Revista Española de Enfermedades Digestivas

Simvastatin: from cholesterol to nitric oxide, from ischemic heart disease to portal hypertension

Simvastatin suppresses the proangiogenic microenvironment of human hepatic stellate cells via the Kruppel-like factor 2 pathway

Background and aims: Statins are reported to have a beneficial effect on portal hypertension (PTH); however, the exact mechanism remains unknown. Hepatic stellate cells (HSCs) can be activated by transforming growth factor beta (TGFβ) and play an important role in angiogenesis leading to PTH. Statins potently stimulate the transcription factor, Kruppel-like factor 2 (KLF2), which can negatively regulate angiogenesis. Our present study aimed to investigate the anti-angiogenic potential of statins in HSCs through the KLF2 pathway. Method: TGFβ-induced human HSCs were exposed to simvastatin. Cell viability and proliferation were determined by MTT and BrdU-proliferation assays, respectively. Cell migration was investigated using a transwell and wound-healing assays. Gene quantification was measured by real-time polymerase chain reaction. Protein expression was detected by western blot analysis and immunohistochemistry. Inflammatory factors were measured using enzyme-linked immunosorbent assays. Result: Simvastatin was found to reduced cell migration and proliferation and inhibit expression of alpha smooth muscle actin in TGFβ-induced HSCs. Furthermore, simvastatin promoted already increased mRNA and protein levels of KLF2 in TGFβ-induced HSCs. In accordance with KLF2 overexpression, simvastatin increased production of endothelial nitric oxide synthesis (eNOS) and downregulated expression of some proangiogenic proteins, such as vascular endothelial growth factor, hypoxia inducible factor-1a and nuclear factor-kappa B in TGFβ-induced HSCs. At the same time, secretion of interferon-gamma increased in TGFβ induced HSCs, which was decreased by simultaneous addition of simvastatin. Conclusion: Simvastatin suppressed the proangiogenic environment of HSCs activated by TGFβ, and KLF2 pathway is involved in the course.

**Mutational profile of KIT and PDGFRA genes in gastrointestinal stromal tumors in Peruvian samples**

Introduction: Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms usually caused by somatic mutations in the genes KIT (c-KIT) or PDGFRA. Mutation characterization has become an important exam for GIST patients because it is useful in predicting the response to the inhibitors of receptor tyrosine kinase (RTK). Objectives: The aim of this study was to determine the frequency of KIT and PDGFRA mutations in 25 GIST samples collected over two years at two national reference hospitals in Peru. There were 21 samples collected from the Instituto Nacional de Enfermedades Neoplásicas (INEN, national cancer center) and 4 samples collected from Hospital A. Loayza. Methods and materials: In this retrospective study, we performed polymerase chain reaction (PCR) amplification and deoxyribonucleic acid (DNA) sequencing of KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12 and 18) genes in 20 FFPE (formalin-fixed, paraffin-embedded) and 5 frozen GIST samples. Results: We report 21 mutations, including deletions, duplications, and missense, no mutations in 2 samples, and 2 samples with no useful DNA for further analysis. Eighty-six percent of these mutations were located in exon 11 of KIT, and 14 % were located in exon 18 of PDGFRA. Conclusions: Our study identified mutations in 21 out of 25 GIST samples from 2 referential national hospitals in Peru, and the mutation proportion follows a global tendency observed from previous studies (i.e., the majority of samples presented KIT mutations followed by a minor percentage of PDGFRA mutations). This study presents the first mutation data of the KIT and PDGFRA genes from Peruvian individuals with GIST.

Octreotide long-active release in the treatment of gastrointestinal bleeding due to vascular malformations: cost-effectiveness study

Introduction: Gastrointestinal hemorrhage due to vascular malformations has a negative impact on patients' quality of life and consumes an important quantity of resources. Objective: Analyze the cost-effectiveness of long-active releasing octreotide (OCT-LAR) in the treatment of gastrointestinal haemorrhage secondary to vascular malformations. Material and methods: Retrospective study, including 19 pacients that were treated with mensual injections of OCT-LAR between 2008-2013. The number of blood transfusions, hemoglobin levels, hospital admissions and possible side effects during the year before treatment and the year after the start of the treatment were assessed, and cost-effectiveness was analyzed. Results: After the beginning of the treatment with OCT-LAR, complete response was observed in 7 patients (36.8 %), partial response in 7 patients (36.8 %) and 5 patients (26.3 %) continued to require admissions, blood transfusions and/or endoscopic treatment. We observed significant reduction in the length of admission per year (in days) before and after the start of the treatment (22.79 versus 2.01 days, p < 0.0001) as well as in the number of blood transfusions administered (11.19 versus 2.55 blood transfusions per year, p = 0.002). The mean haemoglobin levels increased from 6.9 g/dl to 10.62 g/dl (p < 0.0001). We observed reduction of costs of 61.5 % between the two periods (from 36,072.35 € to 13,867.57 € per patient and year, p = 0.01). No side effects related to treatment were described. Conclusion: In conclusion, OCT-LAR seems to be a cost-efficient and safe pharmacological treatment of gastrointestinal haemorrhage secondary to vascular malformations, mainly in patients in whom endoscopic or surgical treatment is contraindicated.

Introducción: la hemorragia digestiva por lesiones vasculares (HDLV) deteriora la calidad de vida de los pacientes y requiere el consumo de una importante cantidad de recursos. Objetivo: analizar la coste-eficiencia de octreótido de depósito (OCT-LAR) en el tratamiento de hemorragia gastrointestinal por lesiones vasculares. Material y métodos: estudio retrospectivo, incluyendo a 19 pacientes que fueron tratados con inyecciones mensuales de OCT-LAR entre los años 2008-2013. Se revisaron los requerimientos transfusionales, niveles de hemoglobina, necesidad de ingreso hospitalario y posibles efectos secundarios en el año previo y posterior al inicio del tratamiento, se analizó la coste-eficiencia. Resultados: tras el inicio de OCT-LAR observamos respuesta completa en 7 pacientes (36,8 %), parcial en otros 7 pacientes (36,8 %) y 5 pacientes (26,3 %) siguieron precisando ingresos, trasfusiones de hemoderivados y/o tratamiento endoscópico. Observamos disminución significativa de los días de ingreso al año, antes y después de tratamiento (22,79 vs. 2,01 días, p < 0,0001) y del número de concentrados de hematíes transfundidos (11,19 vs. 2,55 concentrados de hematíes por paciente/año, p = 0,002). La media de hemoglobina mejoró de 6,95 a 10,62 g/dl (p < 0,0001). Observamos una reducción del 61,5 % del coste entre los dos periodos (de 36.072,35 € a 13.867,57 € por paciente/año, p = 0,01). No se observaron efectos secundarios asociados al tratamiento. Conclusión: en conclusión, OCT-LAR parecer ser un tratamiento farmacológico coste-eficiente y seguro para la hemorragia digestiva secundaria a malformaciones vasculares, especialmente en pacientes no subsidiaros de tratamiento endoscópico o quirúrgico.

Infectious etiology of diarrheas studied in a third-level hospital during a five-year period

Introduction and objective: Infectious diarrheas are highly frequent and responsible for a major consumption of resources. This study identified the main diarrhea-causing microorganisms in a health area of Granada (Spain) and determined changes in the epidemiologic pattern over a five-year period. Material and method: A retrospective study was conducted based on results obtained in the Microbiology Laboratory of Hospital Universitario Virgen de las Nieves (Granada, Spain). Results: Out of the 25,113 stool microbiological and/or parasitological studies ordered, 2,292 microorganisms were identified in 2,152 samples from 1,892 patients. There was a predominance of bacterial diarrheas (50.1 %), mainly caused by Campylobacter spp. (22.2 %), whose frequency increased significantly during the last two years, and by Salmonella spp. (16.4 %), whose frequency remained stable during the whole study period. We highlight the high frequency of Rotavirus (33.5 %), although a significant decrease was observed during the last two years. Salmonella spp. was more frequently detected during the summer and autumn, Campylobacter spp. during the spring, and Rotavirus during the winter. Viral processes were predominant (53.3 %) in pediatric patients, mainly Rotavirus in under 2-yr-olds, whereas bacterial processes predominated in older children and adults. Diarrhea began at community level in 84.2 % of patients, requiring hospitalization in 25.8 % of cases, and diarrhea was nosocomial in the remaining 15.8 %. Conclusions: During the study period, there was a significant increase in the frequency of diarrhea caused by Campylobacter spp., a significant reduction in the frequency of diarrhea due to Rotavirus, and no change in the frequency of diarrhea due to Salmonella spp., all of which showing a marked seasonal distribution.

Introducción y objetivo: las diarreas infecciosas son muy frecuentes y generan un importante consumo de recursos. Se determinaron los principales microorganismos productores de diarrea en un área sanitaria de Granada y la evolución del patrón epidemiológico durante cinco años. Material y método: se realizó un estudio retrospectivo a partir de los resultados obtenidos durante cinco años en el Laboratorio de Microbiología del Hospital Virgen de las Nieves. Resultados: de 25.113 solicitudes de estudio microbiológico y/o parasitológico en heces, se identificaron 2.292 microorganismos, en 2.152 muestras de 1.892 pacientes. Predominaron las diarreas bacterianas (50,1 %), sobre todo por Campylobacter spp. (22,2 %), cuya frecuencia aumentó significativamente en los dos últimos años, y Salmonella spp. (16,4 %), que se mantuvo a lo largo del periodo. Destacó la elevada frecuencia de Rotavirus (33,5 %), aunque disminuyó significativamente en los dos últimos años. Salmonella spp. se detectó más frecuentemente en verano y otoño, Campylobacter spp. en primavera y Rotavirus en invierno. En los pacientes pediátricos predominaron los procesos víricos (53,3 %), destacando Rotavirus en menores de 2 años, mientras que, en niños mayores y adultos, lo hicieron los procesos de origen bacteriano. En el 84,2 % de los pacientes la diarrea se inició a nivel comunitario, siendo necesario el ingreso del 25,8 %, y en el 15,8 %la diarrea fue nosocomial. Conclusiones: durante el periodo analizado se produjo un incremento significativo de la frecuencia de diarreas por Campylobacter spp., y una disminución, también significativa de Rotavirus, manteniéndose la frecuencia de diarreas por Salmonella spp., todas ellas con una marcada distribución estacional.

Advances in knowledge on microscopic colitis: from bench to bedside

Microscopic colitis (MC) is a general term that describes a family of chronic inflammatory bowel diseases, including lymphocytic colitis (LC) and collagenous colitis (CC). The two forms are characterized by chronic watery diarrhea with normal or near normal endoscopic colonic appearance and specific histopathological abnormalities. Data from recent epidemiological studies reported the diagnosis of MC from several different regions in the world, providing that it can be a worldwide condition. The etiopathogenesis of MC still remains unknown but it is generally accepted that MC is a multifactorial disease, probably secondary to an abnormal immune reaction in predisposed individuals, triggered by different luminal factors (infections, drugs, autoimmunity and/or bile acids). Furthermore, some studies show that the epithelial barrier function in the colonic mucosa of MC patients is also impaired. Several mucosal factors of intestinal inflammation have been studied in MC, postulating that an aberrant T-lymphocyte response may lead to a chronic gut inflammatory condition, with the infiltration of colonic mucosa by different proportion of subset of T-lymphocytes. Little is known about the specific inflammatory mediators in MC pathogenesis, but a predominant Th1 type cytokine profile has been demonstrated. Currently, a number of medical treatments have been studied in MC patients, following mainly an empirical treatment approach. Further studies are needed in order to obtain prospective and more evidence-based data. In the future, it will be possible to develop causal treatment approaches after better understanding the molecular mechanisms behind the origin of the disease.

Duodenal Ewing's sarcoma: unusual location and atypical EWRS-1 translocation

Glycogenic hepatopathy: a rare and reversible cause of elevated transaminases in diabetic patients. Case report

Oropharyngeal dysphagia, an underestimated disorder in pediatrics

Oropharyngeal dysphagia is a rather frequent clinical entity in patients with neurological problems that can lead to serious complications such as aspiration pneumonia and other disorders like dehydration or malnutrition due to feeding difficulties. It should be suspected in children with splitting of food intake or prolonged feeding, coughing or choking during feeding, continuous drooling or repeated respiratory symptoms. For the diagnosis, apart from the examination of swallowing, additional tests can be run like the water-swallowing test, the viscosity-volume test (which determines what kind of texture and how much volume the patient is able to tolerate), a fiberoptic endoscopy of swallowing or a videofluoroscopic swallow study, which is the gold standard for the study of swallowing disorders. It requires a multidisciplinary approach to guarantee an adequate intake of fluids and nutrients with minimal risk of aspiration. If these two conditions cannot be met, a gastrostomy feeding may be necessary.

La disfagia orofaríngea es una entidad clínica bastante frecuente en pacientes con problemas neurológicos, que puede conllevar complicaciones graves como las neumonías aspirativas y otras alteraciones como deshidratación o desnutrición por dificultades para la alimentación. Debe sospecharse en niños con fraccionamiento de la toma o ingestas prolongadas, tos o atragantamientos asociados a la alimentación, babeo continuo o sintomatología respiratoria de repetición. Para su diagnóstico, además de la exploración de la deglución, pueden hacerse pruebas complementarias como la prueba de deglución del agua, la de viscosidad-volumen (determina qué tipo de textura y cuánto volumen puede tolerar el paciente), la fibroendoscopia de la deglución y la videofluoroscopia (el gold estándar para el estudio de los trastornos de la deglución). Requiere un abordaje multidisciplinar para asegurar un adecuado aporte oral de líquido y nutrientes, con mínimo riesgo de aspiración. Si estas dos condiciones no son posibles puede ser necesaria la alimentación por gastrostomía.

Drugs in patient with chronic liver diaseases: general recommendations

Lethal pseudomembranous colitis in an immunocompetent patient

Melatonin as a probable cause of diarrhoea

**Chronic abdominal pain in Primary Care and the presence of Helicobacter pylori and parasites in stool**

Pseudoachalasia secondary to infiltration of the pillars of the diaphragm by an urotelial tumor: diagnostic approach with endoscopic ultrasound

Laparoscopic approach to the intrahepatic gallbladder: a case report