Beyond Tumors: Gastric Syphilis Emulating a Gastric Neoplasia.

We present the case of a 35-year-old male with a first-degree family history of gastric cancer (his father was diagnosed at the age of 45), who was presumed to have gastric cancer himself when evaluating the features of his upper endoscopy performed after hematemesis. Surprisingly, no cancer cells were found in the biopsies. Thanks to a different diagnostic suspicion subsequent to performing a full clinical history, a more favorable diagnosis was reached: gastric syphilis.

Detection of Neuroendocrine Tumours by Enteroscopy: A Case Report.

We present the case of a 62-year-old patient who developed melenas and in whom conventional endoscopic tests could not detect any bleeding lesion. In our case, capsule endoscopy and enteroscopy were the pivotal elements in establishing the diagnosis of a neuroendocrine tumour with an atypical location. As a result, it was possible to surgically remove the lesions at an early stage of the malignancy without metastatic disease and without the need for adjuvant therapy. Our case demonstrates the need for these new techniques in tumours of atypical location and aggressive course. Otherwise, this malignancy may be underdiagnosed until an advanced stage.

Esofagitis eosinofílica: algoritmo secuencial de opciones terapéuticas / Esofagitis eosinofílica: sequential algorithm of therapeutic options

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[Multifactorial etiology and pathogenic factors in inflammatory bowel disease]. / Etiología multifactorial y parcelas patogénicas de la enfermedad inflamatoria intestinal.

All the currently available evidence suggests that the two types of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), involve a conflict between the immune system of the intestinal mucosa and intraluminal antigens, mainly the intestinal microflora, which are normally tolerated by the immune system. This conflict is modulated by numerous environmental factors and a clear polygenetic predisposition. The present article reviews the behavior of all the etiologic circumstances (microbial, genetic and environmental) and subsequently analyzes the possible pathogenic factors in which the etiologies can be found, namely: dysfunction of the intestinal epithelium, innate immune system alterations, and distortion of the cellular and humoral arms of the acquired immune system. The role of tissue ischemia in CD and expression of "extraintestinal inflammatory metastases", both in CD and UC, are briefly discussed. Finally, the view that IBD may be a spectrum of pathological processes provoked by distinct etiopathogenic factors and the possible biological significance of the growing incidence of this disease in the western world, coinciding with the decline in infectious diseases in this geographical area, are discussed.

[Gastric mucosa as a target of persistent proinflammatory aggression: pathogenic models of chronic gastritis]. / La mucosa gástrica como estructura diana de agresiones proinflamatorias persistentes: modelos patogénicos de gastritis crónica.

There are several causes of damage and regeneration of the gastric epithelium (erosive gastropathy) and/or histological inflammation of the gastric mucosa (acute or chronic gastritis). After outlining the usual morphology of chronic gastritis, the authors attempt to identify the biological profile of the main pathogenic models. The first, and by far the most frequent, is the model associated with Helicobacter pylori, which, without crossing the mucosal epithelium, provokes an immune reaction. Although incapable of eradicating this bacterium, this immune reaction contributes to the inflammatory lesion provoked by H. pylori in the mucosa. The second -and much less frequent- model is that causing progressive atrophic gastritis through a humoral and cellular autoimmune mechanism. In third place are a group of models defined by a peculiar cytohistologic pattern of inflammation (granulomatous, lymphocytic or eosinophilic gastritis), suggesting similar pathogenic mechanisms for each of these rare morphological forms of gastritis. Lastly, there is a model barely fitting within the scope of this review, which is that provoking chemical gastropathies (bile reflux, NSAIDs, etc.) with minimal cellular inflammation, i.e., minimal gastritis. To aid understanding of the article, the authors provide a brief outline of the functional histology of the gastric wall and the mechanisms defending its integrity in physiological conditions.

La mucosa gástrica como estructura diana de agresiones proinflamatorias persistentes: modelos patogénicos de gastritis crónica / Gastric mucosa as a target of persistent proinflammatory aggression: pathogenic models of chronic gastritis

Son numerosas las circunstancias etiológicas capaces de producir daño y regeneración del epitelio gástrico (gastropatías erosivas) y/o inflamación histológica de su mucosa (gastritis aguda o crónica). Después de recordar la morfología habitual de las llamadas gastritis crónicas, los autores han intentado identificar el perfil biológico de los principales modelos patogénicos de dichas gastritis. El primero, y con mucho el más frecuente, está asociado a la infección por Heliocobacter pylori, germen que, sin atravesar el epitelio mucoso, provoca una reacción inmune que, aunque es incapaz de eliminarlo, contribuye a la lesión inflamatoria que aquél provoca en la mucosa. El segundo modelo, mucho menos frecuente, es el responsable de una gastritis progresivamente atrófica, a través de un mecanismo autoinmune humoral y celular. En tercer lugar podemos citar un conjunto de modelos definidos por el peculiar perfil citohistológico de la inflamación (gastritis granulomatosa, linfocítica o eosinofílica), hecho que sugiere vías patogénicas similares para cada una de estas raras formas morfológicas de gastritis. Por último, hay un modelo que está situado en la frontera del tema de esta revisión, que es el que provoca algunas gastropatías químicas (reflujo biliar, toma de antiinflamatorios no esteroideos, etc.), con mínima expresión inflamatoria celular, es decir, con gastritis mínima. Para comprender mejor el contenido de este trabajo, se recuerda brevemente la histología funcional de la pared gástrica y los mecanismos defensivos de su integridad, en condiciones fisiológicas (AU)

There are several causes of damage and regeneration of the gastric epithelium (erosive gastropathy) and/or histological inflammation of the gastric mucosa (acute or chronic gastritis). After outlining the usual morphology of chronic gastritis, the authors attempt to identify the biological profile of the main pathogenic models. The first, and by far the most frequent, is the model associated with Helicobacter pylori, which, without crossing the mucosal epithelium, provokes an immune reaction. Although incapable of eradicating this bacterium, this immune reaction contributes to the inflammatory lesion provoked by H. pylori in the mucosa. The second —and much less frequent— model is that causing progressive atrophic gastritis through a humoral and cellular autoimmune mechanism. In third place are a group of models defined by a peculiar cytohistologic pattern of inflammation (granulomatous, lymphocytic or eosinophilic gastritis), suggesting similar pathogenic mechanisms for each of these rare morphological forms of gastritis. Lastly, there is a model barely fitting within the scope of this review, which is that provoking chemical gastropathies (bile reflux, NSAIDs, etc.) with minimal cellular inflammation, i.e., minimal gastritis. To aid understanding of the article, the authors provide a brief outline of the functional histology of the gastric wall and the mechanisms defending its integrity in physiological conditions (AU)

Etiología multifactorial y parcelas patogénicas de la enfermedad inflamatoria intestinal / Multifactorial etiology and pathogenic factors in inflammatory bowel disease

Actualmente todo inclina a pensar que la enfermedad inflamatoria intestinal (EII) en sus 2 variantes, la enfermedad de Crohn (EC) y la colitis ulcerosa (CU), traduce un conflicto entre el sistema inmunitario de la mucosa intestinal y los antígenos intraluminales, fundamentalmente de la microflora intestinal, a los que normalmente toleraba. Todo eso modulado por numerosos factores ambientales y una evidente predisposición de carácter poligénico.Sobre este argumento se revisa el comportamiento del conjunto de circunstancias etiológicas (microbianas, genéticas y ambientales) para analizar, a continuación, las posibles parcelas patogénicas en donde se expresan aquellos factores etiológicos, como la disfunción del epitelio intestinal, las alteraciones del sistema inmunitario innato y la distorsión de los brazos celular y humoral del sistema inmunitario adquirido. Se comenta brevemente el papel de la isquemia tisular en la EC y la expresión de las “metástasis inflamatorias extraintestinales”, tanto en la EC como en la CU.Finalmente, se especula sobre la probable consideración de la EII como un espectro de procesos patológicos provocados desde ángulos etiopatogénicos diferentes y el posible significado biológico de su creciente incidencia en el mundo occidental, en coincidencia con el declive de las enfermedades infecciosas en éste(AU)

All the currently available evidence suggests that the two types of inflammatory bowel disease(IBD), Crohn’s disease(CD) and ulcerative colitis(UC), involve a conflict between the immune system of the intestinal mucosa and intraluminal antigens, mainly the intestinal microflora, which are normally tolerated by the immune system. This conflict is modulated by numerous environmental factors and a clear polygenetic predisposition. The present article reviews the be havi or of all the etiologic circumstances(microbial, genetic and environmental)and subsequently analyzes the possible pathogenic factors in which the etiologies can be found, namely: dysfunction of the intestinal epithelium, innate immune system alterations, and distortion of the cellular and humoral arms of the acquired immune system. The role of tissue is chemiain CD and expression of‘‘ extraintestinal inflammatory metastases’’, bothin CD and UC, are briefly discussed. Finally, the view that IBD may be aspectrum of pathological processes provoked by distinct etiopathogenic factor sand the possible biological significance of the growing incidence of this disease in the western world, coinciding with the decline in infectious diseases in this geographical area, are discussed(AU)

[Genetic abnormalities of digestive tract adenocarcinomas and correlation with the histologic sequence of their development]. / Alteraciones genéticas de los adenocarcinomas del aparato digestivo y su correlación con la secuencia de su gestación.

Over 90% of digestive tract malignancies are adenocarcinomas (ADC) and almost 95% of them have gastric (G), colorectal (CR) or pancreatic (P) localizations. The objectives of this work are to review the genetic abnormalities of ADC in these locations and their potential coincidences, along with the histogenetic correlation of their emergence. Genetic abnormalities affecting over 50% of cases include: in G-ADC, inactivation of suppressor genes of p53, APC and DCC tumor in its intestinal variant, hypoexpression of of caderine E in the diffuse variant and hyperexpression of cyclooxygenase-2 and cyclyn D in the intestinal form; in in CR-ADC, inactivation of of genes p53, APC and DCC together with mutational activation of k-ras oncogen, and in P-ADC, the inactivation of suppressor genes p53, p16 and DPC4 along with mutational activation of k-ras oncogen. P-ADC is the one showing a more characteristic and exclusive genetic mark, followed by CR-ADC. Finally, the histogenetic correlation in the tumorigenic sequence is more evident in CR-ADC, followed by P-ADC. The complex biologic reality of G-ADC makes it more difficult to draw its genetic profile and its histogenetic correlation. In order to understand better the arguments of this work, the authors comment on the genetic-molecular basis governing the life and death of normal somatic cells and the biologic profile of the groups of genes mainly involved in tumorigenesis.

Alteraciones genéticas de los adenocarcinomas del aparato digestivo y su correlación con la secuencia de su gestación / Genetic abnormalities of digestive tract adenocarcinomas and correlation with the histologic sequence of their development

Más del 90% de los tumores malignos del aparato digestivo pertenecen a la familia de los adenocarcinomas (ADC) y casi el 95% de éstos presentan localizaciones gástricas (G), colorrectales (CR) o pancreáticas(P). Revisar las alteraciones genéticas que protagonizan los ADC de estas localizaciones y sus posibles coincidencias, junto a la correlación histogénica de su gestación, es el motivo de este trabajo. Lasalteraciones genéticas que afectan a más del 50% de los casos son: en los ADC-G, la inactivación de los genes supresores de tumor p53, APC y DCC, en su variante «intestinal», la hipoexpresión de la caderinaE en la variante «difusa» y la hiperexpresión de la ciclooxigenasa- 2 y la ciclina D en la forma «intestinal»; en los ADC-CR, la inactivaciónde los genes p53, APC y DCC, junto a la activación mutacional del oncogén k-ras y, por último, en los ADC-P, la inactivación de los genes supresores p53, p16 y DPC4 junto a la activación mutacional del oncogén k-ras. El ADC-P es el que muestra una marca genéticamás característica y exclusiva, seguido del ADC-CR. Por último, la correlación histogénica en la secuencia tumorígena es más evidente en los ADC-CR, seguidos de los ADC-P. La compleja realidad biológica de los ADC-G hace más difícil dibujar tanto su perfil genético comosu correlación histogénica. Para comprender mejor los argumentos de este trabajo, los autores recuerdan las bases genéticas y moleculares que regulan la vida y muerte de las células somáticas normales y elperfil biológico de las familias de genes principalmente involucrados en la carcinogenia

Over 90% of digestive tract malignancies are adenocarcinomas (ADC) and almost 95% of them have gastric (G), colorectal (CR) or pancreatic(P) localizations. The objectives of this work are to review the genetic abnormalities of ADC in these locations and their potential coincidences,along with the histogenetic correlation of their emergence. Genetic abnormalities affecting over 50% of cases include: in G-ADC, inactivation of suppressor genes of p53, APC and DCC tumor in its intestinalvariant, hypoexpression of of caderine E in the diffuse variant and hyperexpression of cyclooxygenase-2 and cyclyn D in the intestinal form; in in CR-ADC, inactivation of of genes p53, APC and DCC togetherwith mutational activation of k-ras oncogen, and in P-ADC, the inactivation of suppressor genes p53, p16 and DPC4 along with mutational activation of k-ras oncogen. P-ADC is the one showing a more characteristicand exclusive genetic mark, followed by CR-ADC. Finally, the histogenetic correlation in the tumorigenic sequence is more evident in CR-ADC, followed by P-ADC. The complex biologic reality of G-ADC makes it more difficult to draw its genetic profile and its histogenetic correlation. In order to understand better the arguments of this work, the authors comment on the genetic-molecular basis governing the lifeand death of normal somatic cells and the biologic profile of the groups of genes mainly involved in tumorigenesis

[Gastrointestinal carcinoid tumors: cellular biology, molecular expression and physiopathological consequences of an enigmatic neoplasia]. / Tumores carcinoides gastrointestinales. Biología celular, expresión molecular y consecuencias fisiopatológicas de una neoplasia enigmática.

Gastrointestinal carcinoid tumors arise from cells of the diffuse neuroendocrine system localized in the digestive trace and represent more than 70% of all carcinoid tumors in humans. The present article reviews the following topics: 1) The biological profile of these tumors (histopathology, cytokine markers, metabolic alterations, storage of neuroamines and hormonal proteins, cytodynamic behavior, and biological behavior according to embryological origin). 2) The etiological circumstances (exceptional hereditary factors, association of gastric carcinoid tumors with autoimmune gastritis, little-known exogenous factors). 3) Pathogenic aspects (persistent mitogenesis of endocrine cells associated with hypergastrinemia, inactivation of some putative tumor suppressor genes, the doubtful participation of oncogenes, autocrine action of some cellular growth-stimulating proteins). 4) The repercussions of certain physiopathological events (peritumoral desmoplastic reaction causing the "mass effect" on the digestive tube, the "kidnapping" of dietary tryptophan by tumoral cells toward an abnormal metabolic pathway; the easy metastatic dissemination coexisting with low tumoral aggressivity, and the release into the bloodstream of stored secretory products leading to "carcinoid syndrome" and some endocrine hyperfunction syndromes. Finally, it should be remembered that gastrointestinal carcinoid tumors represent only a proportion of the neoplasms classified as neuroendocrine tumors.

Tumores carcinoides gastrointestinales. Biología celular, expresión molecular y consecuencias fisiopatológicas de una neoplasia enigmática / Gastrointestinal carcinoid tumors: celular biology, molecular expression and fisiopathological consequences of an enigmatic neoplasia

Los tumores carcinoides gastrointestinales (TCa-GI) surgen desde células del sistema neuroendocrino difuso localizadas en el tracto digestivo y representan más del 70% de todos los TCa de los seres humanos. En este trabajo se revisan los siguientes argumentos: 1) El perfil biológico de los TCa-GI (dibujo histopatológico, marcadores citoquímicos, alteraciones metabólicas, almacenamiento de neuroaminas y proteínas hormonales, comportamiento citodinámico y características biológicas en función del origen embriológico). 2) Las circunstancias etiológicas (factores hereditarios excepcionales, asociación de TCa gástricos con gastritis autoinmune, factores exógenos poco conocidos). 3) Aspectos patogénicos (mitogénesis persistente de células endocrinas asociada a hipergastrinemia, inactivación de algunos presuntos genes supresores de tumor, dudosa participación de oncogenes, acción autocrina de algunas proteínas estimuladoras de crecimiento celular). 4) Las repercusiones de ciertos episodios fisiopatológicos (reacción desmoplástica peritumoral responsable del «efecto masa» sobre el tubo digestivo, el «rapto» del triptófano alimentario por parte de las células tumorales hacia una vía metabólica anormal, la fácil diseminación metastásica coexistente con una escasa agresividad tumoral, la liberación al torrente sanguíneo de productos secretores almacenados responsables del «síndrome carcinoide» y de algunos cuadros de hiperfunción endocrina). Conviene recordar que los TCa-GI representan sólo un segmento de los llamados tumores neuroendocrinos y, como tales, deben considerarse

Gastrointestinal carcinoid tumors arise from cells of the diffuse neuroendocrine system localized in the digestive trace and represent more than 70% of all carcinoid tumors in humans. The present article reviews the following topics: 1) The biological profile of these tumors (histopathology, cytokine markers, metabolic alterations, storage of neuroamines and hormonal proteins, cytodynamic behavior, and biological behavior according to embryological origin). 2) The etiological circumstances (exceptional hereditary factors, association of gastric carcinoid tumors with autoimmune gastritis, little-known exogenous factors). 3) Pathogenic aspects (persistent mitogenesis of endocrine cells associated with hypergastrinemia, inactivation of some putative tumor suppressor genes, the doubtful participation of oncogenes, autocrine action of some cellular growth-stimulating proteins). 4) The repercussions of certain physiopathological events (peritumoral desmoplastic reaction causing the «mass effect» on the digestive tube, the «kidnapping» of dietary tryptophan by tumoral cells toward an abnormal metabolic pathway; the easy metastatic dissemination coexisting with low tumoral aggressivity, and the release into the bloodstream of stored secretory products leading to «carcinoid syndrome» and some endocrine hyperfunction syndromes. Finally, it should be remembered that gastrointestinal carcinoid tumors represent only a proportion of the neoplasms classified as neuroendocrine tumors

Perfil genético y bases moleculares de la carcinogénesis pancreática / Genetic profile and molecular bases of pancreatic carcinogenesis

La posibilidad de una secuencia multifásica de la carcinogénesis se ha probado suficientemente en el cáncer colorrectal, al menos el que surge de un pólipo adenomatoso benigno. Sin embargo, y como consecuencia de la difícil accesibilidad del páncreas a los estudios histopatológicos, esta evolución multifásica es más difícil de demostrar en el caso del adenocarcinoma ductal (ADC-d) pancreático, aunque una serie de hechos, revisados en este trabajo, la sugieren vehementemente. En primer lugar, está la definición de un perfil genético-molecular bastante exclusivo del ADC-d, en la medida que se repite en más del 70% de los casos; nos referimos a la asociación de la mutación del oncogén K-ras y la inactivación de los genes supresores de tumor p16, p53 y DPC4. En segundo lugar, se encuentra la identificación de una serie de lesiones del epitelio ductal, en zonas pancreáticas sanas próximas a un ADC-d, que parecen representar estadios histopatológicos precancerosos. Y por último, la sospecha de que los eventos han ido apareciendo, con un cierto orden, durante dichos estadios evolutivos. De todas maneras, lo más probable es que, más que el orden de aparición, sea la acumulación de estos eventos genético-moleculares lo que determine que un epitelio ductal quiescente evolucione a una citohiperplasia mitogénica para terminar en una citodisplasia mutagénica irreversible

The possibility that carcinogenesis is a multiphasic process has been well demonstrated in colorectal cancer, at least in cancers arising from a benign adenomatous polyp. However, because of the difficulty of performing histopathological studies of the pancreas, the multiphasic nature of carcinogenesis is proving more difficult to demonstrate in pancreatic ductal adenocarcinoma (d-ADC), although a series of findings, reviewed in the present article, strongly support this characteristic. Firstly, d-ADC shows a fairly exclusive genetic-molecular profile, found in 70% of cases; this profile consists of the association of the K-ras oncogene and inactivation of the tumor suppressor genes p16, p53 and DPC4. Secondly, a series of lesions in the ductal epithelium, in healthy pancreatic tissue close to a d-ADC, have been identified, which seem to represent precancerous histopathological stages. Lastly, there is the suspicion that the mutations defining this genetic-molecular profile appear gradually, in a certain sequence, throughout the stages of progression. Most probably, rather than the order of appearance, the accumulation of these genetic-molecular events are what prompt quiescent ductal epithelium to progress to mitogenic cellular hyperplasia, leading to irreversible mutagenic cellular dysplasia (AU)

[Genetic profile and molecular bases of pancreatic carcinogenesis]. / Perfil genético y bases moleculares de la carcinogénesis pancreática.

The possibility that carcinogenesis is a multiphasic process has been well demonstrated in colorectal cancer, at least in cancers arising from a benign adenomatous polyp. However, because of the difficulty of performing histopathological studies of the pancreas, the multiphasic nature of carcinogenesis is proving more difficult to demonstrate in pancreatic ductal adenocarcinoma (d-ADC), although a series of findings, reviewed in the present article, strongly support this characteristic. Firstly, d-ADC shows a fairly exclusive genetic-molecular profile, found in 70% of cases; this profile consists of the association of the K-ras oncogene and inactivation of the tumor suppressor genes p16, p53 and DPC4. Secondly, a series of lesions in the ductal epithelium, in healthy pancreatic tissue close to a d-ADC, have been identified, which seem to represent precancerous histopathological stages. Lastly, there is the suspicion that the mutations defining this genetic-molecular profile appear gradually, in a certain sequence, throughout the stages of progression. Most probably, rather than the order of appearance, the accumulation of these genetic-molecular events are what prompt quiescent ductal epithelium to progress to mitogenic cellular hyperplasia, leading to irreversible mutagenic cellular dysplasia.

[Eosinophilic granulocytes: from common residents in normal gastrointestinal mucosa to aggressive agents of eosinophilic gastroenteritis]. / Los granulocitos eosinófilos: de residentes habituales de la mucosa gastrointestinal normal a protagonistas agresivos de la gastroenteritis eosinofílica.

Because of their biological affinity for normal gastrointestinal (GI) mucosa, eosinophilic granulocytes are "normal residents" in the mucosa. This physiological GI eosinophilia translates into a state of "permanent normal inflammation", which means that the mucosa's local immune system is constantly confronted by dietary proteins and indigenous microorganisms. This eosinophilic infiltration of the GI mucosa is increased, reactively, in the course of local inflammatory processes, collagenosis, infections (especially helminthic infections), vasculitis, neoplasms and IgE-dependent allergic reactions to food. Lastly, GI eosinophilia that is clearly aggressive, both because of its intensity and its persistence, is what characterizes eosinophilic gastroenteritis. In the present article, we summarize the ethiopathogenic and clinico-epidemiological features of this process, as well as its position within the field of immunopathologic food intolerance.

Los granulocitos eosinófilos: de residentes habituales de la mucosa gastrointestinal normal a protagonistas agresivos de la gastroenteritis eosinofílica / Eosinophilic granulocytes: from common residents in normal gastrointestinal mucosa to aggressive agents of eosinophilic gastroenteritis

La afinidad biológica que muestran los granulocitos eosinófilos por la mucosa gastrointestinal (GI) normal los convierte en «residentes habituales». Esta eosinofilia GI fisiológica indica el estado de «inflamación normal permanente» que somete a esta mucosa a la confrontación continua del sistema inmunitario local con las proteínas alimentarias y los microorganismos autóctonos. Esta infiltración de eosinófilos de la mucosa GI se incrementa, con carácter reactivo, en el curso de procesos inflamatorios locales, colagenosis, infecciones (sobre todo helmínticas), vasculitis, neoplasias y reacciones alérgicas alimentarias «IgE-dependientes». Por último, una eosinofilia GI claramente agresiva, tanto por su intensidad como por su persistencia, es la que define a la entidad anatomoclínica conocida como gastroenteritis eosinofílica. Los autores resumen los aspectos etiopatogénicos y clínico-epidemiológicos de este proceso, así como su posición patogénica dentro del campo oscuro de las intolerancias alimentarias inmunopáticas

Because of their biological affinity for normal gastrointestinal (GI) mucosa, eosinophilic granulocytes are «normal residents» in the mucosa. This physiological GI eosinophilia translates into a state of «permanent normal inflammation», which means that the mucosa's local immune system is constantly confronted by dietary proteins and indigenous microorganisms. This eosinophilic infiltration of the GI mucosa is increased, reactively, in the course of local inflammatory processes, collagenosis, infections (especially helminthic infections), vasculitis, neoplasms and IgE-dependent allergic reactions to food. Lastly, GI eosinophilia that is clearly aggressive, both because of its intensity and its persistence, is what characterizes eosinophilic gastroenteritis. In the present article, we summarize the ethiopathogenic and clinico-epidemiological features of this process, as well as its position within the field of immunopathologic food intolerance