Pathophysiology of increased intestinal permeability in obstructive jaundice

Abstract

Despite advances in preoperative evaluation and postoperative care, intervention, especially surgery, for relief of obstructive jaundice still carries high morbidity and mortality rates, mainly due to sepsis and renal dysfunction. The key event in the pathophysiology of obstructive jaundice-associated complications is endotoxemia of gut origin because of intestinal barrier failure. This breakage of the gut barrier in obstructive jaundice is multi-factorial, involving disruption of the immunologic, biological and mechanical barrier. Experimental and clinical studies have shown that obstructive jaundice results in increased intestinal permeability. The mechanisms implicated in this phenomenon remain unresolved, but growing research interest during the last decade has shed light in our knowledge in the field. This review summarizes the current concepts in the pathophysiology of obstructive jaundice-induced gut barrier dysfunction, analyzing pivotal factors, such as altered intestinal tight junctions expression, oxidative stress and imbalance of enterocyte proliferation and apoptosis. Clinicians handling patients with obstructive jaundice should not neglect protecting the intestinal barrier function before, during and after intervention for the relief of this condition, which may improve their patients' outcome.

Figure 1

Pathophysiology of obstructive jaundice-induced gut barrier failure, endotoxemia and systemic complications. Absence of intraluminal bile deprives the gut from its bacteriostatic, endotoxin-neutralizing and mucosal-trophic effect leading to increased intestinal bacterial and endotoxin load and mucosal atrophy. These alterations promote bacterial and endotoxin translocation into portal circulation and subsequently, through a decreased clearance capacity of Kupffer cells because of cholestasis, into systemic circulation. Systemic endotoxemia activates a systemic inflammatory response, which is associated with dysfunction of remote organs, while it further aggravates intestinal barrier dysfunction and cholestatic liver injury. Endotoxemia, cytokinemia and increased bile acids concentrations represent important promoters of reactive oxygen species formation in diverse organs, encompassing the intestine. Increased intestinal oxidative stress in obstructive jaundice, contributes to induction of apoptosis and inhibition of cell proliferation in intestinal crypts, leading to mucosal atrophy. In parallel, intestinal oxidative stress, endotoxemia, systemic release of inflammatory mediators and absence of intraluminal bile, disrupts the integrity of enterocytes’ tight junctions by altering the expression of their molecular components. As a consequence the intestinal paracellular route opens, contributing to further escape of endotoxin from the intestinal lumen into portal circulation, thus leading to a vicious cycle.