"Hepatic toxicity by methotrexate with weekly single doses associated with folic acid in rheumatoid and psoriatic arthritis. What is its real frequency?"

INTRODUCTION AND OBJECTIVES: Liver injury caused by methotrexate (MTX) has mostly been investigated without applying criteria for the assessment of causality of drug induced liver injury (DILI). Hence, the existence of DILI by MTX in many cases is debatable. This study aimed to describe the frequency and characteristics of liver injury caused by MTX, applying DILI diagnostic criteria. MATERIAL AND METHODS: Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients who were treated with MTX in association with folic acid were included. Serial determinations of alanine amino transferase (ALT) and aspartate amino transferase (AST) were performed. The Roussel Uclaf Causality Assessment Method (RUCAM) was applied in cases of increases of ALT/AST over 1.5 upper limit of normal. Liver biopsy was considered when the total cumulative dosage (TCD) of MTX was ≥3.5g. RESULTS: A total of 43 patients were analyzed (median follow up 32 (range: 1-48) months; 3.33 ALT/AST determinations per year). Five subjects presented an increase of ALT/AST. All presented a RUCAM score for MTX≤2 (improbable). Three had a RUCAM score for non-steroidal anti-inflammatory drugs ≥7 (probable) and two patients presented non-alcoholic fatty liver disease. Five patients with no other cause for liver disease consented to liver biopsy (TCD MTX: median 5.1; range: 3.5-7.4g). No significant fibrosis or steatosis was evident on histology. CONCLUSIONS: No biochemical or significant histological liver toxicity for MTX was demonstrated when applying causality criteria for DILI. More studies with this methodology are necessary in order to improve the assessment of its frequency.

[Gastric metastases: not only identified at autopsies]. / Metástasis gástricas: un hallazgo no solo de autopsias.

Metastases to the stomach from an extra-digestive neoplasm are an unusual event, identified in less than 2% of cancer patients at autopsy (between 1.7% to 5%). The stomach may be involved by hematogenous spread from a distant primary tumor (most commonly lung, breast and melanoma). Tumors of neighboring organs, such as esophagus, pancreas and gallbladder, may reach the stomach by continuity or by lymphatic-hematogenous spread. Endoscopic routine studies with biopsies have improved the diagnosis of this pathology. Nevertheless, in some cases the histologic study is a false negative because the neoplasia can be placed in the deepest layers of the stomach. We report the case of a 56-year-old man who presented a gastric metastasis of a high gradeuro thelial carcinoma of urinary bladder and we review the literature.

Metástasis gástricas: un hallazgo no solo de autopsias / [Gastric metastases: not only identified at autopsies].

Metastases to the stomach from an extra-digestive neoplasm are an unusual event, identified in less than 2

of cancer patients at autopsy (between 1.7

). The stomach may be involved by hematogenous spread from a distant primary tumor (most commonly lung, breast and melanoma). Tumors of neighboring organs, such as esophagus, pancreas and gallbladder, may reach the stomach by continuity or by lymphatic-hematogenous spread. Endoscopic routine studies with biopsies have improved the diagnosis of this pathology. Nevertheless, in some cases the histologic study is a false negative because the neoplasia can be placed in the deepest layers of the stomach. We report the case of a 56-year-old man who presented a gastric metastasis of a high gradeuro thelial carcinoma of urinary bladder and we review the literature.

Metástasis gástricas: un hallazgo no solo de autopsias. / [Gastric metastases: not only identified at autopsies].

Metastases to the stomach from an extra-digestive neoplasm are an unusual event, identified in less than 2

of cancer patients at autopsy (between 1.7

to 5

). The stomach may be involved by hematogenous spread from a distant primary tumor (most commonly lung, breast and melanoma). Tumors of neighboring organs, such as esophagus, pancreas and gallbladder, may reach the stomach by continuity or by lymphatic-hematogenous spread. Endoscopic routine studies with biopsies have improved the diagnosis of this pathology. Nevertheless, in some cases the histologic study is a false negative because the neoplasia can be placed in the deepest layers of the stomach. We report the case of a 56-year-old man who presented a gastric metastasis of a high gradeuro thelial carcinoma of urinary bladder and we review the literature.

[Liver diseases in rheumatoid and psoriatic arthritis]. / Enfermedades hepáticas en artritis reumatoidea y psoriásica.

OBJECTIVE: The aim of this study was to evaluate the prevalence, risk factors and features of liver diseases (LD) in rheumatoid and psoriatic arthritis. PATIENTS AND METHODS: From July 2007 to January 2010, 118 non-selected patients were consecutively examined. The assessment consisted of a medical record, biochemical studies and abdominal ultrasounds. The diagnosis of fatty liver disease was based on the ultrasound drug induced liver injury (DILI) was evaluated by the Maria-Victorino system criteria. Liver biopsy associated with chronic administration of methotrexate was performed using the histological classification of Kleiner et al. For the statistical analysis chi square test with Yates correction, Student's t test or Mann-Whitney test were applied when appropriate. In the multivariate analysis a binary logistic regression was used. The threshold of significance was P < 0.05. RESULTS: LD was diagnosed in 47 patients (39.8%). The most frequent LD was fatty liver disease in 35 patients (29.7%), followed by DILI in 15 (12.7%), associated with non-steroidal anti-inflammatory drugs (NSAID). In the multivariate analysis, obesity was the only independent risk factor associated with fatty liver disease [Odds ratio (OR) 6.4 (confidence interval (CI) 95%: 2.5-16.1; P = 0.000)] and fatty liver disease was the only risk factor associated with DILI [OR 7.7 (CI 95%: 2.0-30.0; P = 0.003)]. CONCLUSIONS: In our series, there was a high prevalence of LD, being fatty liver disease associated with obesity the most frequent finding. The second frequent disease was DILI, being fatty liver disease its main risk factor. The presence of obesity and the use of NSAIDs, especially in patients with steatosis, arise from our results as two conditions that require special care in handling this particular population.

Role of the life span determinant P66(shcA) in ethanol-induced liver damage.

Mice lacking the 66 kDa isoform of the adapter molecule shcA (p66(shcA)) display increased resistance to oxidative stress and delayed aging. In cultured cell lines, p66 promotes formation of Reactive Oxygen Species (ROS) in mitochondria, and apoptotic cell death in response to a variety of pro-oxidant noxious stimuli. As mitochondrial ROS and oxidative cell damage are clearly involved in alcohol-induced pathology, we hypothesized that p66 may also have a role in ethanol. In vivo, changes observed in p66+/+ mice after 6-week exposure to ethanol in the drinking water, including elevated serum alanine aminotransferase (ALT), liver swelling and evident liver steatosis, were significantly attenuated in p66-/- mutant mice. Biochemical analysis of liver tissues revealed induction of the p66 protein by ethanol, whereas p66-deficient livers responded to alcohol with a significant upregulation of the mitochondrial antioxidant enzyme MnSOD, nearly absent in control mice. Evidence of an inverse correlation between expression level of p66 and protection from alcohol-induced oxidative stress was also confirmed in vitro in primary hepatocytes and in HepG2-E47 cells, an ethanol-responsive hepatoma cell line. In fact, MnSOD upregulation by exposure to ethanol in vitro was much more pronounced in p66KO versus wild-type isolated liver cells, and blunted in HepG2 cells overexpressing p66shc. p66 overexpression also prevented the activation of a luciferase reporter gene controlled by the SOD2 promoter, indicating that p66 repression of MnSOD operates at a transcriptional level. Finally, p66 generated ROS in HepG2 cells and potentiated oxidative stress and mitochondrial depolarization by ethanol. Taken together, the above observations clearly indicate a role for p66 in alcohol-induced cell damage, likely via a cell-autonomous mechanism involving reduced expression of antioxidant defenses and mitochondrial dysfunction.

Oxidative stress and antioxidant defenses in ethanol-induced cell injury.

Although in the past several mechanisms and factors have been proposed to be responsible for alcoholic liver disease (ALD), at present the involvement of oxygen free radicals and consequently of oxidative stress has acquired remarkable credit. In numerous experimental studies it has been shown the occurrence of alcohol-induced generation of oxygen- and ethanol-derived free radicals through different pathways and from different sources. Mitochondria appear to be both an important source of reactive oxygen species (ROS) and also a primary target of ethanol-induced damage. The consistent induction of the mitochondrial antioxidant enzyme manganese superoxide dismutase (Mn-SOD) observed in experimental animals after acute and chronic ethanol administration has all the characteristics of a "stress response" to an oxidative insult.

Liver necrosis induced by acute intraperitoneal ethanol administration in aged rats.

It is generally agreed that the deleterious pathophysiological effects of ethanol are caused, at least partially by an increase in free radical production. However, little attention has been directed to the effects of ethanol upon elderly organisms. Male Wistar rats at ages 3, 6, 12, 18 and 24 months were treated either with a single i.p. dose of 35% ethanol (v/v) at 3 g ethanol/kg body weight or an isovolumetric amount of 0.9% saline solution. We then assessed the plasma levels of transaminases and hepatic levels of oxidative stress-related parameters, followed by liver histological evaluation. The younger rats (3 months old) were not affected by the treatment with ethanol with respect to any of the studied parameters except for a lowering of total hepatic GSH and an increase in hepatic thiobarbituric acid reactants (TBARS) formation, while animals older than 3 months were increasingly more affected by the treatment. Acute ethanol treatment elicited the similar responses to those in the 3 months-old group, plus a decrease in the hepatic and plasma levels of beta-carotene and the plasma level of alpha-tocopherol, as well as an increase in the activity of plasma transaminases. In the 12,18 and 24 months old groups, there was increasing liver necrosis. These findings suggest that liver damage induced by acute ethanol administration in elderly rats may involve a lack of antioxidants.

Colestasis inducida por meloxican / Meloxicam-induced cholestasis

The cholestasis by meloxicam has not been often described. However, we present here the clinic, laboratory, histologic and follow up of a patient with cholestatic hepatitis produced by this drug.

Colestasis inducida por meloxican / Meloxicam-induced cholestasis

The cholestasis by meloxicam has not been often described. However, we present here the clinic, laboratory, histologic and follow up of a patient with cholestatic hepatitis produced by this drug. (Au)

Determinación del RNA genómico y replicativo del virus de la hepatitis C en pacientes tratados con interferón / Determination of genomic RNA and replicative hepatitis C viruses in patients treated with interferon

En este ensayo se trató de correlacionar la evolución clínica e histológica de un grupo de pacientes tratados con IFN, con la presencia del RNA genómico y replicativo del HCV en plasma y tejido hepático. Se estudiaron 11 pacientes con hepatitis crónica "C" diagnosticada por elevación de transaminasas durante los últimos 6 meses, anti-HCV positivo "(Elisa II)", y cuadro histológico compatible. En todos ellos se efectuó biopsia hepática y extracción de sangre en paralelo, inmediatamente antes y después de finalizar el tratamiento con 4.5 millones de IFN Alfa2a administrado 3 veces por semana, durante 6 meses. El tecijo hepático se almacenó a-80§c y el plasma a-20§c hasta su procesamiento. La extracción de RNA se realizó a partir de 100microliter de plasma y de 20mg de tejido hepático con isotiocianato de guanidinio (Chomcznski). La transcripción reversa se llevó a cabo "primers" sense o antisense para detectar la hélice replicativa (-) o genómica (+) respectivamente. El cDNA de la región 5' no codificante fue amplificado por el sistema "nested". Antes del tratamiento los 11 pacientes evidenciaron la presencia de la hélice genómica en tecijo hepático y plasma. En cambio la hélice replicativa se detectó en 5 casos en hígado, 7 pacientes se revelaron como respondedores y 4 como no respondedores. En los pacientes respondedores las hélices genómica y replicativa en hígado desaparecieron en un 43 por ciento y 57 por ciento respectivamente, y en plasma se observó un descenco del 71 por ciento para la hélice genómica y de un 100 por ciento para la hélice replicativa. En los 4 pacientes no respondedores la hélice genómica permaneció en tecijo hepático y plasma, en cambio la replicativa se mantuvo en tejido hepático y se negativizó en un 75 por ciento en plasma. El índice de Knodell, que determina el estadío histológico, disminuyó en 5 de lo 7 respondedores y permaneció igual en 3 de los 4 no respondedores...

Determinación del RNA genómico y replicativo del virus de la hepatitis C en pacientes tratados con interferón / Determination of genomic RNA and replicative hepatitis C viruses in patients treated with interferon

En este ensayo se trató de correlacionar la evolución clínica e histológica de un grupo de pacientes tratados con IFN, con la presencia del RNA genómico y replicativo del HCV en plasma y tejido hepático. Se estudiaron 11 pacientes con hepatitis crónica "C" diagnosticada por elevación de transaminasas durante los últimos 6 meses, anti-HCV positivo "(Elisa II)", y cuadro histológico compatible. En todos ellos se efectuó biopsia hepática y extracción de sangre en paralelo, inmediatamente antes y después de finalizar el tratamiento con 4.5 millones de IFN Alfa2a administrado 3 veces por semana, durante 6 meses. El tecijo hepático se almacenó a-80ºc y el plasma a-20ºc hasta su procesamiento. La extracción de RNA se realizó a partir de 100microliter de plasma y de 20mg de tejido hepático con isotiocianato de guanidinio (Chomcznski). La transcripción reversa se llevó a cabo "primers" sense o antisense para detectar la hélice replicativa (-) o genómica (+) respectivamente. El cDNA de la región 5 no codificante fue amplificado por el sistema "nested". Antes del tratamiento los 11 pacientes evidenciaron la presencia de la hélice genómica en tecijo hepático y plasma. En cambio la hélice replicativa se detectó en 5 casos en hígado, 7 pacientes se revelaron como respondedores y 4 como no respondedores. En los pacientes respondedores las hélices genómica y replicativa en hígado desaparecieron en un 43 por ciento y 57 por ciento respectivamente, y en plasma se observó un descenco del 71 por ciento para la hélice genómica y de un 100 por ciento para la hélice replicativa. En los 4 pacientes no respondedores la hélice genómica permaneció en tecijo hepático y plasma, en cambio la replicativa se mantuvo en tejido hepático y se negativizó en un 75 por ciento en plasma. El índice de Knodell, que determina el estadío histológico, disminuyó en 5 de lo 7 respondedores y permaneció igual en 3 de los 4 no respondedores...(AU)