Pathobiology of Fatal Gastrointestinal GVHD
Severe GVHD of the gut is often fatal following unresponsiveness to steroid therapy. Autopsy and surgical resection of affected portions demonstrate a range of changes including extensive ulceration with circumferential mucosal sloughing with formation of luminal casts of necrotic debris. Radiographic studies are useful in pointing out the areas with the most severe involvement, particularly in the small intestines where segmental stenotic areas can develop. Surgical attempts to resect these affected intestinal segments have been unsuccessful in reducing mortality. A less common finding of persistent gut GVHD associated with sclerotic chronic GVHD (cGVHD) is submucosal fibrosis involving the small bowel and colon, as well as the esophagus. Current investigations on the pathobiology of treatment resistant gut GVHD have focused on the small vessels’ role in initiation or persistence of gut GVHD, and the role the microbiota plays leading to dysbiosis of the crypt stem cell niche. A recent clinical trial used lithium to overcome refractoriness to treatment and stimulate crypt regeneration by induction of Wnt signaling, which blocks the inhibitory effect of GSK-3.
KeywordsCrypt stem cell niche Diffuse intestinal ulceration Gastrointestinal GVHD Submucosal and periserosal fibrosis in gastrointestinal GVHD Radiology of gut GVHD Collagenous colitis Surgical resection for severe gut GVHD Lithium for gut GVHD Microvessel involvement in gut GVHD
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