RESUMEN
We performed whole exome sequencing in individuals from a family with autosomal dominant gastropathy resembling Ménétrier disease, a premalignant gastric disorder with epithelial hyperplasia and enhanced EGFR signalling. Ménétrier disease is believed to be an acquired disorder, but its aetiology is unknown. In affected members, we found a missense p.V742G variant in MIB2, a gene regulating NOTCH signalling that has not been previously linked to human diseases. The variant segregated with the disease in the pedigree, affected a highly conserved amino acid residue, and was predicted to be deleterious although it was found with a low frequency in control individuals. The purified protein carrying the p.V742G variant showed reduced ubiquitination activity in vitro and white blood cells from affected individuals exhibited significant reductions of HES1 and NOTCH3 expression reflecting alteration of NOTCH signalling. Because mutations of MIB1, the homolog of MIB2, have been found in patients with left ventricle non-compaction (LVNC), we investigated members of our family with Ménétrier-like disease for this cardiac abnormality. Asymptomatic left ventricular hypertrabeculation, the mildest end of the LVNC spectrum, was detected in two members carrying the MIB2 variant. Finally, we identified an additional MIB2 variant (p.V984L) affecting protein stability in an unrelated isolated case with LVNC. Expression of both MIB2 variants affected NOTCH signalling, proliferation and apoptosis in primary rat cardiomyocytes.In conclusion, we report the first example of left ventricular hypertrabeculation/LVNC with germline MIB2 variants resulting in altered NOTCH signalling that might be associated with a gastropathy clinically overlapping with Ménétrier disease.
Asunto(s)
Cardiomiopatías/patología , Gastritis Hipertrófica/patología , Mutación Missense/genética , Receptores Notch/metabolismo , Gastropatías/patología , Ubiquitina-Proteína Ligasas/genética , Disfunción Ventricular Izquierda/patología , Animales , Animales Recién Nacidos , Cardiomiopatías/etiología , Cardiomiopatías/metabolismo , Estudios de Casos y Controles , Células Cultivadas , Exoma/genética , Femenino , Gastritis Hipertrófica/etiología , Gastritis Hipertrófica/metabolismo , Regulación de la Expresión Génica , Humanos , Masculino , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Linaje , Fenotipo , Ratas , Receptores Notch/genética , Transducción de Señal , Gastropatías/etiología , Gastropatías/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/metabolismoRESUMEN
Successful pluripotent stem cell differentiation methods have been developed for several endoderm-derived cells, including hepatocytes, ß-cells and intestinal cells. However, stomach lineage commitment from pluripotent stem cells has remained a challenge, and only antrum specification has been demonstrated. We established a method for stomach differentiation from embryonic stem cells by inducing mesenchymal Barx1, an essential gene for in vivo stomach specification from gut endoderm. Barx1-inducing culture conditions generated stomach primordium-like spheroids, which differentiated into mature stomach tissue cells in both the corpus and antrum by three-dimensional culture. This embryonic stem cell-derived stomach tissue (e-ST) shared a similar gene expression profile with adult stomach, and secreted pepsinogen as well as gastric acid. Furthermore, TGFA overexpression in e-ST caused hypertrophic mucus and gastric anacidity, which mimicked Ménétrier disease in vitro. Thus, in vitro stomach tissue derived from pluripotent stem cells mimics in vivo development and can be used for stomach disease models.
Asunto(s)
Diferenciación Celular , Células Madre Embrionarias/fisiología , Medicina Regenerativa/métodos , Estómago/fisiología , Ingeniería de Tejidos/métodos , Animales , Diferenciación Celular/efectos de los fármacos , Linaje de la Célula , Células Madre Embrionarias/efectos de los fármacos , Células Madre Embrionarias/metabolismo , Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Gastritis Hipertrófica/genética , Gastritis Hipertrófica/metabolismo , Gastritis Hipertrófica/patología , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Proteínas Hedgehog/metabolismo , Histamina/farmacología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Ratones , Ratones Endogámicos ICR , Organogénesis , Pepsinógeno A/metabolismo , Fenotipo , Esferoides Celulares , Estómago/citología , Estómago/efectos de los fármacos , Factores de Tiempo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transfección , Factor de Crecimiento Transformador alfa/genética , Factor de Crecimiento Transformador alfa/metabolismoRESUMEN
La enfermedad de Ménétrier es una entidad poco frecuente en el niño, caracterizada por una gastroenteropatía pierde proteínas con engrosamiento de la mucosa gástrica y edemas generalizados. La etiología vírica es la más frecuente, siendo el citomegalovirus el agente infeccioso más habitualmente implicado. A diferencia del adulto, es un trastorno autolimitado y con buen pronóstico en el niño. Se revisa a 4 pacientes (3 varones y una mujer) diagnosticados de enfermedad de Ménétrier en los últimos 5 años. La edad media de presentación fue de 28,7 meses (rango: 10-48 meses). La sintomatología clínica más común fue fiebre, vómitos y edemas. La endoscopia demostró engrosamiento de pliegues gástricos y erosiones en grado variable. Todos los pacientes asociaban infección gástrica por citomegalovirus y presentaron una evolución favorable, con resolución del trastorno en pocas semanas
Menetrier's disease is a rare entity in children, characterized by a protein-losing gastroenteropathy with thickening of the gastric mucosa and generalized edema. The most common etiology is viral, and cytomegalovirus is the agent most frequently implicated. Unlike in the adult, it is a self-limited disorder with a good prognosis in children. Four patients (three boys and one girl) diagnosed with Ménétrier disease in the past five years were reviewed. The mean age at presentation was 28.7 months (range: 10-48 months). The most common clinical symptoms were fever, vomiting, and edema. Endoscopy showed thickened gastric folds and erosions in several stages. All patients had an associated gastric cytomegalovirus infection, and a favorable outcome, with resolution of the disorder,was observed within a few weeks
Asunto(s)
Humanos , Masculino , Femenino , Niño , Gastritis Hipertrófica/diagnóstico , Gastritis Hipertrófica/metabolismo , Endoscopía del Sistema Digestivo , Endoscopía del Sistema Digestivo/instrumentación , Citomegalovirus/patogenicidad , Gastritis Hipertrófica/congénito , Gastritis Hipertrófica/complicaciones , Endoscopía del Sistema Digestivo/mortalidad , Endoscopía del Sistema Digestivo , Citomegalovirus/crecimiento & desarrolloAsunto(s)
Endoscopía del Sistema Digestivo , Gastritis Hipertrófica/diagnóstico , 2-Piridinilmetilsulfinilbencimidazoles/uso terapéutico , Biopsia , Femenino , Mucosa Gástrica/patología , Gastritis Hipertrófica/tratamiento farmacológico , Gastritis Hipertrófica/metabolismo , Gastritis Hipertrófica/patología , Humanos , Inmunohistoquímica , Lactante , Antígeno Ki-67/metabolismo , Pantoprazol , Inhibidores de la Bomba de Protones/uso terapéutico , Factor de Crecimiento Transformador alfa/metabolismoRESUMEN
BACKGROUND: Juvenile polyposis syndrome with gastric involvement may mimic Ménétrier's disease, which is correlated to transforming growth factor (TGF)α overproduction and PDX1 upregulation in the gastric fundus. AIM: We report a family with juvenile polyposis syndrome where one member showed typical features of Ménétrier's disease and concomitant Helicobacter pylori infection. METHODS: We studied a 31-year-old woman belonging to a family with juvenile polyposis syndrome, who exhibited a particular form of hyperplastic gastropathy diagnosed as Ménétrier's disease with Helicobacter pylori infection. RESULTS: TGFα overexpression and undetectable PDX1 expression were demonstrated in the fundic gastric biopsy specimens. In all affected members of the family we identified a 4-bp deletion in exon 9 of SMAD4 gene, a mutation usually associated with a more virulent form of juvenile polyposis syndrome with a higher incidence of gastric and colonic polyposis. CONCLUSION: To explain the association of juvenile polyposis syndrome with Ménétrier's disease we hypothesized a new mechanism that involves TGFß-SMAD4 pathway inactivation and TGFα overexpression related to Helicobacter pylori infection.
Asunto(s)
Mucosa Gástrica/metabolismo , Gastritis Hipertrófica/genética , Proteínas de Homeodominio/metabolismo , Poliposis Intestinal/congénito , Síndromes Neoplásicos Hereditarios/genética , Proteína Smad4/genética , Transactivadores/metabolismo , Factor de Crecimiento Transformador alfa/metabolismo , Adolescente , Adulto , Preescolar , Femenino , Gastritis Hipertrófica/complicaciones , Gastritis Hipertrófica/metabolismo , Regulación de la Expresión Génica , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/metabolismo , Helicobacter pylori , Humanos , Poliposis Intestinal/complicaciones , Poliposis Intestinal/genética , Poliposis Intestinal/metabolismo , Masculino , Síndromes Neoplásicos Hereditarios/complicaciones , Síndromes Neoplásicos Hereditarios/metabolismo , Linaje , Proteína Smad4/fisiología , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/fisiología , Regulación hacia ArribaRESUMEN
BACKGROUND: Familial occurrence of Ménétrier disease is rare and has been reported only in few instances. METHODS: Affected patients from a large pedigree were evaluated at the clinical, endoscopic, and pathological levels. RESULTS: Affected members presented with gastropathy of variable severity but without protein loss. Endoscopy and pathology findings were consistent with Ménétrier disease; however, gastric transforming growth factor α (TGF-α) immunohistochemistry and real-time polymerase chain reaction showed no increase in TGF-α expression. CONCLUSIONS: We describe a unique, 4-generation pedigree with autosomal dominant gastropathy exhibiting the typical clinical, endoscopic, and pathological findings of Ménétrier-like disease, though in the absence of protein loss and with no increase in the levels of gastric TGF-α. Members of this family may be affected by a novel and previously unrecognised hereditary form of gastric hyperplasia.
Asunto(s)
Gastritis Hipertrófica/genética , Genes Dominantes , Proteínas/metabolismo , Estómago/patología , Factor de Crecimiento Transformador alfa/metabolismo , Estudios de Casos y Controles , Preescolar , Familia , Femenino , Mucosa Gástrica/metabolismo , Gastritis Hipertrófica/metabolismo , Humanos , Hiperplasia , Masculino , LinajeRESUMEN
Ménétrier's disease (MD) is a rare, acquired, premalignant disorder of the stomach characterized by enlarged gastric folds with foveolar hyperplasia, the phenotype of antralization of gastric glands, hypochlorhydria and hypoproteinemia. The etiology of MD is unknown, but both increased signaling by transforming growth factor-α and infection with Helicobacter pylori (H. pylori) have been implicated. Here, a case involving 70-year-old man who lost weight after developing anorexia and diarrhea is reported. He was diagnosed as MD without H. pylori infection, and in spite of intensive care, he died 40 days after admission. An autopsy confirmed MD. Immunohistochemistry revealed overexpression of transforming growth factor-α in the foveolar region of the gastric mucosa. The autopsy also distinguished this H. pylori-negative MD from hyperplastic polyp of the stomach, which is important in clarifying the entity of H. pylori-negative MD.
Asunto(s)
Mucosa Gástrica/metabolismo , Gastritis Hipertrófica/etiología , Factor de Crecimiento Transformador alfa/metabolismo , Anciano , Ciclooxigenasa 2/metabolismo , Dilatación Patológica , Endosonografía , Resultado Fatal , Mucosa Gástrica/patología , Gastritis Hipertrófica/epidemiología , Gastritis Hipertrófica/metabolismo , Gastritis Hipertrófica/terapia , Infecciones por Helicobacter/epidemiología , Helicobacter pylori , Humanos , Inmunohistoquímica , Insuflación , Masculino , Transducción de Señal/fisiologíaRESUMEN
Hyperactivation of the epidermal growth factor receptor (EGFR) in gastric cells due to excess of its ligand transforming growth factor-α (TGFA) is associated with hyperplastic lesions in Ménétrier's disease patients and in transgenic mice. Other EGFR ligands, however, have never been associated with stomach diseases. Here, we report that overexpression of the EGFR ligand betacellulin (BTC) results in a severe, age-dependent hyperplasia of foveolar epithelium. The stomach weight of affected mice reached up to 3g representing more than 10% of total body weight. The preexisting corpus mucosa was severely depleted, and both parietal and chief cells were replaced by proliferating foveolar epithelium. The lesions were more severe in male as compared to female transgenic mice, and partially regressed in the former after castration-mediated androgen removal. The gastric hyperplasia fully disappeared when BTC-tg mice were crossed into the Egfr(Wa5) background expressing a dominant-negative EGFR, indicating that the phenotype is EGFR-dependent. This is, to our knowledge, the first report of hyperplastic gastric lesions due to the overexpression of an EGFR ligand other than TGFA. BTC-tg mice are therefore a new, promising model for studying EGFR-dependent gastric polyps.
Asunto(s)
Receptores ErbB/metabolismo , Pólipos/metabolismo , Pólipos/patología , Gastropatías/metabolismo , Gastropatías/patología , Animales , Betacelulina , Modelos Animales de Enfermedad , Femenino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Gastritis Hipertrófica/metabolismo , Gastritis Hipertrófica/patología , Hiperplasia/metabolismo , Hiperplasia/patología , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Masculino , Ratones , Ratones TransgénicosRESUMEN
Analysis of cellular signaling networks typically involves targeted measurements of phosphorylated protein intermediates. However, phosphoproteomic analyses usually require affinity enrichment of phosphopeptides and can be complicated by artifactual changes in phosphorylation caused by uncontrolled preanalytical variables, particularly in the analysis of tissue specimens. We asked whether changes in protein expression, which are more stable and easily analyzed, could reflect network stimulation and inhibition. We employed this approach to analyze stimulation and inhibition of the epidermal growth factor receptor (EGFR) by EGF and selective EGFR inhibitors. Shotgun analysis of proteomes from proliferating A431 cells, EGF-stimulated cells, and cells co-treated with the EGFR inhibitors cetuximab or gefitinib identified groups of differentially expressed proteins. Comparisons of these protein groups identified 13 proteins whose EGF-induced expression changes were reversed by both EGFR inhibitors. Targeted multiple reaction monitoring analysis verified differential expression of 12 of these proteins, which comprise a candidate EGFR inhibition signature. We then tested these 12 proteins by multiple reaction monitoring analysis in three other models: 1) a comparison of DiFi (EGFR inhibitor-sensitive) and HCT116 (EGFR-insensitive) cell lines, 2) in formalin-fixed, paraffin-embedded mouse xenograft DiFi and HCT116 tumors, and 3) in tissue biopsies from a patient with the gastric hyperproliferative disorder Ménétrier's disease who was treated with cetuximab. Of the proteins in the candidate signature, a core group, including c-Jun, Jagged-1, and Claudin 4, were decreased by EGFR inhibitors in all three models. Although the goal of these studies was not to validate a clinically useful EGFR inhibition signature, the results confirm the hypothesis that clinically used EGFR inhibitors generate characteristic protein expression changes. This work further outlines a prototypical approach to derive and test protein expression signatures for drug action on signaling networks.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Colorrectales/metabolismo , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Gastritis Hipertrófica/metabolismo , Neoplasias Glandulares y Epiteliales/metabolismo , Neoplasias/metabolismo , Proteómica , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Western Blotting , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cetuximab , Cromatografía Liquida , Neoplasias Colorrectales/tratamiento farmacológico , Factor de Crecimiento Epidérmico/farmacología , Gastritis Hipertrófica/tratamiento farmacológico , Gefitinib , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Fosforilación/efectos de los fármacos , Estudios Prospectivos , Quinazolinas/farmacología , Transducción de Señal/efectos de los fármacos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Trasplante HeterólogoRESUMEN
Ménétrier's disease is a rare hyperproliferative protein-losing gastropathy of the gastric foveolar epithelium. Most common symptoms include epigastric pain with fullness and vomiting, and generalized peripheral edema with hypoalbuminemia. Radiologically, the wall of the gastric body and fundus is diffusely thickened, often with antral sparing. Giant rugal edematous folds are seen on gastroscopy, and histology of biopsy material shows diffuse foveolar hyperplasia with cystic dilatation of the glandular portion of the gastric mucosa in the absence of significant inflammatory infiltrate. The recent discovery of transforming growth factor α overexpression opens the way of epidermal growth factor receptor blockade with cetuximab as first-line treatment modality in severe cases of Ménétrier's disease.
Asunto(s)
Gastritis Hipertrófica/diagnóstico , Gastritis Hipertrófica/etiología , Gastritis Hipertrófica/metabolismo , Gastritis Hipertrófica/terapia , Humanos , Factor de Crecimiento Transformador alfa/metabolismoAsunto(s)
Colitis Ulcerosa/metabolismo , Mucosa Gástrica/metabolismo , Gastritis Hipertrófica/metabolismo , Mucina 2/metabolismo , Mucina 3/metabolismo , Mucinas/metabolismo , Factor de Crecimiento Transformador alfa/metabolismo , Niño , Colitis Ulcerosa/epidemiología , Comorbilidad , Femenino , Gastritis Hipertrófica/epidemiología , Humanos , Mucina 5AC/metabolismo , Regulación hacia Arriba/fisiologíaRESUMEN
Ménétrier's disease, a rare hyperproliferative disorder of the stomach, is associated with chronic abdominal pain, vomiting, weight loss, and edema, as well as an increased risk of gastric cancer. Therapy, other than surgical resection of the stomach, is limited to supportive measures and reflects the limited understanding of Ménétrier's disease pathogenesis. Data reported in this issue describe a promising targeted therapeutic approach and provide new insight into the causes of Ménétrier's disease.
Asunto(s)
Mucosa Gástrica/metabolismo , Gastritis Hipertrófica/terapia , Transducción de Señal , Adulto , Animales , Gatos , Receptores ErbB/metabolismo , Gastritis Hipertrófica/metabolismo , HumanosRESUMEN
Ménétrier's disease is a rare premalignant disorder of the stomach with no proven effective medical therapy. Increased epidermal growth factor receptor signaling has been implicated in the pathogenesis of Ménétrier's disease. We conducted a single-arm clinical trial with cetuximab, a monoclonal antibody that blocks epidermal growth factor receptor signaling, in nine individuals with clinically and histologically documented severe Ménétrier's disease that impaired quality of life to the extent that gastrectomy was being considered. Of the seven patients who completed the 1-month course of treatment, all showed statistically significant improvement both clinically (quality-of-life indices) and biochemically (increased parietal cell mass and gastric acidity). Furthermore, all seven patients who completed the 1-month trial elected to continue treatment, and four subsequently showed near-complete histological remission. Cetuximab should be considered as first-line therapy for Ménétrier's disease.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Gastritis Hipertrófica/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados , Cetuximab , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Femenino , Gastritis Hipertrófica/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Calidad de VidaRESUMEN
Menetrier's disease is an uncommon disease in childhood, characterized by gastric hypertrophy and hypoalbuminemia secondary to protein loss through the gastric mucosa. This paper describes a series report of protein-losing gastropathy associated with cytomegalovirus (CMV) infection in children and reviews the literature. We reviewed the medical records of eight children with diagnosis of Menetrier's disease or protein-losing gastropathy with evidence of acute CMV infection. During a five-year period there were eight children that were diagnosed with CMV-associated protein-losing gastropathy, all in one medium-sized pediatric ward in a general hospital. The mean age was 32 months and there was no gender predominance. The most common presenting symptoms were vomiting and edema. Average symptoms' duration prior to admission was 3.2 weeks and mean albumin at presentation was 1.8 g/dl (range, 1.5-2.5 g/dl; normal values, 3.5-5 g/dl). All eight children fully recovered. In conclusion, CMV infection should be suspected in every child who presents with protein-losing gastropathy. The availability of newer, rapid diagnostic techniques such as polymerase chain reaction (PCR) may facilitate diagnosis, as serology studies may be misleading. Usually, only supportive care is required, but treatment with ganciclovir may be considered for severe or prolonged cases.
Asunto(s)
Infecciones por Citomegalovirus/complicaciones , Mucosa Gástrica/patología , Gastritis Hipertrófica/fisiopatología , Gastritis Hipertrófica/virología , Hipoalbuminemia/etiología , Enteropatías Perdedoras de Proteínas/etiología , Niño , Preescolar , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/fisiopatología , Femenino , Gastritis Hipertrófica/metabolismo , Humanos , Hipertrofia/patología , Hipoalbuminemia/diagnóstico , Inmunoglobulina M/inmunología , Lactante , Masculino , Índice de Severidad de la Enfermedad , Estómago/patología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Ménétrier's disease has been reported to be associated with Helicobacter pylori infection. The aim of this study was to investigate the genetic characteristics of various virulence factors and cytokine expression profiles in Helicobacter pylori isolated from patients with Ménétrier's disease. The genotyping of virulence factors was accomplished by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Induction of various cytokines in MKN45 cells or gastric fibroblasts by Helicobacter pylori stimulus was measured by real-time reverse transcription-PCR. We found that the Helicobacter pylori strain isolated from a patient with Ménétrier's disease was different from other strains in the MseI-RFLP pattern of the ureC gene. Helicobacter pylori isolated from a patient with Ménétrier's disease showed the highest hepatocyte growth factor (HGF) and TNF-alpha mRNA expressions from gastric fibroblasts, and the highest TNF-alpha expression from MKN45 cells. The results in this study suggest that the difference in cytokine production, depending on the difference in bacteria components, plays an important role in the development of Ménétrier's disease.
Asunto(s)
Fibroblastos/metabolismo , Gastritis Hipertrófica/genética , Gastritis Hipertrófica/microbiología , Infecciones por Helicobacter/complicaciones , Helicobacter pylori/genética , Helicobacter pylori/patogenicidad , Factor de Crecimiento de Hepatocito/metabolismo , Gastropatías/genética , Gastropatías/microbiología , Citocinas/metabolismo , Gastritis Hipertrófica/metabolismo , Genotipo , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/microbiología , Helicobacter pylori/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Longitud del Fragmento de Restricción , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Gastropatías/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , VirulenciaRESUMEN
Vascular endothelial growth factor (VEGF) promotes protein leakage from blood vessels and endothelial cell growth. The expression of transforming growth factor (TGF)-alpha and its receptor is increased in the gastric mucosa of patients with Ménétrier's disease. Since TGF-alpha stimulates the expression of VEGF mRNA in cultured keratinocytes, we hypothesized that VEGF may play an important role in the protein leakage of Ménétrier's disease. Immunohistochemistry was performed using specific antibodies against VEGF and CD31 in gastric tissue specimens from 7 patients with Ménétrier's disease and 10 controls. The effect of recombinant TGF-alpha on VEGF production by cultured lamina propria mononuclear cells (LPMCs) was assessed. VEGF expression was detected for LPMCs and occasional epithelial cells of the gastric mucosa of Ménétrier's patients. VEGF-positive LPMCs were increased in tissues from patients with Ménétrier's disease (P<0.001). Of the LPMCs, T-lymphocytes and macrophages were the major sources of VEGF. CD31-positive blood vessels were increased in Ménétrier's tissue. (P<0.05). Recombinant TGF-alpha induced the production of VEGF in cultured LPMCs (P<0.05). In conclusion, the increased expression of VEGF, as a result of overproduction of TGF-alpha, may play a key role in the pathophysiology of Ménétrier's disease.
Asunto(s)
Gastritis Hipertrófica/patología , Factor A de Crecimiento Endotelial Vascular/análisis , Adulto , Anciano , Vasos Sanguíneos/química , Células Cultivadas , Relación Dosis-Respuesta a Droga , Células Endoteliales/química , Células Endoteliales/citología , Femenino , Gastritis Hipertrófica/metabolismo , Humanos , Inmunohistoquímica , Leucocitos Mononucleares/química , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Masculino , Persona de Mediana Edad , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/análisis , Factor de Crecimiento Transformador alfa/farmacologíaAsunto(s)
Aclorhidria/patología , Tumor Carcinoide/patología , Gastritis Hipertrófica/diagnóstico , Neoplasias Primarias Múltiples/patología , Células Parietales Gástricas/patología , Neoplasias Gástricas/patología , Aclorhidria/complicaciones , Aclorhidria/metabolismo , Albúminas/metabolismo , Tumor Carcinoide/complicaciones , Tumor Carcinoide/metabolismo , Diagnóstico Diferencial , Gastritis Hipertrófica/metabolismo , Hiperplasia/complicaciones , Hiperplasia/metabolismo , Hiperplasia/patología , Neoplasias Primarias Múltiples/complicaciones , Neoplasias Primarias Múltiples/metabolismo , Células Parietales Gástricas/metabolismo , Neoplasias Gástricas/complicaciones , Neoplasias Gástricas/metabolismoRESUMEN
This report focuses on a 59-year-old male Japanese patient with Ménétrier's disease who suffered from severe hypoproteinemia and tested positive for Helicobacter pylori when initially admitted to hospital. Blood levels of intact glucagon-like peptide-2 (GLP-2) were determined by specific bioassay, using serum-induced cAMP production in COS-7 cells expressing recombinant human GLP-2 receptors as a functional readout. Eradication of H. pylori led to remission of Ménétrier's disease as well as a partial yet significant decrease in GLP-2 levels, and also improved hypoproteinemia. These observations suggest a possible link between excess systemic endogenous production of GLP-2, a gut hormone that induces mucosal growth, and the hypertrophic gastropathy in a Ménétrier's disease patient with H. pylori infection.
Asunto(s)
Gastritis Hipertrófica/metabolismo , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori , Péptidos/metabolismo , 2-Piridinilmetilsulfinilbencimidazoles , Amoxicilina/uso terapéutico , Antibacterianos , Antiulcerosos/uso terapéutico , Gastritis Hipertrófica/complicaciones , Péptido 2 Similar al Glucagón , Péptidos Similares al Glucagón , Infecciones por Helicobacter/complicaciones , Humanos , Lansoprazol , Masculino , Persona de Mediana Edad , Minociclina/uso terapéutico , Omeprazol/análogos & derivados , Omeprazol/uso terapéutico , Inducción de RemisiónRESUMEN
Chronic inflammation of the gastric epithelium is believed to induce mucosal changes that can eventually develop into gastric cancer. In gastrin-deficient (G-/-) mice exhibiting chronic inflammation in the hypochlorhydric stomach, we documented a prominent fundic mucous cell lineage sharing morphological similarity with preneoplastic changes reported in Helicobacter-infected mice. To study the identity and origin of this cell lineage, we screened for different gastric mucosal cell markers. The clusters of large, foamy cells stained for trefoil factor 2 (TFF2/SP), MUC6 and the lectin Griffonia Simplicifolia II (GSII), but not for the intestine-specific transcription factor Cdx2, suggested that they arise from gastric mucous neck cells. Ki67-labeled GSII-positive neck cells in Helicobacter felis-infected, but not G-/- stomachs, suggested that mucous neck cell proliferation accounted for expansion of this compartment in the H. felis model of gastritis, but not the G-/- model. Using RNase protection assays and quantitative PCR, we found that interferon gamma (IFNgamma) was the most abundant proinflammatory cytokine in the G-/- stomach. We also found that this Th1 cytokine can increase the abundance of mucous neck cells, since its infusion into mice recapitulated the appearance of these cells as observed in both G-/- and H. felis-infected mice. Using the human gastric cell line NCI-N87, we showed that IFNgamma induces the secretion of mucus and expression of MUC6, TFF2 and pepsinogen II, but not of pepsinogen I and intrinsic factor. In conclusion, our results demonstrate that inflammation, specifically the proinflammatory cytokine IFNgamma, induced expansion of the fundic mucous neck cell compartment, which likely represents both increased mucus production and cell number.
Asunto(s)
Biomarcadores/metabolismo , Mucosa Gástrica/patología , Gastritis Hipertrófica/patología , Interferón gamma/metabolismo , Mucinas/metabolismo , Animales , Línea Celular , Linaje de la Célula , Fundus Gástrico/efectos de los fármacos , Fundus Gástrico/metabolismo , Fundus Gástrico/patología , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Gastritis Hipertrófica/metabolismo , Gastritis Hipertrófica/microbiología , Expresión Génica/efectos de los fármacos , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/patología , Helicobacter felis/fisiología , Interferón gamma/genética , Interferón gamma/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mucinas/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor Trefoil-2RESUMEN
BACKGROUND: Lymphocytic gastritis is a rare condition found in approximately 1% of dyspeptic patients. An association with Helicobacter pylori infection has been described. Hypertrophic lymphocytic gastritis is a rare cause of gastrointestinal protein loss. Here, we describe a patient with hypertrophic lymphocytic gastritis, in whom gastrointestinal protein loss resolved completely following H. pylori eradication. CASE REPORT: A 38-year old obese man without gastrointestinal symptoms showed a markedly decreased serum protein (53 g/l, normal 66-85 g/l), a decreased serum albumin (33 g/l, normal 35-52 g/l) and decreased serum immunoglobulin G and immunoglobulin M levels. A renal cause for protein loss was excluded, liver function was normal. Endoscopy of the upper gastrointestinal tract revealed enlarged rigid gastric folds, and an H. pylori-associated lymphocytic gastritis. 99mTc-labelled albumin scintigraphy showed an increased activity in the upper left abdomen compatible with protein secretion in the stomach, and tracer pooling in the upper small bowel. Push enteroscopy with histology demonstrated a normal upper small bowel. Two months after eradication therapy, cure of H. pylori infection was documented and serum protein (71 g/l) and albumin (41 g/l) had returned to normal, while lymphocytic gastritis was still present. One year after eradication therapy endoscopy of the upper gastrointestinal tract and histology and laboratory values were normal. CONCLUSION: Protein-losing gastropathy caused by H. pylori-associated hypertrophic lymphocytic gastritis can be cured solely by H. pylori eradication therapy.