Serious liver injury induced by Nimesulide: an international collaboration study reporting 57 cases

Nimesulide is a non-steroidal anti-inflammatory drug still marketed in many countries. We aim to analyze the clinical phenotype, outcome, and histological features of nimesulide-induced liver injury (nimesulide-DILI). We analyzed 57 cases recruited from the Spanish and LATIN DILI registries. Causality was assessed by the RUCAM scale. Mean age of the whole case series was 59 years (86% women) with a median time to onset of 40 days. A total of 46 patients (81%) were jaundiced. Nimesulide-DILI pattern was hepatocellular in 38 (67%), mixed in 12 (21%), and cholestatic in 7 (12%) cases. Transaminases were elevated with a mean of nearly 20-fold the upper limit of normality (ULN), while alkaline phosphatase showed a 2-fold mean elevation above ULN. Total bilirubin showed a mean elevation of 13-fold the ULN. Liver histology was obtained in 14 cases (25%), most of them with a hepatocellular pattern. Median time to recovery was 60 days. Overall, 12 patients (21%) developed acute liver failure (ALF), five (8.8%) died, three underwent liver transplantation (5.3%), and the remaining four resolved. Latency was ≤15 days in 12 patients (21%) and one patient developed ALF within seven days from treatment initiation. Increased total bilirubin and aspartate transaminase levels were independently associated with the development of ALF. In summary, nimesulide-DILI affects mainly women and presents typically with a hepatocellular pattern. It is associated with ALF and death in a high proportion of patients. Shorter (≤15 days) duration of therapy does not prevent serious nimesulide hepatotoxicity, making its risk/benefit ratio clearly unfavorable.The present study has been supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional - FEDER (contract numbers: PI18-00901; PI 18/01804; PT20/00127) and Agencia Española del Medicamento. Plataforma ISCiii de Investigación Clínica and CIBERehd are funded by ISCIII. MRD holds a Joan Rodes (JR16/00015)/Acción B clinicos investigadores (B-0002-2019) research contract from ISCIII and Consejería de Salud de Andalucía, IAA holds a Sara Borrell research contract from the National Health System, ISCIII (CD 20/00083)

Intraductal papillary mucinous neoplasm of the pancreas (IPMN): clinico-pathological correlations and surgical indications

<p>Abstract</p> <p>Background</p> <p>Intraductal papillary mucinous neoplasms (IPMNs) are increasingly recognized entities, whose management remains sometimes controversial, due to the high rate of benign lesions and on the other side to the good survival after resection of malignant ones.</p> <p>Methods</p> <p>Retrospective analysis of a prospectively collected Western series of IPMN.</p> <p>Results</p> <p>Forty cases of IPMN were analysed (1992-2007). Most patients were symptomatic (72.5%); cholangio-MRI had the best diagnostic accuracy both for the tumour nature (83.3%) and for the presence of malignancy (57.1%). ERCP was done in 8 cases (20%), and the results were poor. Thirteen patients were treated by pancreatic resection and 27 were maintained in follow-up. Total pancreatectomy was performed in 46% of the cases; in situ and invasive carcinoma were recognized in 15.4% and 38.4% of the cases, respectively. The mean follow-up was 42 months (range 12-72). One only patients with nodal metastases died 16 months after the operation for disease progression, while 91.6% of the operated patients are disease free. Out of the 27 not resected patients, 2 out of 4 presenting a lesion at high risk for malignancy died, while the remaining are in good conditions and disease free, with a mean follow-up of 31 months.</p> <p>Conclusion</p> <p>Therapeutic indication for IPMNs is mainly based upon radiological evaluation of the risk of malignancy. While the main duct tumours should be resected, preserving whenever possible a portion of the gland, the secondary ducts tumours may be maintained under observation, in absence of radiological elements of suspicion such as size larger than 3 cm, or a wall greater than 3 mm or nodules or papillae in the context of the cyst.</p

Diagnosis and treatment of non-alcoholic fatty liver disease: Argentine Association for the Study of Liver Diseases, year 2019

El hígado graso no alcohólico (HGNA) es la enfermedad hepática crónica más frecuente en todo el mundo, con una prevalencia aproximada de 25% a nivel global. Su prevalencia es mucho mayor en pacientes con sobrepeso, obesidad y diabetes tipo 2 y es considerada como la manifestación hepática del síndrome metabólico. El espectro de la enfermedad hepática es muy amplio, desde la esteatosis simple a la esteatohepatitis, fibrosis, cirrosis y sus complicaciones, como el hepatocarcinoma. La mayoría de los pacientes afectados no progresará a la fibrosis avanzada/cirrosis. A pesar de esto, se ha descripto que la hepatopatía es la tercera causa de muerte entre los pacientes con HGNA, luego de las enfermedades cardiovasculares y las malignas. Entre la enorme cantidad de afectados, lo más importante es identificar a los que están en riesgo de evolución a la cirrosis o sus complicaciones y conocer las opciones de diagnóstico y tratamiento. En esta Guía organizada por la Asociación Argentina para el Estudio de las Enfermedades del Hígado se revisan las definiciones, los aspectos epidemiológicos, la historia natural y un enfoque práctico sobre algoritmos posibles para estimar la gravedad de la hepatopatía en cada caso, además de analizar los avances en el tratamiento y recomendaciones para el seguimiento. Es importante señalar que no se han publicado datos sobre incidencia o prevalencia de la enfermedad en población general de Argentina, y se alienta a la realización de los mismos.. Nonalcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease worldwide, with an estimated global prevalence of approximately 25%, that is much higher in patients with overweight, obesity and type 2 diabetes. NAFLD is considered as the hepatic manifestation of metabolic syndrome. It has a wide spectrum, from simple steatosis to steatohepatitis, fibrosis, cirrhosis and its complications, such as hepatocellular carcinoma. Most of the affected patients will not evolve to advanced fibrosis or cirrhosis. Despite this, it has been described that the hepatic disease is the third cause of death among patients with nonalcoholic fatty liver, after cardiovascular and malignant diseases. Among the huge number of patients affected, the main challenge is to identify those who are at risk of developing cirrhosis or its complications and to recognize the diagnostic and treatment options. In this Guideline, endorsed by the Argentine Association for the Study of Liver Diseases, the definitions, epidemiological aspects, natural history and a practical approach to possible algorithms to estimate the severity of liver disease in the individual patient are reviewed; in addition to analyzing advances in treatment and proposing recommendations for follow-up. It is important to note that no data on the incidence or prevalence of the disease have been published in the general population of Argentina, and it is encouraged to carry them out.Fil: Fassio, Eduardo. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Dirchwolf, Melisa. Hospital Privado de Rosario; ArgentinaFil: Barreyro, Fernando Javier. Universidad Nacional de Misiones. Facultad de Ciencias Exactas, Químicas y Naturales. Departamento de Microbiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; ArgentinaFil: Adrover, Raúl. No especifíca;Fil: Alonso, M. Inés. No especifíca;Fil: Amante, Marcelo. No especifíca;Fil: Ameigeiras, Beatriz. No especifíca;Fil: Barreyro, Fernando J.. No especifíca;Fil: Benavides, Javier. No especifíca;Fil: Bessone, Fernando. No especifíca;Fil: Cairo, Fernando. No especifíca;Fil: Camino, Alejandra. No especifíca;Fil: Cañero Velasco, M. Cristina. No especifíca;Fil: Casciato, Paola. No especifíca;Fil: Cocozzella, Daniel. No especifíca;Fil: Daruich, Jorge. No especifíca;Fil: De Matteo, Elena. No especifíca;Fil: Dirchwolf, Melisa. No especifíca;Fil: Fassio, Eduardo. No especifíca;Fil: Fernández, José Luis. No especifíca;Fil: Fernández, Nora. No especifíca;Fil: Ferretti, Sebastián. No especifíca;Fil: Figueroa, Sebastián. No especifíca;Fil: Galoppo, Marcela. No especifíca;Fil: Godoy, Alicia. No especifíca;Fil: González Ballerga, Esteban. No especifíca;Fil: Graffigna, Mabel. No especifíca;Fil: Guma, Carlos. No especifíca;Fil: Lagues, Cecilia. No especifíca;Fil: Marino, Mónica. No especifíca;Fil: Mendizábal, Manuel. No especifíca;Fil: Mesquida, Marcelo. No especifíca;Fil: Odzak, Andrea. No especifíca;Fil: Peralta, Mirta. No especifíca;Fil: Ridruejo, Ezequiel. No especifíca;Fil: Ruffillo, Gabriela. No especifíca;Fil: Sordá, Juan A.. No especifíca;Fil: Tanno, Mario. No especifíca;Fil: Villamil, Alejandra. No especifíca;Fil: Colombato, Luis. No especifíca;Fil: Fainboim, Hugo. No especifíca;Fil: Gadano, Adrián. No especifíca;Fil: Galoppo, Cristina. No especifíca;Fil: Villamil, Federico. No especifíca

Trends and determinants of epinephrine prescriptions: a proxy of anaphylaxis epidemiology?

Purpose of review: Epinephrine autoinjectors (EAIs) are recommended to all patients previously experiencing anaphylaxis reaction in order to prevent further reactions and fatalities. Under that perspective, EAI prescription could be considered as a proxy of anaphylaxis epidemiology. Nevertheless EAI prescription rates are still unacceptably low. Recent findings: The review focuses on potential determinants, in addition to clinical indications, which might impact EAI prescription rates by exploring the scientific literature published within the past 18 months, wherever available. Although some controversial results, age, sex, ethnicity, geographical setting and socioeconomic conditions might influence both physician prescription behaviour and EAIs' accessibility from the patient's side, which hampers the accuracy of EAI prescription as a proxy of anaphylaxis. Low EAI prescription and refill rates have been recorded even in the absence of significant socioeconomic barriers, suggesting that economical limitations only partially account for the issue, and cultural restrictions have also to be considered and addressed. Summary: In addition to providing the same opportunities in terms of EAI availability in all countries worldwide, implementing the resources for anaphylaxis management in terms of practical knowledge, education, and allergy specialist networks is an urgent need, even in the absence of socioeconomic barriers.Purpose of review: Epinephrine autoinjectors (EAIs) are recommended to all patients previously experiencing anaphylaxis reaction in order to prevent further reactions and fatalities. Under that perspective, EAI prescription could be considered as a proxy of anaphylaxis epidemiology. Nevertheless EAI prescription rates are still unacceptably low. Recent findings: The review focuses on potential determinants, in addition to clinical indications, which might impact EAI prescription rates by exploring the scientific literature published within the past 18 months, wherever available. Although some controversial results, age, sex, ethnicity, geographical setting and socioeconomic conditions might influence both physician prescription behaviour and EAIs' accessibility from the patient's side, which hampers the accuracy of EAI prescription as a proxy of anaphylaxis. Low EAI prescription and refill rates have been recorded even in the absence of significant socioeconomic barriers, suggesting that economical limitations only partially account for the issue, and cultural restrictions have also to be considered and addressed. Summary: In addition to providing the same opportunities in terms of EAI availability in all countries worldwide, implementing the resources for anaphylaxis management in terms of practical knowledge, education, and allergy specialist networks is an urgent need, even in the absence of socioeconomic barriers

Natural history of hepatitis C virus infection in a cohort of asymptomatic post-transfused subjects

Background &amp; aims. Studies about the natural history of hepatitis C virus (HCV) infection report variable progression to cirrhosis depending on study design. Retrospective cross-sectional liver clinic studies overestimate the rate of fibrosis progression due to inclusion of patients with more severe disease leaving mild and asymptomatic patients underrepresented. We evaluated fibrosis progression in a group of “healthy” asymptomatic subjects, attending to a voluntary campaign for the detection of HCV infection.Material and methods. A detection campaign was launched on subjects transfused before 1993. Of 1699 volunteers, 61(3.6%) had HCV infection. A liver biopsy was performed in 40 (65%). Assessed risk factors for liver fibrosis were: sex, body mass index, alcohol consumption (> 20 g/d♀ - >40g/d♂), genotype, HLA-DRB1 alleles, present age, age at infection and duration of infection.Results. 25 (62.5%) were women with a median age of 52.5 years. The median duration of infection was 21.5 years with a median age at infection of 27 years. As regards fibrosis, 25 (62.5%) had a Low Stage (F0-F1), 8 patients, 20%, had severe fibrosis, one patient (2.5%) had cirrhosis. Alcohol consumption was the only risk factor associated with fibrosis progression.Conclusions. The low progression to cirrhosis may be explained by the clinical characteristics of ourpopulation: asymptomatic middle-aged “healthy” subjects infected at young age. The progression to severe fibrosis was noticeable; hence a longer follow-up might demonstrate changes in this outcome. Significant alcohol consumption clearly worsens the natural history of HCV infection; this is no so evident for occasional or mild alcohol consumers

Nitrofurantoin-induced liver injury: long-term follow-up in two prospective DILI registries.

Nitrofurantoin is a synthetic antibiotic that is recommended as first-choice treatment for uncomplicated urinary tract infections. The prescription of this drug has increased dramatically, especially in Latin American countries. We described the demographics, clinical characteristics, biochemical features, and outcome of nitrofurantoin-induced liver injury. We analyzed 23 cases from the Latin American DILI Network (LATINDILI) and the Spanish DILI Registry. Causality was assessed with the RUCAM and RECAM scale. Of the 23 DILI cases included in our series, 96% patients were women, and the mean age of the whole cohort was 61 years. The median time of drug exposure was 175 days (interquartile range [IQR] 96-760), with 11 patients who were prescribed nitrofurantoin for more than six months. Hepatocellular damage was the most frequent pattern of liver injury (83%), and nearly half of the patients had an asymptomatic presentation (52%). Neither death nor liver transplantation was documented in this series. Overall, 65% of the patients (n = 15) presented with positive autoantibody titres. The median time to resolution was 81 days (IQR 57-141), and 15 patients (83%) recovered within six months. Five patients (22%) developed nitrofurantoin-induced autoimmune-like hepatitis (NI-AILH), of whom two were characterized by a persistent increase in transaminases that required immunosuppressive treatment to achieve normalization of liver enzymes. Clinicians who prescribe nitrofurantoin should be aware that patients who had taken nitrofurantoin for a long term may be at risk of developing nitrofurantoin-induced autoimmune-like hepatitis

Cyproterone acetate induces a wide spectrum of acute liver damage including corticosteroid-responsive hepatitis: Report of 22 cases

Background & Aims: Cyproterone acetate (CPA), an anti-androgenic drug for prostate cancer, has been associated with drug-induced liver injury (DILI). We aim to expand the knowledge on the spectrum of phenotypes and outcomes of CPA-induced DILI. Methods: Twenty-two males (70±8 years; range 54-83) developing liver damage as a result of CPA therapy (dose: 150±50mg/day; range 50-200) were included. Severity index and causality by RUCAM were assessed. Results: From 1993 to 2013, 22 patients were retrieved. Latency was 163±97days. Most patients were symptomatic, showing hepatocellular injury (91%) and jaundice. Liver tests at onset were: ALT 18±13×ULN, ALP 0.7±0.7×ULN and total serum bilirubin 14±10mg/dl. International normalized ratio values higher than 1.5 were observed in 14 (66%) patients. Severity was mild in 1 case (4%), moderate in 7 (32%), severe in 11 (50%) and fatal in 3 (14%). Five patients developed ascitis, and four encephalopathy. One patient had a liver injury that resembled autoimmune hepatitis. Eleven (50%) were hospitalized. Nineteen patients recovered after CPA withdrawal, although three required steroid therapy (two of them had high ANA titres). Liver biopsy was performed in seven patients (two hepatocellular collapse, one submassive necrosis, two cholestatic hepatitis, one cirrhosis with iron overload and one autoimmune hepatitis). RUCAM category was 'highly probable' in 19 (86%), 'probable' in 1 (4%), and 'possible' in 2 (9%). Conclusions: CPA-induced liver injury is severe and can be fatal, and may occasionally resemble autoimmune DILI. The benefit/risk ratio of this drug should be thoroughly assessed in each patient.Fil: Bessone, Fernando. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Lucena, M. L.. Universidad de Málaga; España. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas ; EspañaFil: Roma, Marcelo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Stephens, Camilla. Universidad de Málaga; España. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas ; EspañaFil: Medina Cáliz, Inmaculada. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas ; España. Universidad de Málaga; EspañaFil: Frider, Bernardo. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; ArgentinaFil: Tsariktsian, Guillermo. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; ArgentinaFil: Hernández, Nelia. Universidad de la República; UruguayFil: Bruguera, Miquel. Liver Unit; EspañaFil: Gualano, Gisela. Hospital Alejandro Posadas; ArgentinaFil: Fassio, Eduardo. Hospital Alejandro Posadas; ArgentinaFil: Montero, Joaquin. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Reggiardo, María V.. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Ferretti, Sebastian Eduardo. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Colombato, Luis. Hospital Británico de Buenos Aires; ArgentinaFil: Tanno, Federico. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Ferrer, Jaime. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Zeno, Lelio. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Tanno, Hugo. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Andrade, Raúl J.. Universidad de Málaga; España. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas ; Españ

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

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