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

BACKGROUND & 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. Of the cases, 4.1% had a fatal outcome, and 24 patients (12%) 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 (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 herbal and dietary supplements associated with the worst outcome, whereas DILI caused by amoxicillin-clavulanate, nitrofurantoin, and diclofenac, which 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 herbal and dietary supplements, 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.

Mixed Infections Unravel Novel HCV Inter-Genotypic Recombinant Forms within the Conserved IRES Region.

Hepatitis C virus (HCV) remains a significant global health challenge, affecting millions of people worldwide, with chronic infection a persistent threat. Despite the advent of direct-acting antivirals (DAAs), challenges in diagnosis and treatment remain, compounded by the lack of an effective vaccine. The HCV genome, characterized by high genetic variability, consists of eight distinct genotypes and over ninety subtypes, underscoring the complex dynamics of the virus within infected individuals. This study delves into the intriguing realm of HCV genetic diversity, specifically exploring the phenomenon of mixed infections and the subsequent detection of recombinant forms within the conserved internal ribosome entry site (IRES) region. Previous studies have identified recombination as a rare event in HCV. However, our findings challenge this notion by providing the first evidence of 1a/3a (and vice versa) inter-genotypic recombination within the conserved IRES region. Utilizing advanced sequencing methods, such as deep sequencing and molecular cloning, our study reveals mixed infections involving genotypes 1a and 3a. This comprehensive approach not only confirmed the presence of mixed infections, but also identified the existence of recombinant forms not previously seen in the IRES region. The recombinant sequences, although present as low-frequency variants, open new avenues for understanding HCV evolution and adaptation.

Enfermedad de Wilson: presentación hepática y revisión bibliográfica / Wilson's disease: liver presentation and literature review / Doença de Wilson: apresentação hepática e revisão de literatura

Resumen: La Enfermedad de Wilson es un trastorno genético raro que puede presentarse a cualquier edad y se caracteriza por el depósito de cobre a nivel hepático y cerebral. La afectación hepática abarca desde formas asintomática hasta falla hepática fulminante o cirrosis. Su diagnóstico precoz tiene implicancias pronósticas ya que el tratamiento puede lograr un balance negativo de cobre, permitir el control sintomático y prevenir la progresión de la enfermedad. Se presenta el caso de un hombre de 27 años, con dolor abdominal, en el que se hizo el diagnóstico de Enfermedad de Wilson a partir de una hipertransaminasemia leve. Los hallazgos que orientaron al diagnóstico fueron una cupruria aumentada por inducción con D-penicilamina y una cuantificación de cobre en tejido hepático seco elevada. Con un estadio de fibrosis leve, se comenzó tratamiento con D-penicilamina con buena tolerancia y la normalización de las alteraciones bioquímicas.

Abstract: Wilson's disease is a rare genetic disorder that can occur at any age and is characterized by copper deposition in the liver and brain. Liver involvement ranges from asymptomatic forms to fulminant hepatic failure or cirrhosis. Its early diagnosis has prognostic implications since the treatment can achieve a negative copper balance, allow symptomatic control and prevent the progression of the disease. We present the case of a 27-year-old man with abdominal pain, who was diagnosed with Wilson's disease from mild hypertransaminasemia. The findings that led to the diagnosis were an increased cupruria by induction with D-penicillamine and a quantification of copper in elevated dry liver tissue. With a stage of mild fibrosis, treatment with D-penicillamine was started with good tolerance and normalization of biochemical alterations.

Resumo: Doença de Wilson é uma doença genética rara que pode ocorrer em qualquer idade e é caracterizada pela deposição de cobre no fígado e no cérebro. O envolvimento do fígado varia de formas assintomáticas a insuficiência hepática fulminante ou cirrose. Seu diagnóstico precoce tem implicações prognósticas, uma vez que o tratamento pode alcançar um balanço negativo do cobre, permitir o controle sintomático e prevenir a progressão da doença. Apresentamos o caso de um homem de 27 anos com dor abdominal, diagnosticado com doença de Wilson de hipertransaminasemia leve. Os achados que levaram ao diagnóstico foram aumento da cuprúria por indução com D-penicilamina e quantificação de cobre em tecido hepático seco elevado. Com uma fase de fibrose leve, o tratamento com D-penicilamina foi iniciado com boa tolerância e normalização das alterações bioquímicas.

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.

Hepatotoxicidad, un problema global con especificidades locales: hacia la creación de una Red Hispano Latinoamericana de Hepatotoxicidad / Hepatotoxicity, a global problem with local features: toward the creation of a Pan-American Hepatotoxicity Network

El daño hepático tóxico inducido por fármacos (DILI) es una de las afecciones hepáticas más compleja debido a su capacidad de presentarse como cualquier otra enfermedad hepática aguda o crónica, potencial gravedad, y la ausencia de biomarcadores específicos para establecer la certeza diagnóstica que se sustenta en su sospecha y exclusión de causas alternativas. La incapacidad del proceso de desarrollo de los medicamentos de cribar completamente las moléculas hepatotóxicas e identificar a los sujetos susceptibles continúa haciendo imprescindible la farmacovigilancia poscomercialización. Los registros de hepatotoxicidad se convierten en un instrumento idóneo para la recogida sistemática, según criterios consensuados y con continuidad de datos bien definidos. Se describen sumariamente las aportaciones del Registro Español de Hepatotoxicidad, y de otros registros internacionales, y se invoca la oportunidad de incorporar a Latinoamérica en las iniciativas en marcha lo que promoverá la investigación y la comprensión de los complejos mecanismos involucrados en esta reacción adversa (AU)

Drug-induced liver damage is one of the most complex liver diseases due to its similar presentation to other acute or chronic liver processes, its potential severity and the absence of specific biomarkers to confirm diagnosis, which is based on clinical suspicion and exclusion of alternative causes. Because the drug development process fails to completely screen out hepatotoxic molecules and identify susceptible individuals, postmarketing pharmacovigilance remains essential. Hepatotoxicity registries are the ideal instrument for systematic and continual data collection, using preestablished criteria based on consensus. The present article briefly describes the contributions of the Spanish Hepatotoxicity Registry and those of other international registries. Hopefully, Latin American registries will be incorporated into existing initiatives, which will stimulate research and improve understanding of the complex mechanisms involved in this adverse reaction (AU)

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

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.

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.