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Abstract

IntroductionThe Fontan procedure was developed as a means for separating the systemic and pulmonary circulation in patients with tricuspid atresia, and was then applied to other patients with a functionally single ventricle [1]. Venous hypertension is a general feature of this circulation. A late complication develops in some patients, consisting of a substantial decrease of serum protein and γ-globulin, an increase in stool α 1 -antitrypsin level, and a substantial loss of circulating lymphocytes [2][3][4][5]. These features are typical of protein-losing enteropathy (PLE), and are associated with significant mortality [4,[6][7][8].In the present report, we describe our observation of enteric infection and inflammatory response at the onset of PLE in a child with Fontan circulation. We have also reviewed the findings in seven other patients with longstanding PLE.185 EBV = Epstein-Barr virus; ELISA = enzyme-linked immunosorbent assay; IL = interleukin; PLE = protein-losing enteropathy. AbstractIntroduction Protein-losing enteropathy (PLE) is a recognised complication of the Fontan circulation. Its pathogenesis is not fully understood, however, and it is unclear why its onset occurs months or even years after Fontan surgery. Patients We report a 4.5-year-old girl with Fontan circulation who developed PLE almost 1 year after surgery. At the time of onset the patient had rotavirus enteritis and streptococcal tonsillitis. We have reviewed the records of seven other patients with longstanding PLE. In six of these patients we identified infections at the onset of symptoms. None of our patients had evidence of opportunistic infection. Discussion and conclusion The immune system of patients with PLE is compromised, but reports on recurrent opportunistic infections are rare. The present observations suggest that infection and inflammation may be associated with the onset of PLE. The mechanism of how infection may trigger PLE warrants further investigation.

Heparan Sulfate Plays a Central Role in a Dynamic in Vitro Model of Protein-losing Enteropathy

“…The most likely explanation is that genetic factors and Fontan-induced venous hypertension predispose for PLE, which precipitates upon a series of sequential or simultaneous environmental insults. Consistent with this hypothesis, seven out of eight post-Fontan patients have been diagnosed with viral infections at the onset of PLE symptoms (5), indicating that this additional insult triggered PLE. Jejunal biopsies, taken during episodes with PLE, revealed an increased IFN␥ concentration (7), most likely as a response to the viral infection and elevated levels of the pro-inflammatory cytokine TNF␣ (6).…”

“…The evidence for this is that patients do not suffer from PLE continuously; rather, PLE is episodic. Its onset is often associated with viral infections and a pro-inflammatory state (2,(5)(6)(7)(8), indicating that multiple factors combine to trigger PLE. Most intriguing is the loss of heparan sulfate (HS) proteoglycans (HSPG) specifically from the basolateral surface of intestinal epithelial cells only during PLE episodes (1, 2, 9, 10) followed by its reappearance when PLE resolves (2).…”

Protein losing enteropathy: comprehensive review of the mechanistic association with clinical and subclinical disease states

“…It is necessary to postulate that some unidentified abnormality other than elevated venous pressure must render a subset of Fontan subjects susceptible to chronic lymphatic rupture. The PLE observed in Fontan subjects has been reported to be triggered by an enteric infection 59,60. It seems possible that such tissue injury initiates PLE, which then becomes self-sustaining, possibly in part secondary to the enhanced lymph production engendered by the hypoalbuminemia that results from protein loss into the gut.…”

Molecular functions of syndecan-1 in disease

“…Protein-losing enteropathy (PLE) is characterized by excessive efflux of plasma proteins into the intestinal lumen, and is often associated with viral infections, increased IFNγ and TNFα levels, and a pro-inflammatory state (Lenz et al, 2003). Loss of syndecan-1 or HS from the basolateral surface of intestinal cells was found to be closely associated with PLE episodes, whereas both were induced when the disease resolved (Bode et al, 2008).…”