Prospective evaluation of gut mucosal barrier injury following various myeloablative regimens for haematopoietic stem cell transplant

Abstract

Summary:We determined gut mucosal barrier injury (MBI) among 129 recipients of an allogeneic or autologous haematopoietic stem cell transplant (HSCT) who had been given different myeloablative regimens by measuring integrity using the lactulose/rhamnose (RHA) ratio and absorption using the ratios of rhamnose/3-O-methylglucose and xylose/3-O-methylglucose. Regimens that did not contain idarubicin induced oral mucositis and disturbed gut integrity and absorption earlier than did those containing the anthracycline. By contrast, regimens containing idarubicin induced more severe and prolonged oral and gut MBI. Gut integrity and absorption of most patients were still abnormal at discharge from hospital. These results confirm that the integrity and absorptive capacity of the gut is affected adversely by myeloablative regimens in general, although only two patterns of mucosal injury emerged depending on whether or not idarubicin was used. Mucosal barrier injury (MBI) of the oral cavity is reported to affect more than 60% of haematopoietic stem cell transplant (HSCT) recipients given myeloablative preparative regimens. 1 Wardley and colleagues showed that the character, onset and progression of oral mucositis were markedly influenced by the nature of the conditioning therapy. For instance, high-dose melphalan aggravated oral mucositis, whereas its onset was delayed after busulphan. 2 Much less is known about the gastrointestinal counterpart of oral mucositis, although gut injury results in significant morbidity and mortality. 3 Sugar permeability tests can objectively determine changes in permeability (integrity and absorption) and have been found to complement the signs and symptoms associated with gut toxicity such as nausea, vomiting, diarrhoea and abdominal cramps. 4 However, it is not known whether gut MBI is also affected differently by the various myeloablative regimens. Moreover, our standard conditioning regimen consists of idarubicin, cyclophosphamide and TBI, 5 and is known to induce prolonged and severe oral mucositis. 6 Therefore, we employed a sugar permeability test to determine differences in gut permeability, integrity and absorption of a cohort of HSCT recipients given different myeloablative regimens. Patients, methods and materials Patients

Intestinal mucosal dysfunction and infection during remission-induction therapy for acute myeloid leukaemia

“…1,29 The integrity of the oropharyngeal mucosa does not necessarily predict the state of distal tissues. 29 Our observations on a relatively small sample confirming previous reports 7,[15][16][17]21 are consistent with this hypothesis. In addition, our observations further re-enforce the independence of the chemotherapy-induced intestinal cytotoxicity and myelotoxicity.…”

“…12,13 The evaluation of drug-related treatment effects have focused primarily on visual estimates of the severity of oropharyngeal mucosa damage and upon nausea, vomiting, abdominal pain and diarrhoea as quantitative surrogates of gastrointestinal damage caudal to the oropharynx using a variety of operator-dependent quantitative and semiquantitative scoring systems. 1 More recently, functional measures of the integrity of the intestinal epithelial barrier using orally administered saccharide or radio-labelled probes have been applied to the study of gastrointestinal mucositis among haematopoietic stem cell transplant recipients 5,7,[14][15][16][17] and in acute myeloid leukaemia. [18][19][20][21] Intestinal permeability may be reflected by an elevated ratio of the concentration of lactulose to mannitol or rhamnose in fractional urinary excretion studies, 21,22 carrier-mediated transcellular absorption by the serum level of a five-carbon sugar, D-xylose, 18 and enterocyte mass by serum citrulline levels.…”

“…[1][2][3][4] Cytotoxic regimens have differential potentials for producing epithelial damage [5][6][7] and invasive infection. 8 Moreover, oral and gastroenterological mucositis adds significantly to the economic burden of cancer chemotherapy.…”

Irinotecan disrupts tight junction proteins within the gut

“…10 In 1997, Keefe et al identified a transient abnormality in intestinal permeability in patients receiving high-dose chemotherapy. 23 Marked abnormalities in intestinal permeability have also been shown in patients receiving various myeloablative treatments 24 indicating that intestinal function is compromized by various cytotoxic regimens. Further, morphological defects in tight junctions have been identified, with Keefe et al (2000) demonstrating significant increases in the number of open intestinal tight junctions in patients receiving high-dose chemotherapy.…”

“…This buffer has previously been shown to have no gut toxicity effects. 51 Groups of rats were killed by exsanguination and cervical dislocation while under 3% isoflourane in 100% O 2 anesthesia at times 6,24,48,72,96, and 120 h post-irinotecan treatment. The entire gastrointestinal tract (from the pyloric sphincter to the rectum) was dissected out and separated into the small intestine (pyloric sphincter to ileocecal sphincter) and colon (ascending colon to rectum).…”