairment is a major source of morbidity and moñality following OLT. Aim: To describe the incidence and the type of neurological complications occurring in the post-operative period of OLT in patients transplanted in our hospital. Material and methods: Between March 1994 and August 2007, 76 adult patients underwent OLT. Data on incidence, time of onset, and outcome of central nervous system (CNS) complications have been obtained from our program data base and patient charts. Results: Twenty three patients (30.3 percent) had CNS complications following OLT. The leading complications were immunosuppressive drug-related neurological impairment in nine patients (39.1 percent), peripheral nerve damage in five patients (21.7 percent), central pontine myelinolysis in four patients (17.4 percent), cerebrovascular disease in three (13 percent) and CNS infection in three (13 percent). Most CNS events (90 percent) occurred in the first 2 weeks after OLT. Five patients with neurological complications died (22 percent). Conclusions: CNS complications occurred in almost one fifth of the population studied, and they had a poor outcome, as previously reported).

Trasplante hepático en Chile: Aspectos generales, indicaciones y contraindicaciones (Documento de consenso) / General considerations, indications and contraindications for liver transplantation in Chile: A multicenter consensus development document

Liver transplantation is an excellent therapeutic option for terminal liver disease. During the last decades the results of liver transplantation have improved significantly with a patient survival rate of nearly 90 percent at one year and 80 percent at 5 years of follow-up. The main indications for liver transplantation include: end-stage liver disease associated to cirrhosis, acute liver failure, and hepatic tumors (mainly hepatocarcinoma). The absolute contraindications for a transplant are less frequent than in the past, and include: severe co-morbidity (cardiac or pulmonary), sepsis, advanced HIV disease and extra-hepatic malignancy. This document presents a Consensus of the main groups performing liver transplantation in Chile, about its indications and contraindications. It also reviews general aspects of liver transplantation, including the selection and referral of liver transplant candidates, allocation of organs and the evaluation of severity of liver disease.