Drug-Induced Liver Injury in Latin America: 10-year experience of the Latin American DILI (LATINDILI) Network Drug-induced liver injury in Latin America.

BACKGROUND AND AIMS: Latin America is a region of great interest for studying the clinical presentation of idiosyncratic drug-induced liver injury (DILI). A comprehensive analysis of patients enrolled into the LATINDILI Network over a decade is presented. METHODS: Demographics, clinical presentation, histological findings and outcome of prospectively recruited DILI cases in the LATINDILI Network were analyzed. Suspected culprit drugs were classified according to the Anatomical Therapeutic Chemical classification. Causality was assessed using the Roussel Uclaf Causality Assessment Method (RUCAM) scale. RESULTS: Overall, 468 idiosyncratic DILI cases were analyzed (62% women, mean age 49 years). Hepatocellular injury predominated (62%), jaundice was present in 60% of patients and 42% were hospitalized. 4.1% of the cases had a fatal outcome, and 24 (12%) patients developed chronic DILI. The most common drug classes were systemic anti-infectives (31%), musculoskeletal agents (12%), antineoplastic and immunomodulating agents (11%), and herbal and dietary supplements (HDS, 9%). Notably, none of the patients with DILI due to antibacterials or immunosuppressants had a fatal outcome. In fact, Hy's law showed to have drug-specific predictive value, with anti-tuberculosis drugs, nimesulide and HDS associated with the worst outcome, whereas DILI caused by amoxicillin-clavulanate, nitrofurantoin and diclofenac that fulfilled Hy's law did not have a fatal outcome. CONCLUSION: Features of DILI in Latin America are comparable to other prospective registries. However, the pattern of drugs responsible for DILI differs. An increasing incidence of HDS, with high mortality rate, and likewise nimesulide and nitrofurantoin was noted. Thus, public health policies should raise awareness of the potential adverse effects of these compounds.

Herbal and Dietary Supplements-Induced Liver Injury in Latin America: Experience From the LATINDILI Network.

BACKGROUND: Herbal and dietary supplements (HDS) consumption, a growing cause of hepatotoxicity, is a common practice among Latin-American populations. OBJECTIVES: To evaluate clinical, laboratory features and outcome in HDS-hepatotoxicity included in the Latin America-Drug Induced Liver Injury (LATINDILI) Network. METHODS: A total of 29 adjudicated cases of HDS hepatotoxicity reported to the LATINDILI Network from October 2011 through December 2019 were compared with 322 DILI cases due to conventional drugs and 16 due to anabolic steroids as well as with other series of HDS-hepatotoxicity. RESULTS: From 367 DILI cases, 8% were attributed to HDS. An increasing trend in HDS-hepatotoxicity was noted over time (p = .04). Camellia sinensis, Herbalife® products, and Garcinia cambogia, mostly used for weight loss, were the most frequently adjudicated causative agents. Mean age was 45 years (66% female). Median time to onset was 31 days. Patients presented typically with hepatocellular injury (83%) and jaundice (66%). Five cases (17%) developed acute liver failure. Compared to conventional medications and anabolic steroids, HDS hepatotoxicity cases had the highest levels of aspartate and alanine transaminase (p = .008 and p = .021, respectively), had more re-exposure events to the culprit HDS (14% vs 3% vs 0%; p = .026), and had more severe and fatal/liver transplantation outcomes (21% vs 12% vs 13%; p = .005). Compared to other DILI cohorts, less HDS hepatotoxicity cases in Latin America were hospitalized (41%). CONCLUSIONS: HDS-hepatotoxicity in Latin-America affects mainly young women, manifests mostly with hepatocellular injury and is associated with higher frequency of accidental re-exposure. HDS hepatotoxicity is more serious with a higher chance of death/liver transplantation than DILI related to conventional drugs.

Resistance-associated substitutions and response to treatment in a chronic hepatitis C virus infected-patient: an unusual virological response case report.

BACKGROUND: Direct-Acting agents (DAAs) target and inhibit essential viral replication proteins. They have revolutionized the treatment of Hepatitis C virus (HCV) infection reaching high levels of sustained virologic response. However, the detection of basal resistance-associated substitutions (RASs) to DAAs in naïve patients could be important in predicting the treatment outcome in some patients exhibiting failures to DAA-based therapies. Therefore, the aim of this work was to evaluate the presence of RASs as minority variants within intra-host viral populations, and assess their relationship to response to therapy on a multiple times relapser patient infected chronically with HCV. CASE PRESENTATION: A male HCV infected-patient with a genotype 1a strain was evaluated. He had previously not responded to dual therapy (pegylated interferon-α plus ribavirin) and was going to start a direct-acting agent-based therapy (DAAs). He showed no significant liver fibrosis (F0). Viral RNA was extracted from serum samples taken prior and after therapy with DAAs (sofosbubir/ledipasvir/ribavirin). NS5A and NS5B genomic regions were PCR-amplified and the amplicons were sequenced using Sanger and next-generation sequencing (NGS) approaches. RASs were searched in in-silico translated sequences for all DAAs available and their frequencies were determined for those detected by NGS technology. Sanger sequencing did not reveal the presence of RASs in the consensus sequence neither before nor after the DAA treatment. However, several RASs were found at low frequencies, both before as well as after DAA treatment. RASs found as minority variants (particularly substitutions in position 93 within NS5A region) seem to have increased their frequency after DAA pressure. Nevertheless, these RASs did not become dominant and the patient still relapsed, despite perfect adherence to treatment and having no other complications beyond the infection (no significant fibrosis, no drug abuse). CONCLUSIONS: This report shows that some patients might relapse after a DAA-based therapy even when RASs (pre- and post-treatment) are detected in very low frequencies (< 1%) within intra-host viral populations. Increased awareness of this association may improve detection and guide towards a personalized HCV treatment, directly improving the outcome in hard-to-treat patients.

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.

IL28B gene polymorphism rs12979860, but not rs8099917, contributes to the occurrence of chronic HCV infection in Uruguayan patients.

BACKGROUND: Host single-nucleotide polymorphisms (SNPs) near the interleukin 28B (IL28B) locus are associated with sustained virological response to antiviral therapy and with spontaneous Hepatitis C Virus (HCV) clearance. Prevalence of these SNPs varies depending on ethnicity. The impact of IL28B SNPs in HCV-infected patients is currently unknown in Uruguay. Therefore, the aim of this study was to evaluate and compare the distribution of polymorphisms in the IL28B gene (rs12979860 and rs8099917) among HCV-infected patients and healthy individuals in Uruguay and thus assess their possible association with the establishment of HCV infection. METHODS: DNA was recovered from 92 non-infected individuals and 78 HCV-infected patients and SNPs were determined by RFLP and allelic discrimination by real-time PCR. RESULTS: The distribution of rs12979860 genotypes for the infected population was 29.5%-CC, 47.4%-CT and 23.1%-TT and for the control group 45.7%, 42.4% and 11.9%, respectively. Prevalence in both infected and uninfected individuals is similar to that reported in other countries with admixed populations. The distribution of rs8099917 genotypes for the infected population was 57.7%-TT, 27.2%-TG and 14.1%-GG and for the control group 60.9%, 33.7% and 5.4%, respectively. The comparison of rs12979860 genotype distribution between the two populations evidenced a higher prevalence of the favourable genotype (CC) in the uninfected control group (p < 0.05). Additionally, results generated using logistic regression analysis show that individuals carrying rs12979860-TT or CT genotypes have a higher likelihood of developing chronic hepatitis upon infection with HCV, when compared to CC carriers, considering rs8099917 genotype as constant. CONCLUSION: Patients with HCV infection have a statistically significant lower prevalence of the favourable rs12979860 genotype when compared to uninfected individuals; therefore we can establish that only IL28B rs12979860-CT and TT genotypes seem to contribute to the occurrence of chronic HCV infection in the cohort of Uruguayan population studied. Considering that a trend towards a higher frequency of "good" response genotypes was observed in responder patients, we believe that IL28B rs12979860 genotyping could be a useful tool for predicting different therapies outcome, including in the DAA era.

Clinical epidemiology of acute hepatitis C in South America.

There is scarce data pertaining to acute hepatitis C (aHC) infection in South America. We aimed to describe clinical characteristics and evolution of aHC in a South American cohort. A retrospective survey was conducted at 13 hepatology units. All patients ≥16 years old with aHC diagnosis were included. Demographic, clinical and outcome information were registered in a standardized ad hoc questionnaire. Sixty-four patients were included. The majority were middle-aged (median age: 46 years) and female (65.6%); most of them were symptomatic at diagnosis (79.6%). HCV-1 was the most prevalent genotype (69.2%). Five patients had liver failure: three cases of severe acute hepatitis, one case of fulminant hepatitis and one case of acute-on-chronic liver failure. Nosocomial exposure was the most prevalent risk factor. Evolution was assessed in 46 patients. In the untreated cohort, spontaneous resolution occurred in 45.8% and was associated with higher values of AST/ALT and with the absence of intermittent HCV RNA viremia (P = 0.01, 0.05, and 0.01, respectively). In the treated cohort, sustained virological response was associated with nosocomial transmission and early treatment initiation (P = 0.04 each). The prevalence of nosocomial transmission in this South-American cohort of aHC stresses the importance of following universal precautions to prevent HCV infection. J. Med. Virol. 89:276-283, 2017. © 2016 Wiley Periodicals, Inc.

[Noninvasive diagnosis of esophageal varices in cirrhotic patients]. / Diagnóstico no invasivo de la presencia de várices esofágicas en pacientes cirróticos.

INTRODUCTION: Variceal bleeding is a frequent and serious complication of cirrhosis. Early detection of varices by videogastroscope (VGC) is recommended in all patients with cirrhosis to determine the need for prophylactic treatment. Have been described noninvasive markers of the presence of esophageal varices, which could prevent the realization of VGC for that purpose. OBJECTIVE: To determine and compare noninvasive (longitudinal diameter of spleen, platelet count, platelet reason / spleen) as predictors of the presence of esophageal varices. MATERIAL AND METHODS: We retrospectively studied 125 patients with cirrhosis from any cause. They had VGC, blood count and abdominal ultrasonography. The diagnostic accuracy for determining the presence of esophageal varices or large varices according to the different variables was studied using the area under the ROC curve (AUROC). RESULTS: The prevalence of esophageal varices was 63.2% and 42.4% were diagnosed with large varices. The reason platelets/spleen and platelet count showed an AUROC of 0.74 for the detection of esophageal varices. The cut-off for the ratio platelets / spleen was 1.010 (sensitivity 72.15% and specificity 71.74%) for the presence of varices and 870 for the presence of clinically significant varices (sensitivity 62.26% and specificity 62.50%). The analysis according to these breakpoints showed that 23.6% of patients with scores higher than 1,010 had large varices and 45% of patients with values lower than 870 had not large varices. CONCLUSIONS: Although the reason platelets/spleen showed an AUROC acceptable, its implementation would entail a risk of not diagnosing large varices in almost a quarter of the population studied.

[Primary biliary cirrhosis: clinical and epidemiological features in an Uruguayan population]. / Cirrosis biliar primaria: aspectos clinico- epidemiológicos en una población uruguaya.

INTRODUCTION: Primary biliary cirrhosis (PBC) is a chronic cholestatic, autoimmune, liver disease produced by inflammation and destruction of the interlobular bile ducts. It is more frequent among female patients and is usually diagnosed in the fifth decade of life. OBJECTIVE: Our objective was to describe the clinical and epidemiological characteristics of patients with PBC in Uruguay. MATERIAL AND METHODS: This descriptive study included patients from 3 medical centers diagnosed with PBC in the period January 2002 to September 2011. The diagnosis was based on the presence of at least two of the following requirements: cholestasis, antimitochondrial antibodies (AMA) (or AMA subtype 2) or positive antinuclear antibodies (ANA) (anticentromere pattern) and compatible biopsy. Data recorded were sex, age, symptoms, related illness, laboratory results, images and histology at the moment of the diagnosis. RESULTS: We included 81 patients, 94% were women and the mean age was 56 years old (range: 31 to 79 years old). Symptoms were present in 59 patients (73%) and pruritus, found in 51 of them (86%), was the most frequent symptom. Positive AMA was found in 84% of cases. Histological study was available in 35 patients (43%) and 13 of them (37%) had cirrhosis. The mean survival according to the presence or absence of cirrhosis was 9.17 years (95% confidence interval: 6.79-11.56) and 10.7 years (95% confidence interval: 9.27-12.14), respectively (P = 0.03). CONCLUSIONS: Female predominance and frequent association with other autoimmune diseases were confirmed in this group. Although there was a high percentage of symptomatic and cirrhotic patients at diagnosis, only the presence of cirrhosis was associated with a lower survival.

Pretreatment Hepatitis C Virus NS5A/NS5B Resistance-Associated Substitutions in Genotype 1 Uruguayan Infected Patients.

Hepatitis C Virus (HCV) infection treatment has dramatically changed with the advent of direct-acting antiviral agents (DAAs). However, the efficacy of DAAs can be attenuated by the presence of resistance-associated substitutions (RASs) before and after treatment. Indeed, RASs detected in DAA treatment-naïve HCV-infected patients could be useful for clinical management and outcome prediction. Although the frequency of naturally occurring HCV NS5A and NS5B RASs has been addressed in many countries, there are only a few reports on their prevalence in the South American region. The aim of this study was to investigate the presence of RASs to NS5A and NS5B inhibitors in a DAA treatment naïve cohort of Uruguayan patients infected with chronic hepatitis C and compare them with reports from other South American countries. Here, we found that naturally occurring substitutions conferring resistance to NS5A and NS5B inhibitors were present in 8% and 19.2%, respectively, of treatment-naïve HCV genotype 1 infected patients. Importantly, the baseline substitutions in NS5A and NS5B herein identified differ from the studies previously reported in Brazil. Furthermore, Uruguayan strains subtype 1a clustered within all major world clades, showing that HCV variants currently circulating in this country are characterized by a remarkable genetic diversity.

Naturally occurring NS3 resistance-associated variants in hepatitis C virus genotype 1: Their relevance for developing countries.

Hepatitis C virus (HCV) is a major cause of global morbidity and mortality, with an estimated 130-150 million infected individuals worldwide. HCV is a leading cause of chronic liver diseases including cirrhosis and hepatocellular carcinoma. Current treatment options in developing countries involve pegylated interferon-α and ribavirin as dual therapy or in combination with one or more direct-acting antiviral agents (DAA). The emergence of resistance-associated variants (RAVs) after treatment reveals the great variability of this virus leading to a great difficulty in developing effective antiviral strategies. Baseline RAVs detected in DAA treatment-naïve HCV-infected patients could be of great importance for clinical management and outcome prediction. Although the frequency of naturally occurring HCV NS3 protease inhibitor mutations has been addressed in many countries, there are only a few reports on their prevalence in South America. In this study, we investigated the presence of RAVs in the HCV NS3 serine protease region by analysing a cohort of Uruguayan patients with chronic hepatitis C who had not been treated with any DAAs and compare them with the results found for other South American countries. The results of these studies revealed that naturally occurring mutations conferring resistance to NS3 inhibitors exist in a substantial proportion of Uruguayan treatment-naïve patients infected with HCV genotype 1 enrolled in these studies. The identification of these baseline RAVs could be of great importance for patients' management and outcome prediction in developing countries.

Diagnóstico no invasivo de la presencia de várices esofágicas en pacientes cirróticos / [Noninvasive diagnosis of esophageal varices in cirrhotic patients].

INTRODUCTION: Variceal bleeding is a frequent and serious complication of cirrhosis. Early detection of varices by videogastroscope (VGC) is recommended in all patients with cirrhosis to determine the need for prophylactic treatment. Have been described noninvasive markers of the presence of esophageal varices, which could prevent the realization of VGC for that purpose. OBJECTIVE: To determine and compare noninvasive (longitudinal diameter of spleen, platelet count, platelet reason / spleen) as predictors of the presence of esophageal varices. MATERIAL AND METHODS: We retrospectively studied 125 patients with cirrhosis from any cause. They had VGC, blood count and abdominal ultrasonography. The diagnostic accuracy for determining the presence of esophageal varices or large varices according to the different variables was studied using the area under the ROC curve (AUROC). RESULTS: The prevalence of esophageal varices was 63.2

were diagnosed with large varices. The reason platelets/spleen and platelet count showed an AUROC of 0.74 for the detection of esophageal varices. The cut-off for the ratio platelets / spleen was 1.010 (sensitivity 72.15

) for the presence of varices and 870 for the presence of clinically significant varices (sensitivity 62.26

). The analysis according to these breakpoints showed that 23.6

of patients with scores higher than 1,010 had large varices and 45

of patients with values lower than 870 had not large varices. CONCLUSIONS: Although the reason platelets/spleen showed an AUROC acceptable, its implementation would entail a risk of not diagnosing large varices in almost a quarter of the population studied.

Cirrosis biliar primaria: aspectos clinico- epidemiológicos en una población uruguaya / [Primary biliary cirrhosis: clinical and epidemiological features in an Uruguayan population].

INTRODUCTION: Primary biliary cirrhosis (PBC) is a chronic cholestatic, autoimmune, liver disease produced by inflammation and destruction of the interlobular bile ducts. It is more frequent among female patients and is usually diagnosed in the fifth decade of life. OBJECTIVE: Our objective was to describe the clinical and epidemiological characteristics of patients with PBC in Uruguay. MATERIAL AND METHODS: This descriptive study included patients from 3 medical centers diagnosed with PBC in the period January 2002 to September 2011. The diagnosis was based on the presence of at least two of the following requirements: cholestasis, antimitochondrial antibodies (AMA) (or AMA subtype 2) or positive antinuclear antibodies (ANA) (anticentromere pattern) and compatible biopsy. Data recorded were sex, age, symptoms, related illness, laboratory results, images and histology at the moment of the diagnosis. RESULTS: We included 81 patients, 94

were women and the mean age was 56 years old (range: 31 to 79 years old). Symptoms were present in 59 patients (73

) and pruritus, found in 51 of them (86

), was the most frequent symptom. Positive AMA was found in 84

of cases. Histological study was available in 35 patients (43

) and 13 of them (37

) had cirrhosis. The mean survival according to the presence or absence of cirrhosis was 9.17 years (95

confidence interval: 6.79-11.56) and 10.7 years (95

confidence interval: 9.27-12.14), respectively (P = 0.03). CONCLUSIONS: Female predominance and frequent association with other autoimmune diseases were confirmed in this group. Although there was a high percentage of symptomatic and cirrhotic patients at diagnosis, only the presence of cirrhosis was associated with a lower survival.