74: Radiation injury in the gastrointestinal tract

Radiation injury in the gastrointestinal tract

Lalitha S. Y. Nanduri, Nicole C. Panarelli, and Chandan Guha

Albert Einstein College of Medicine, Montefiore Medical Center, New York, USA

Radiation enteropathy is the most prevalent complication from radiation therapy (RT) of the abdominal and pelvic cancers and, in the United States, the patients suffering from radiation‐related intestinal dysfunction far exceed those suffering from inflammatory bowel disease. Because the symptoms of radiation enteropathy are like those of other bowel disorders, comprehensive care and management of symptoms tailored to RT toxicity are not available and most interventional strategies include conservative medical treatment, hyperbaric oxygen therapy, and surgery.

The histopathological analysis of tissue specimens can often aid in establishing the diagnosis and excluding other etiologies for a patient’s symptoms. The histological appearance of lesions observed in tissue specimens is often characteristic of acute or delayed radiation injury. However, no individual histological feature is pathognomonic for radiation‐induced intestinal damage. Therefore, histological findings may mimic other pathological conditions and must be interpreted carefully within the appropriate clinical context for a given patient.

Patients may present with acute symptoms days or weeks after RT is initiated or with delayed clinical syndromes that may occur years after therapy. Clinical symptoms include odynophagia, diarrhea, nausea, vomiting, or gastrointestinal bleeding; the symptoms depend on the location of the radiation field, the dose of irradiation, and the fractionation schedule. The delayed effects of therapeutic irradiation are more likely to present with chronic diarrhea, fibrosis, ulcer formation, or bleeding, and are thought to be secondary to damage to the vasculature of the organs involved.

Acute radiation enteropathy

The histological and pathological features of acute radiation enteropathy are poorly defined because the acute effects of RT are generally transient and well tolerated and tissue samples are rarely obtained. Thus, much of what is known about the acute effects of irradiation has been derived from a few studies in humans and more extensive experiments using animal models of radiation injury.

The early effects primarily involve the gastrointestinal mucosa, which is lined by rapidly proliferating epithelial cells that are sensitive to radiation injury. The earliest recognizable histological features occur within hours and include apoptosis of lamina propria lymphocytes, endothelial cells, and epithelial cells, followed by growth arrest of proliferating intestinal epithelial cells. This results in loss of replicating cells in the squamous epithelium of the esophagus and the columnar epithelial cells in the gastric, small intestinal, and colonic epithelium. Mature, differentiated epithelial cells continue to be lost by extrusion, and in the absence of replacement by replication of the progenitor cells, there is subsequent loss of mucosal function; attenuation and damage to the squamous epithelium in the esophagus; reduced numbers of parietal and chief cells in the gastric epithelium, which will decrease gastric secretion of pepsinogen and hydrochloric acid respectively; and progressive loss of the small intestinal villous epithelium, which decreases absorptive surface area and, in some patients, leads to transient malabsorption of fats and other macromolecules, or acute diarrhea.

Radiation ileitis that may result from pelvic radiation may be associated with bile acid malabsorption and result in diarrhea that often responds to bile acid sequestration. In the colon, there are reduced numbers of mitoses and epithelial cell atypia with loss of nuclear polarity in the columnar epithelium lining the crypts. Loss of goblet cells leads to decreased mucus production. Microabscesses composed of granulocytes and eosinophils may be present. Mucosal and submucosal edema may also be observed in both the small intestine and colon.

The survival of the intestinal stem cell population is compromised at higher single doses of irradiation, limiting epithelium repair. Fractionated irradiation protocols allow higher total doses to be administered by allowing repair and recovery of replicating epithelial cells and stem cells between fractions. If damage to the stem cell population is severe after high doses of radiation, then epithelial integrity and barrier function are lost, leading to translocation of luminal bacteria and eventual death from loss of fluids and serum proteins, hemorrhage, and sepsis 7–10 days after irradiation.

Mouse models of radiation enteritis and associated pathology

Mouse models of the whole body, partial body (with 2.5% bone marrow shielding), and abdominal radiation models are used to study radiation damage to the intestine. Radiation‐induced intestinal toxicity varies with the dose of radiation and the field of irradiation, in addition to age, and the gender of the mice. Healthy mouse intestinal villi lined with epithelial cells are supported by the vascular and nervous system, stromal cells, and immune cells in the lamina propria (Figure 74.1a). Intestinal epithelium mainly consists of columnar enterocytes that mainly absorb nutrients. Goblet cells are present along with enterocytes, and they produce mucins that form the mucus layer of the intestine (Figure 74.1a).

The loss of epithelial cells is balanced by the continuous production of new cells by intestinal stem cells such as Lgr5+ cells (cells expressing Lgr5, a Wnt target gene, a marker of organ stem cells with self‐renewal capacity) that reside at the base of the crypts. Paneth cells are granulated secretory cells present at the crypt base alternating between Lgr5+ cells as a great source of antimicrobial peptides, wnt proteins (secreted glycoproteins that activate different intracellular signal transduction pathways, and regulate cell proliferation), and other immunomodulatory molecules. Radiation‐induced ablation of cycling Lgr5+ stem cells results in the irreversible loss of epithelial cells, thereby affecting the cell balance and functionality of the intestine. Post‐11 Gy partial body radiation, hematoxylin and eosin staining of the mice intestine showed loss of crypts at the base of the villi, distorted lamina propria, loss of epithelial cells in the villi, and reduction in villi length (Figure 74.1c) in comparison to the nonirradiated mouse intestine with intact villi and crypts (Figure 74.1b). Surviving crypts are measured in terms of surviving stem cells in the crypts using staining for stem cell marker Lgr5 or staining for lysozyme (Lyz1) for labeling Paneth cells. Similarly, mucin‐producing goblet cells are labeled with alcian blue staining that binds to mucins.

Figure 74.2b shows a decrease in the number of goblet cells (blue) in the villi and crypt post‐11 Gy (x‐ray) partial body radiation in comparison to that of many blue goblet cells, seen in unirradiated intestinal villi and in the transient amplifying zone (Figure 74.2a). Histological scoring of several healthy crypts per mm area is used as a parameter to quantify the extent of radiation injury between the different doses of radiation and nonirradiated controls. Loss of epithelial cells and dysfunctional mucosal barriers lead to increase in permeability of the intestine, thereby increasing microbial entry into the blood.

in vivo proliferation post‐11 Gy (x‐ray) partial body irradiation in mice is observed by administering 5‐ethynyl‐2′‐deoxyuridine (EdU) intraperitoneally, which will label the proliferating cells by incorporating into their replicating DNA. Two hours following injection, the intestines were collected and processed for immunohistochemical detection of EdU. Figure 74.3 shows that irradiated mice intestine has a very low EdU labeling in the crypts, indicating lack of active proliferation in the crypts (Figure 74.3b). In comparison, almost all the crypts are EdU+ in unirradiated mice (Figure 74.3a), indicating active proliferation of intestinal epithelial cells. This further confirmed the radiation‐induced loss of actively proliferating stem cells in the intestinal crypts.

Image described by caption.

Figure 74.1 (a) Graphical representation of healthy mouse intestine microenvironment showing crypt base cells (CBCs), the stem cell niche; long finger‐like projecting villi containing enterocytes, goblet cells; and transient amplifying (TA) zone. Hematoxylin and eosin staining of the nonirradiated (b) and 12 Gy partial body irradiated (c)

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Nov 27, 2022 | Posted by in GASTROENTEROLOGY | Comments Off on 74: Radiation injury in the gastrointestinal tract
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