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Original Research |
Institute of Nutrition and Food Technology (INTA), University of Chile (M.P.M., M.G., C.R., M.A., D.B., S.H.), Santiago, CHILE
Arturo López Pérez Foundation (T.Y.), Santiago, CHILE
Address correspondence to: M. Pía de la Maza MD, MSc, INTA, University of Chile, J.P. Alessandri 5540, Santiago, CHILE. E-mail: mpmaza{at}uec.inta.uchile.cl.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Methods: Fifteen patients were studied before and after pelvic irradiation. A clinical, nutritional and routine clinical laboratory assessment was performed. Nutritional parameters included dietary recall, subjective global assessment, anthropometric measurements (body mass index, skinfold thickness at four sites and circumferences of arm, waist and hip), hand grip strength, indirect calorimetry and Dual Energy X-ray absortiometry (DEXA). Intestinal parameters included permeabilty to sugars (assessed by lactulose and mannitol urinary excretion), intestinal transit time (measured by hydrogen breath test after ingestion of lactulose) and jejunal biopsies.
Results: Thirteen patients presented diarrhea during radiation therapy. After five weeks, intestinal permeability increased, while intestinal transit time decreased. The second biopsy showed hypertrophy of villae and crypts. Simultaneously, patients lost weight at the expense of fat free mass. Resting energy expenditure was elevated prior to treatment and declined after five weeks. Changes in caloric ingestion were not significant.
Conclusions: Our results indicate that pelvic radiation induces a loss of fat free mass along with intestinal morphologic and functional changes.
Key words: radiotherapy, actinic enteritis, pelvic radiation, intestinal permeability
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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The terminal ileum, sigmoid colon and rectum are the sites most frequently damaged by pelvic radiation, while jejunum and proximal ileum are seldom involved; nevertheless, mortality of radiation enteritis is fourfold higher than colonic lesions [6]. Whether significant tissue injury occurs in organs distant to the radiation field is still controversial [1,18].
In humans, acute histologic changes shortly after radiation consist of reduction of crypt mitoses, villous shortening, plasma cell infiltration of the lamina propria, megalocytosis of epithelial cells and, less frequently, formation of microabsceses of the crypts, all which are potentially reversible [1]. Both acceleration of intestinal transit time and decreased bile salts resorption at the terminal ileum play a role in the appearance of diarrhea [7,8,9,10]. Simultaneously, intestinal permeability to water soluble macromolecules increases after intestinal radiation [4]. Most studies demonstrate that acute changes of permeability recover after several weeks of completion of radiation therapy. However, the impact of the above mentioned alterations on the clinical course or nutritional status of the patient have not been systematically assessed.
Morphologic and functional small bowel alterations and changes in gastrointestinal motility, together with anorexia, are considered relevant determinants of the long term detrimental effect on nutritional status observed in these patients [11]. To improve therapeutic strategies for patients that develop chronic bowel actinic damage, it is crucial to understand the factors that influence the acute phase of the damage and that may represent risk factors for chronic damage. Following this line of thought in this study we investigated clinical symptoms and nutritional changes after external pelvic radiation, relating them to functional and morphologic modifications of the small bowel, after five weeks of treatment. Thus, results will provide a systematic description of acute changes, to what extent small intestinal changes may participate in the alterations observed, and will serve as a basis for future characterization of chronic damage in these patients.
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METHODS |
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Exclusion criteria were diabetes mellitus, chronic renal failure (serum creatinine >2 mg/dL), liver or cardiac failure, other cancers, chronic diarrhea, intestinal or gastric resections, and previous radiation treatments.
Nutritional status of each patient was classified by means of the Subjective Global Assessment (SGA) [12] immediately after incorporation to the protocol. Clinical symptoms and medications prescribed were registered throughout the study period. Before beginning and immediately after completing the five-week pelvic radiation, the following nutritional and gastrointestinal parameters were studied: nutrient intake by means of a 24-hour dietary recall; percent of body fat, calculated on the basis of anthropometric measurements (weight, height, skinfold thickness using a Lange caliper at four standard locations) according to Durnin and Womersley [13] and circumferences of arm, waist and hips; grip muscle strength, using a hand grip dynamometer (Therapeutic Instruments, Model 0032); body fat mass and fat-free mass, measured by Dual Energy X-ray absortiometry (DEXA) in a LUNAR densitometer (LUNAR Corp. Madison, WI); resting energy expenditure (REE), by indirect calorimetry in a canopy system (Sensor Medics 2900). After an overnight fast, blood samples were drawn to perform routine clinical laboratory tests (blood cell count, blood glucose, creatinine, blood urea nitrogen, total protein, albumin, total bilirubin, hepatic aminotransferases, total cholesterol, triglycerides, uric acid and electrolytes), using automated methods. Urinary lactulose/mannitol and sucrose excretion tests were used to assess intestinal and gastric permeability respectively [14,15]. Orocecal transit time was evaluated by the hydrogen breath test after ingestion of lactulose, following routine procedures described elsewhere [16]. Jejunal biopsies were obtained before and within 48 hours after finishing radiotherapy in eight patients. The tissue was obtained with a fluoroscopically guided double port Crosby-Kugler capsule at the Ligament of Treitz, fixed in Bouin, serially sectioned at 5µ and stained with hematoxylin-eosin. Histological assessment followed the classic 1–4 scale in which 1 represents normal mucosa and 4 severely damaged (flat) mucosa [17]. Due to ethical considerations only two samples were obtained from each participant. In well-oriented sections villus and crypt heights were measured by two observers in a blind fashion. On the basis of these measurements total mucosal thickness was calculated. Each figure represents the average of at least three measurements, done in at least two different areas of the biopsies.
Gastrointestinal and general symptoms were recorded during the five-week study period. Participants marked on a list of symptoms those they had experienced during the week. Each symptom was graded from 0 (absent) to 3 (severe enough to alter activities of daily living). Diarrhea was defined as stools with an increase in water content or an increase in the number of bowel movements.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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During the study period, most patients developed gastrointestinal symptoms, mainly diarrhea (13 patients), abdominal pain (12 patients) and nausea (1 patient). In addition, 12 patients had urologic complains, with positive urine cultures in four. Episodes of diarrhea were mild and intermittent, lasting between 2–13 days, and were managed as outpatients, with 6 mg Loperamide/day, restriction of dietary fiber and oral hydration.
Before radiotherapy, clinical laboratory parameters in all patients were within normal ranges, except for five cases that had low hematocrit. Hematologic parameters and cholesterol decreased significantly, while triglycerides increased after radiotherapy (Table 1).
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- 0.9 ± 1.4 Kg, p = 0.03), as did arm circumference ( - 0.4 ± 0.7 cms, p = 0.04). Body fat calculated from anthropometric measurements, decreased slightly ( - 1 ± 1.4%, p = 0.05). Likewise, after the 5 weeks period of pelvic radiation, DEXA detected a significant decrease in total body mass ( - 0.7 ± 1.3 Kg, p = 0.03), and fat free mass ( - 1.1 ± 1.5 Kg, p = 0.001), without modification of fat mass (Table 2).
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Histological assessment of duodenal biopsies obtained before radiotherapy revealed normal mucosal morphology (stage 1 or 2 in the scale 1/4) in all cases. After pelvic radiation, in most biopsies there were significant changes, which consisted of patchy areas with longer villi, and figures of several crypts opening to one single villus (Fig. 2). Because this technique requires a well-oriented section, the areas suitable to perform morphometry were those in which these two main findings were less prominent. Due to this histologic appearance it was not adequate to carry out morphometric measurements on second biopsies.
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DISCUSSION |
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Energy released by ionic radiation induces several events, especially in fast replicating cells, such as hematopoietic tissues and intestinal epithelium, leading to its damage and death. During acute continuous exposure to radiation, the main defense mechanism is cellular renovation, stimulated by depletion of actively proliferating cells. Therefore, actinic damage is lessened when cellular depletion is balanced with cellular proliferation [18]. Radiation-induced injury is explained by cytotoxic effects of free radicals, damaging, the endothelial cells of intestinal capillaries. The ensuing mucosal damage is reflected in morphologic and functional impairment, such as increased permeability to macromolecules [19]. Evidence indicates that microvascular injury is one of the main determinants of intestinal dysfunction after radiation, which becomes more evident in chronic radiation enteritis [20].
The small bowel is specially susceptible to radiation injury, but the mechanisms involved are not completely understood. Several clinical and functional manifestations of this damage were apparent in this study, namely mild diarrhea, decreased intestinal transit time and increased permeability. Interestingly, these changes were associated with morphologic changes suggestive of mucosal recovery (enlargement and duplication of villae) in the proximal intestinal segments, which received a considerably smaller fraction of the radiation dose (calculated as 2 Gy). This suggests that either such a dose is capable of inducing damage or that there are indirect mechanisms involved. Both alternatives deserve further study.
With the information obtained in this study it was not possible to assess whether previous surgery or low weight induces more actinic damage to the small bowel, as previously described; among Chilean women, obesity and overweight are currently highly prevalent, and this was also the case among the study patients [21]. At the same time, most of the study patients had previous abdominal surgery (such as cholecystectomies, cesarean sections, appendectomies, adnexectomies and hysterectomies) making it difficult to identify subgroups.
Nutritional status deterioration was mainly at the expense of fat free mass, as assessed by DEXA. Our intra-assay variability is less than 1% [22]. Variations of total body water also influence LBM assessment by DEXA [23], although we have employed it successfully in cirrhotic patients [24]. It is unlikely that the changes reported here would be due to dehydration because, although most patients had diarrhea, the episodes were mild, and ceased well before the second evaluation. Moreover, the decrease in LBM is in agreement with a reduction of whole body REE (which were elevated before treatment in these patients), without changes in REE corrected by unit of FFM, which was not dependent on a reduction in caloric intake, as assumed previously by other authors [25].
The selective loss of FFM observed in this study, associated with an increase of serum triglycerides, resembles a systemic inflammatory reaction in response to intestinal radiation [26]; it is also possible that it is related to a decrease in macronutrient availability due to low dietary intake, but this seems not to be the case since this latter did not change significantly; finally nutrient malabsorption may also play a role but was not investigated in this study. An increased permeability to bacteria or endotoxins has been proposed as the event that could initiate and perpetuate the systemic inflammatory response (SIRS) in several conditions leading to nutritional wasting [27,28,29] and multiple organ failure [30,31]. However, several recent studies suggest that intestinal damage predisposes to distant organ injury, even in the absence of detectable bacteria or endotoxins. It has been proposed that certain gut-derived factors, such as cytokines, could produce these systemic effects via the lymphatic route [26]. The effects of ionizing radiation on vascular endothelial cells are also consistent with the initiation of an inflammatory response, including adhesion of leukocytes and increased vascular permeability. Local liberation of pro-inflammatory mediators and production of free radicals and proteases by leukocytes seem to be directly involved in tissue damage [32]. This reaction to radiation resembles intestinal damage due to ischemia-reperfusion [19] and has been prevented by free radical scavengers in animal models [33,34,35]. Further studies in humans must be performed in order to demonstrate if this mechanism explains SIRS and wasting in human beings under radiation treatment.
In conclusion, standard external pelvic radiation for treatment of gynecological malignancies induced acute intestinal alterations, which are associated with a wasting-like pattern of body composition changes. The mechanisms involved, and whether the severity of acute alterations is associated with a higher probability of progression to chronic actinic enteritis, deserve further investigation.
Received January 12, 2001. Accepted September 20, 2001.
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REFERENCES |
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This article has been cited by other articles:
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  E Y Huang, C J Wang, H C Hsu, and L M Sun Characteristics and predictive factors of early-onset diarrhoea during pelvic irradiation Br. J. Radiol., May 1, 2006; 79(941): 419 - 424. [Abstract] [Full Text] [PDF]
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 M. P. de la Maza, G. M. Agudelo, T. Yudin, V. Gattas, G. Barrera, D. Bunout, and S. Hirsch Long-Term Nutritional and Digestive Consequences of Pelvic Radiation J. Am. Coll. Nutr., April 1, 2004; 23(2): 102 - 107. [Abstract] [Full Text] [PDF]
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