Mechanisms of radiation damage

As a result of radiation, double-stranded DNA damage occurs in cells. This favors the onset of pathways leading to the activation of the tumor suppression gene P53, which results in a cycle stoppage, with repair of damage or apoptosis. Intestinal crypts are susceptible to this injury and cell death results in mucosal damage. It is important to consider that if apoptosis occurs in the stem cell, crypts cannot be regenerated, which contributes to the exposure of the lamina propria, which is normally sterile to germs ⁶.

On the other hand, there is vascular damage, which appears to be key in both acute and chronic radiation enteritis. It has been recognized that apoptosis of endothelial cells leads to stem cell dysfunction and subsequent stem cell damage ⁷.

All of this results in an inflammatory response mediated by T lymphocytes, macrophages, and neutrophils, damaging the extracellular matrix of the lamina propria and causing mucosal and submucosal involvement, which results in impaired immune recognition and bacterial translocation. In this way, the inflammatory process leading to fibrosis and stenosis is perpetuated ⁸.

Despite the cessation of the radiation therapy, the inflammatory process can continue, and its mechanisms are poorly understood. In fact, it is considered that there is an exaggerated response that contributes to severe ulceration, in which the chronic course of the disease is mediated by ischemia and fibrosis. In acute involvement, the main component is the damage of rapid cell proliferation, which results in reduced functional surface area and decreased secretion and motility capacity. Meanwhile, in the case of chronic involvement, obliterating endarteritis is the most important characteristic, with the consequent reduction of functional epithelial surface ⁹.

Secondary symptoms to radiation injury to the gastrointestinal tract

The gastrointestinal tract extends over a large surface, which is why it is easily affected by radiation. Symptoms can be acute and chronic, with clinical manifestations that may occur during or after radiation. Initially, acute mucosal damage and post-treatment inflammation occurs up to 90 days after radiation therapy. Such signs are usually reversible. Late symptoms may also appear months or years after radiation therapy. In fact, symptoms have been reported after 30 years of treatment, and they are usually related to transmural fibrosis and vascular sclerosis, whose reversibility likelihood is lower ¹⁰.

In the small intestine, the degree of damage depends on the dose and the segment volume included in the radiation field. Thus, the segment volume has a direct relationship with toxicity, regardless of the radiation dose used. Other predictors are concomitant use of chemotherapy and previous surgery. Similarly, radiation dose is related to late toxicity. In fact, the estimated toxicity in 5 and 50 % of patients with irradiation of 1/3 of the small bowel is 50 and 60 Gray (Gy), respectively. In addition, the estimated toxicity in 5 and 50% of patients with whole-bowel irradiation is 40 and 55 Gy ^10,11.

When small bowel involvement occurs, early symptoms are nausea, vomiting, and abdominal pain during the first 2 weeks; there are related to the release of inflammatory cytokines. Diarrhea and abdominal pain occur during the first 2 weeks in 20-70% of patients undergoing abdominal or pelvic radiation therapy. These signs and symptoms are the result of direct damage to the mucosa, resulting in atrophy and decreased blood flow. It is important to consider that acute symptoms usually resolve within the first 3 weeks after radiation therapy is completed, due to regeneration of the epithelium ¹².

In relation to late symptoms or chronic radiation enteritis, there are two main classes: Malabsorption syndrome with chronic diarrhea, and chronic pseudo-obstructive syndrome. Chronic diarrhea following radiation therapy is often secondary to different processes such as biliary acid malabsorption, bacterial overgrowth, fat malabsorption, rapid intestinal transit, and lactose intolerance. Stenosis, fistulas, and intestinal obstruction have been described as more severe late symptoms in 5-10% patients with severe damage and poor prognosis, with a 5-year mortality rate of 58%. Stenosis management is complex and results in unfavorable outcomes ^12,13.

Short bowel syndrome, in which there is inadequate capacity for intestinal absorption, has also been described. The causes associated with this syndrome are surgery and intestinal fistula, which lead to malabsorption of macro and micronutrients, as well as of electrolytes and water. All this leads to rapid motility and intestinal transit, resulting in watery diarrhea and dehydration. This contributes to inadequate absorption of electrolytes, magnesium, and vitamin B12, and the occurrence of megaloblastic anemia, demyelinating neuropathy, and malabsorption of bile acids.

In short, malnutrition is secondary to short bowel syndrome, which, given the increase in mortality rates and the need for hospitalization, is an important finding related to chronic radiation enteritis. In addition, before radiation therapy begins, up to 33% of patients already have a baseline malnutrition condition, and after the procedure is performed, about 83% of them show significant weight loss.

Bacterial overgrowth, caused by the abnormal and excessive increase of bacteria in the small intestine, can also occur, which perpetuates malabsorption, weight loss, and malnutrition. This is also associated with stenosis, absence of ileocecal valve, and the colon ¹⁴.

Diagnostics

Diagnosis should be suspected according to clinical findings, which are characterized by nausea, vomiting, abdominal pain, diarrhea, or gastrointestinal bleeding, and are associated with a history of radiation therapy. The latter constitutes a diagnosis of exclusion.

Diagnosis is usually made from segmental involvement of the intestine, in regions of a radiation field observed in imaging and/or endoscopic studies, or histology reports. This diagnosis serves to exclude other causes and to establish the extent of the disease ¹⁵.

Thus, patients with abdominal pain, nausea, and vomiting could be initially assessed by performing an abdominal CT scan or magnetic resonance imaging, the findings of which include intestinal thickening, a mucosal superscan, and luminal stenosis. In the final stages of the disease, stenotic and obstruction segments of the small intestine occur as a result of fibrosis ^15,16.

When endoscopic and histological studies are performed, findings compatible with radiation damage include pallor, friability, and telangiectasias, which can be multiple, large, and serpiginous. These changes tend to be continuous. Histological findings of radiation enteritis include diffuse collagen deposition, thickening of the mucosa and serosa, inflammatory cell infiltrates, vascular sclerosis, and occlusive vasculitis ¹⁶.

Treatment

In early stages of the radiation enteritis, pharmacological management may be provided to reduce intestinal transit. Loperamide and codeine phosphate act on the μ (ROM) receptors in the myenteric plexus to reduce symptoms of diarrhea. Correction of altered electrolytes and micronutrients such as potassium, magnesium, selenium, zinc and vitamin B12 levels is essential.

Regarding bacterial overgrowth, antimicrobial management using rifaximin is possible. Also, in case of malabsorption of bile acids, cholestyramine favors the reduction of episodes of diarrhea. Probiotics have been reported to decrease the severity of enteritis and a high concentration probiotic preparation of 8 live, lyophilized bacterial species is reported to reduce the incidence and severity of diarrhea.

This probiotic preparation consists of bacterial species that are normally found in human gastrointestinal microflora. These include 4 strains of lactobacilli (Lactobacillus casei, Lactobacillus plantarum, Lactobacillus acidophilus and Lactobacillus delbrueckii, subspecie: bulgaricus), 3 strains of bifidobacteria (Bifidobacterium longum, Bifidobacterium breve and Bifidobacterium infantis), and 1 strain of Streptococcus salivary. Likewise, Lactobacillus rhamnosus reduces bowel movements and improves fecal consistency ^17,18.

Diet modification is also important to reduce symptoms and the consumption of high-fiber and high-residue (raw vegetables) foods should be avoided. Hydration is important and using hypotonic fluids (500 mL/d) and saline glucose rehydration solution (100 mmol/L Na) is recommended ¹⁸.

On the other hand, parenteral nutrition is indicated in patients who cannot be managed with oral supplements. Indeed, it has been reported that patients with chronic radiation enteritis and managed with parenteral nutrition have a 5-year survival rate of 64%, which is associated with adverse effects due to vascular access and long-term liver dysfunction ¹⁸.

Surgery is indicated for chronic enteritis cases with signs of intestinal obstruction or in which fistulas, stenosis, perforation, and continuous bleeding occur. The objective of surgical management is to eliminate all radiation-induced lesions by resecting all involved elements and to avoid internal derivations. There is a significant risk of morbidity after surgery. In particular, the possibility of short bowel syndrome is high. In case of intestinal obstruction, surgery is controversial, reaching a morbidity of 30-50%, a mortality of 10-15%, and a 60% reoperation rate ¹⁹.