DIARRHEA IN EARLY LIFE: PROGRESS IN DIAGNOSIS AND CONTROL OF DISEASE
Terrin, Gianluca (2010) DIARRHEA IN EARLY LIFE: PROGRESS IN DIAGNOSIS AND CONTROL OF DISEASE. [Tesi di dottorato] (Inedito)
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Diarrheal diseases occurring in early life (< 3 years) are an heterogeneous group of abnormalities including gastrointestinal infections, food hypersensitivity and allergy, immune dysregulation, and primary abnormalities of the enterocyte. Diarrhea is a leading cause of illness and death in children younger than 3 years worldwide, causing 1-3 million deaths every year. Despite defining etiology of diarrhea is critical to decide therapy and prevention strategy, the overall prevalence of early onset diarrhea was not clearly defined because of the large spectrum of etiologies and difficulties in patient selection. From a clinical point of view, diarrhea needs to be classified taking into account certain characteristics such as trends over time (acute or chronic, using a limit of 4 week to separate the two conditions) and the characteristics of the feces. Acute diarrheal diseases occurring in early life, usually due to infectious agent or food allergy, were burdened by an increased mobility and mortality, whereas chronic evolution of early onset diarrhea frequently suggests a congenital disorder determined by genetic defects. Using this classification a pediatrician can decide upon diagnosis and therapy more rationally. However, acute diarrhea may be also a symptom of the onset of chronic organic or functional disease. In younger children acute diarrhea will lead to severe dehydration. Fluid loss and dehydration are the cause of death in nearly all children with acute diarrhea. Over 3 decades ago, the discovery of mechanisms of intestinal electrolytes transport, which was the basis for the development of oral treatment of dehydration, was hailed as the most important medical advance of the 20th century. Complications can be prevented by the early and adequate oral administration of a rehydration solution, by normal food for the child's age, and through induction of benefical intestinal microbiota composition. The evidence-based guidelines of the ESPGHAN and Cochrane analyses, based also on studies reported in this manuscript, indicate zinc and probiotics as useful therapeutic aids for children younger than 3 years with acute diarrhea. Chronic diarrhea in early life includes a group of rare chronic enteropathies characterized by a heterogeneous etiology, which in most cases is related to an identified or to an as yet unidentified genetic defect, generally inherited as an autosomal recessive trait. These congenital diarrheal disorders (CDD, OMIM 251850) represent one of the most challenging clinical conditions for pediatric gastroenterologists because of the severity of the clinical picture and the broad range of conditions in its differential diagnosis. Early in life, patients affected by CDD usually present with severe diarrhea that within a few hours leads to a life-threatening condition secondary to massive dehydration and metabolic acidosis. Consequently, children affected by CDD require a prompt diagnosis and assistance. Clinical manifestations are variable from severe conditions leading to intestinal failure, to milder forms with subtle clinical signs that may remain undiagnosed until adulthood, when patients have just developed irreversible complications. Intestinal failure may lead to the necessity of total parenteral nutrition with further complications for the health of the subject affected by these disorders. The number of conditions included within the CDD group has gradually increased over the years. Now it is clear that CDD depend on defects in the structure and function of absorptive, enteroendocrine or inflammatory cells of the gut, determined by mutations in genes expressed throughout the gastrointestinal tract involving different segments and different cells. Therefore, we have proposed that CDD could be classified into 4 groups: (i) Absorption and transport of nutrients and electrolytes; (ii) Enterocyte differentiation and polarization; (iii) Enteroendocrine cell differentiation; and (iv) Modulation of the intestinal immune response. In recent years, many new genes have been identified. Such molecular techniques as positional candidate genes and genome-wide linkage analysis have clarified the role of these genes in the physiology of the gastrointestinal tract. Understanding the function of this genes may open new diagnostic and therapeutic perspectives for chronic and acute forms of early onset diarrhea. The early postnatal period represents a critical window during which the evolving intestine is programmed by intrinsic (genetic programming) and extrinsic factors (microbe, nutrition, drugs). Intestinal content may modify pretranslational and post-translational gene expression. These ‘‘epigenetic’’ mechanisms are involved in the development of gut enzymes, hormones, transporters, and immunity. Occurrence of diarrheal diseases and related treatments, during this temporarily window, may influence the entire body health status in the short and long-term period. In this scenario, accurate identification and adequate control of diarrheal disorders occurring in early life are crucial for reducing morbidity and mortality. Finally, advances made in the pathophysiology of chronic early onset diarrheal disorders could contributed to a better understanding the mechanisms also of the more common acute diarrheal diseases and to identify novel strategy for disease control. Starting from these considerations, we elaborate selected items focusing on the new diagnostic, therapeutic and preventive strategies for diarrheal diseases occurring in early life. In conclusion, during the PhD project, using a bench to bedside approach, several progresses in the field of diarrhea occurring in early life have been obtained. Epidemiology and etiology of diarrhea have been clarified, new therapeutic and preventive approaches have been developed for control of acute and chronic diarrhea occurring in early life. In addition, a novel model for the study of congenital diarrheal disease has been set. This model could be usefull to reduce the distance from in vitro to in vivo research on these rare conditions, and to identify new therapeutic targets for more common diarrheal disease occurring early in life. The main future target was the intestinal ecosystem (i.e., epithelium, immunity, microflora, nutrients), a dynamic network that could be modulated by different therapeutic and nutritional approaches. Epigenetic modulation of gene expression in early life elicited by nutrients, in order to modify the natural course of the disease, represents the new research frontier.
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