Clinics in gastroenterology最新文献

The gut is a long convoluted tube, in which food is processed and nutrients, salt and water are absorbed. The degree of absorption depends to a large extent on the degree of contact between the luminal contents and the absorptive epithelium. Motor activity can influence the degree of absorption because it regulates the degree of contact with the epithelium and it may also induce secretion by a reflex mechanism. Many factors that induce diarrhoea are associated with ‘abnormal’ and highly propagative forms of motor activity that can clear material through the gut, allowing insufficient epithelial contact for absorption. These propulsive motor patterns may be provoked by distension of the gut with fluid, but they can also occur in response to diarrhoeogenic factors when there is minimal distension.

Patients who complain of increased frequency, urgency and incontinence but pass normal stool volumes often have an abnormality in the motor activity of the anorectum. Thus, the generation of abnormal or propagated forms of motor activity must be regarded as an important component of the pathogenesis of all types of diarrhoea and an increased stool volume can be regarded as the end result of a vicious spiral (Figure 12) that may start with a primary abnormality in either motor activity or epithelial transport.

Bacteria and their toxins are responsible for an enormous burden of diarrhoeal disease. Knowledge about the toxins and their mechanisms of action is limited. Thus, although considerable information is available about the mechanism of action of cholera toxin and a small number of heat-stable enterotoxins, information on the role and action of many others is incomplete. The demonstration of a toxic effect in a test system does not necessarily imply that that activity is relevant to the pathogenesis of the diarrhoea. On the other hand, the absence of a toxic effect in experimental systems does not eliminate the possibility that a toxin is responsible for a particular organism's clinical effects. This is a field of active research and much more work is clearly required.

Congenital chloride diarrhoea is an autosomal recessive disease characterized by life-long watery diarrhoea of prenatal onset with high faecal Cl⁻ concentration. Seventy-nine patients have so far been reported. The basic defect involves the active Cl⁻/HCO₃⁻ exchange mechanism of the distal ileum and colon. The defect causes impaired absorption of Cl⁻, acidity of intestinal contents because of impaired excretion of HCO₃⁻, and, secondarily, impaired Na⁺ absorption.

Intra-uterine diarrhoea leads to hydramnios and often to premature birth. Unless adequately treated, most patients will die of hypo-electrolytaemic dehydration within the 1st few months of life. Some infants will survive in such a state, with severe alkalosis, hypochloraemia, hypokalaemia, and retarded growth and development. Their plasma renin and aldosterone concentrations will become grossly elevated, and pathological changes will develop in the kidneys. The diagnosis is established when faecal Cl⁻ concentration exceeds 90 mmol/1 after water and electrolyte deficits have been corrected.

Congenital chloride diarrhoea should be treated with full oral replacement of the faecal losses of Cl⁻, Na⁺, K⁺, and water. This therapy will abolish all the secondary disorders, provide for normal growth and development, and prevent renal disease. Though this therapy does not abolish the diarrhoea, most children will become toilet trained at a normal age, their social adjustment will be unimpaired, and they will live a perfectly normal life.

Eicosanoids are unsaturated fatty acid compounds derived from 20-carbon ‘essential’ fatty acids, the most important being arachidonate. Both cyclo-oxygenase and lipoxygenase products of arachidonate are abundant in the human gut and their biological effects include modulation of fluid and electrolyte secretion, motor activity, mucosal blood flow, and cytoprotection, in addition to chemotaxis and immune response in inflammation. In health, these lipid mediators reinforce or synergize normal homeostatic mechanisms that could proceed in their absence.

Receptors for control of intestinal secretion can be divided into two major classes, one of which triggers the production of cyclic AMP and another, which initiates phospholipid breakdown and arachidonate release. An intimate connection appears to exist between phospholipid metabolism, cytosolic Ca²⁺ levels, electrogenic anion secretion, Na⁺ pump rate, electroneutral Na⁺/H⁺ exchange activity, and intracellular pH. Ca²⁺-dependent secretagogues affect fluid and electrolyte transport in the small and the large bowel by increasing Ca²⁺ entry and Ca²⁺ mobilization through stimulation of eicosanoid formation, prostaglandins of the E type being the most important. Secretory diarrhoea may be thought of, therefore, as cellular Ca²⁺ intoxication.

Uncontrolled formation of eicosanoids, perhaps with a changed spectrum of arachidonate metabolites, may not only be the source of diarrhoea associated with mucosal inflammation, but may also be critical for cell proliferation resulting in abnormal cell differentiation, which seems to be the link between long-standing inflammatory bowel disease and the increased risk of colonic neoplasia.

A better understanding of the pathophysiological role of eicosanoids in diarrhoeal disease has allowed reinterpretation of the rationale behind current therapy.