Radiation Enteritis

Etiology

Ionizing radiation (IR) consists of photon-based (x-rays and gamma rays) or particle radiation. Photon radiation is used most commonly for cancer treatment. High-energy photons create ionizing electrons that then directly break chemical bonds. X-rays or gamma rays create 1000 ionization tracks per Gray (Gy) and mainly produce reactive oxygen species from water, such as hydroxyl radicals, singlet oxygen, superoxide, and hydrogen peroxide that indirectly cause damage within cells. The role of oxygen is critical for the effects of free radicals to be effective. Oxygen not only can participate in the cascade of free radical generation, but it can also “fix” damage in biologic molecules and so prevent its repair. Hypoxia is one cause of radiation treatment failure.

DNA damage is the hallmark of radiation therapy. Most DNA damage from daily environmental exposure occurs in the form of single-strand breaks and base damage, which is repaired by base excision repair. However, IR causes complex damage consisting of 15 to 20 double-strand breaks per cell per Gy. Double-strand breaks can also be repaired through nonhomologous end joining and homologous recombination; however, the complex damage of IR may overwhelm these repair mechanisms.

Clinical Features and Pathophysiology of Injury

Radiation can cause acute and chronic gastrointestinal toxicity ( Table 78.1 ). Acute effects secondary to radiation therapy in the gastrointestinal tract occur due to depletion of the radiation-sensitive progenitor cells from which the mature cells are derived. ARE can occur with doses as low as 5 to 12 Gy. Tissue function is then maintained by the nonproliferating differentiated cells until they are also depleted after normal cell turnover. Despite depletion of dividing crypt cells within days of irradiation in the small bowel, symptoms of acute toxicity will take approximately 2 weeks to manifest because the nonproliferative villi do not show immediate depletion following irradiation but rather slough into the lumen over time. The quiescent stem cell population is few in number and gives rise to the progenitor population. Lethal toxicity may occur due to depletion of the large progenitor population, not the stem cell population, which is considered radioresistant possibly due to high levels of antioxidants. However, the regeneration of progenitor and stem cells determines the severity of acute toxicity, with more regeneration allowed with fractionated doses.

In murine studies, no mucosal changes are seen 2 hours after radiation therapy; however, apoptotic epithelial cells and leukocytes (mainly neutrophils) are increased at 6 and 16 hours after radiation. Muscularis mucosa edema, granulocyte infiltration, lymph vessel ectasia, and apoptosis deeper in the crypts are seen 24 hours after radiation. Increased goblet and apoptotic cells are seen across the entire epithelium at 48 hours post radiation. There are also marked decreases in the aerobic and anaerobic bacteria between 2 and 24 hours after radiation treatment. Erythematous mucosa can also be seen. Acute radiation toxicity was found to activate the Fas and glycolysis pathways in mice, both pathways that can induce cell apoptosis and activate inflammation.

CRE is characterized by fibroblast and collagen proliferation, as well as obliterative vasculitis causing transmural injury. Fibrosis is the end result, and transforming growth factor beta (TGF-β) plays a critical role in the mechanism. CRE most frequently occurs in the ileum and ileocecal valve, given the fixed location and proximity to the pelvis.

Risk factors for radiation enteritis include treatment volume; total dose; fractionation dose and schedules; combined surgical and chemotherapeutic modalities; medical comorbidities, such as vascular, connective tissue, and inflammatory bowel diseases and human immunodeficiency virus (HIV); and genetic susceptibility, such as single nucleotide polymorphisms (SNPs) and ataxia telangiectasia ( Table 78.2 ). Prior laparotomy is also a risk factor for CRE, and studies have shown a 4.25 increased rate of late gastrointestinal complications in irradiated patients. The majority of patients requiring surgical intervention for CRE have undergone radiation due to gynecologic (62%) and rectal cancers (22% to 36%).

The degree of normal tissue toxicity in the small bowel depends not only on the dose of radiation but also on the amount of bowel irradiated. However, studies trying to determine toxicity to small bowel have used inconsistent methods of measuring the small bowel. Predictive models of toxicity show that the volume of small bowel receiving greater than 15 Gy should be restricted to less than 120 mL if individual bowel loops are delineated; however, if the entire peritoneal cavity that the small bowel can move is delineated, radiation greater than 45 Gy should be limited to 195 mL. Radiation doses are generally limited to 4500 to 5000 cGy due to small bowel toxicity.

Other risk factors include euthyroid sick syndrome, which consists of low triiodothyronine (T ₃ ) levels. A multivariate analysis found that chemotherapy was associated with CRE (odds ratio [OR] = 3.59, 1.20 to 10.73). ARE has also been associated with the development of subsequent CRE.

CRE accounts for the major morbidity of IR. Twenty percent of patients were found to have CRE in a survey study of 100 patients who received radiation therapy due to prostate, cervical, endometrial, or rectal cancer. Three percent reported requiring hospitalization due to diarrhea or bowel obstruction. Radiation enteritis accounted for 11% of cases in a review of 688 adults with chronic intestinal failure from benign disease resulting in long-term parenteral nutrition (PN). These patients suffered from short bowel syndrome (SBS), motility disorders, and extensive parenchymal disease. Patients with SBS on PN with a history of irradiation had significantly higher rates of cirrhosis and portal hypertension compared with nonirradiated SBS patients on PN. A prospective longitudinal study of 27 patients undergoing pelvic and/or abdominal irradiation with follow-up time of 2 years found that at least one parameter of bowel function was abnormal in 16 of 18 patients who completed all measurements. Significantly changed parameters included increased stool frequency, decreased bile acid absorption, and more rapid small intestinal transit time. Malabsorption of carbohydrates and bile salts occurs from loss of villi, and fat malabsorption occurs due to bacterial overgrowth. Kong et al. reported a significant increase in the etiology of SBS secondary to radiation enteritis in recent years in China (17% of SBS cases from 2004 to 2009 vs. 26% from 2009 to 2010; P < .05). Neoadjuvant chemoradiotherapy has become standard for rectal cancer. Zakaria et al. reported two cases of efferent loop terminal ileum obstruction secondary to radiation enteritis discovered after takedown of ileostomy after proctectomy due to rectal cancer.

Intestinal failure can be due to malabsorption secondary to anatomic SBS or functional SBS secondary to mucosal damage. Anatomic SBS is secondary to surgical resection or fistula that can bypass segments of small bowel. Functional SBS is characterized by mucosal damage in the setting of adequate small bowel length. Intestinal failure secondary to CRE has a worse prognosis (approximately 70% survival rate at 5 years) compared with other causes of SBS. In their analysis, death secondary to recurrent cancer was censored, and so the underlying pathology of CRE-induced intestinal failure truly affected survival. Various studies have reported that between 3% and 14% of patients requiring home PN do so because of CRE.