Ulysses G. Meneghelli
Professor Titular do Departamento de Clínica Médica
da Faculdade de Medicina de Ribeirão Preto (USP)
Chagas' disease is provoked by a protozoon, Trypanosoma cruzi, Chagas, 1909. The acute form of the disease can be particularly severe or even lethal, but may also be non-apparent or may be confused with other diseases, frequently going unperceived. In most cases the disease is diagnosed during the chronic phase, when the major and most common expressions of the disease are manifestations of cardiac involvement (arrhythmias, disorders of nerve impulse conduction, cardiomegaly, cardiac failure and sudden death) and of the digestive tract (dysphagia, megaesophagus, intestinal constipation, megacolon). The predominance of one or another of these manifestations is the basis for the recognition of the cardiac (1) and digestive (2) forms of the disease, as opposed to the indeterminate form, which can only be revealed by positivity of the serologic test.
The etiology of megaesophagus and megacolon, which are endemic in South America, especially in the rural zones of Brazil, was linked to Chagas' disease only more than 40 years after the discovery of the disease, based on serologic (3) and histopathological (4) studies, on experimental reproduction of the disease in laboratory animals (5) and on patient follow-up during the acute phase of the disease (6). Although megaesophagus and megacolon are the most common and most expressive digestive manifestations of the chronic phase of Chagas' disease, others occur less frequently, such as megaduodenum, megajejunum and megaileum. In addition, dysfunction of the small intestine of chagasic patients can be demonstrated by functional tests even in the absence of symptomatic manifestations.
The pathogeny of dysfunction and dilation of segments of the digestive tract in Chagas' disease is based on denervation of the complex network of intramural neurons, today known as enteric nervous system. The destruction of intramural neurons in megaesophagus and megacolon was identified many years ago (7,8) and was later confirmed by meticulous neuronal counts performed in megaesophagus and in non-dilated esophagus, in the stomach , in different parts of the small intestine, in megacolon, and in non-dilated colon of chagasic patients (9).
presentation, chagasic enteropathy will be approached from the viewpoint of involvement of
the duodenum, jejunum and ileum alone or in combination, due to Chagas' disease in the
chronic phase. Chagasic enteropathy is much less frequent and less studied than esophageal
and colon disease of the same etiology. However, studies on this type of disease are
important to expand knowledge about the digestive form of Chagas' disease, to include it
among the causes of the intestinal pseudo-obstruction syndrome and of bacterial overgrowth
in the small intestine, and mainly for adequate diagnosis and treatment.
II - Structural changes: intramural denervation and "megas"
Small bowel dysfunction and dilation are due to the lesions and destruction of neurons of the enteric nervous system in the involved viscera. In experimentally infected animals, denervation of the submucosal and myenteric plexuses of the small bowel has been confirmed (10,11,12). The same occurs in naturally infected cats and dogs (13). The percentages of denervation shown in Table 1 were detected in humans with the chronic phase of Chagas' disease and with no dilation of any segment of the small bowel. In cases of enteric "megas", denervation is likely to reach much higher percentages, as also observed in megaesophagus and megacolon. The complete disappearance of intramural neurons has been documented in cases of megaduodenum (17).
Table 1 - Percent reduction in the number of neurons of the enteric nervous system of the small bowel of patients with chronic Chagas' disease.
As a consequence of denervation, the duodenum becomes hypersensitive to cholinergic agents and this type of response to the application of an acetylcholine analogue can be a way to demonstrate intramural denervation. The Mecholyl (metacholine) test performed with manometric monitoring of the duodenum showed hyperactive reactions in 70% of chagasic patients with megaesophagus, as opposed to only 10 % of chagasic patients without "megas", demonstrating that duodenopathy is more frequent in patients with clear involvement of other segments of the digestive tube by the disease (18).
Electron microscopy reveled that the neuronal lesions of the jejunum are less intense than those of the esophagus or colon and that the remaining cells show ultrastructural lesions. The least damaged cells show an increase in the number and volume of osmophilic granules suggesting hypersecretion of neurotransmitters, perhaps reflecting the complexity of the disorder of neuroregulation of the functions of the organ. The presence of inflammatory foci and of interstitial fibrosis in smooth muscle has also been recorded (19). Hypertrophy of the circular and longitudinal musculature was detected in the duodenum (17).
The mechanisms determining the degenerative lesions of the neurons and even their complete destruction in the viscera of the digestive tract of chagasic patients are still incompletely understood. They act starting from the acute phase of the disease (20) but continue during the chronic phase. It was first proposed that a neurotoxin released by the parasite near the focal points of infection during the acute phase of the disease was a preponderant determinant of neural injury (20). The possibility has been raised that the inflammatory process itself may be the cause of denervation or that denervation may result from the participation of specific cellular and humoral responses to T. cruzi developed by the host, including autoimmunity (21,22,23,24).
The final result of denervation of the enteric nervous system determined by Chagas' disease is dilation of the involved organ, the most expressive manifestation of the digestive form of the disease. Koeberle (20) proposed that, as a consequence of damage to intramural innervation, motor uncoordination of the attacked visceral organ occurs, followed by delayed transit of its content, stagnation and retention, continuous distention of muscle fibers which become hypertrophied, and finally dilation ("mega"). He considered the functional status of the visceral organ to be an important factor in the determination of the "mega". According to the cited author, the "mega" will develop only if the functional activity of the visceral organ is continuously demanded. He proposed that dilation of the esophagus and colon occurs more frequently than dilation of other viscera of the digestive tube because more demands are made on these organs since, in contrast to other segments and especially the small bowel, they work with solid material. He considered the presence of a defect in sphincter function to be an important factor in the development of the "mega", as is the case for megaesophagus, but not an essential one, citing the megaduodenum and megajejunum as a proof. He also stated that the degree of denervation and of the corresponding functional disorder may affect the duration of the time needed for the development of the "mega". However, other factors have been considered to participate in the pathogeny of the "megas" (23).
The detection of "megas" in the small bowel is not frequent, but the megaduodenum is considered to be the segment of the digestive tube that is most often found to be dilated after the colon and esophagus. In a series of 800 autopsies, 185 cases of megacolons, 158 of megaesophagus and only 20 of megaduodenum and 4 of megajejunum were detected (9). Dilation of the ileum is exceptionally rare (25). Dilation of the segments of the small bowel is frequently associated with megaesophagus and/or megacolon (17,18). When a radiological method is used, however, the incidence of megaduodenum increases. Fonseca (26) detected dilation of the first portion of the duodenum in 30% of cases of megaesophagus.
III - Physiopathology
The function most consistently found to be altered in chagasic enteropathy is motor activity, which greatly depends on the regulatory activity of the enteric nervous system. Although dilation of the duodenum, jejunum and ileum is not frequent, the motor impairment of segments of the small bowel is high in the digestive form of Chagas' disease. Radiological studies have revealed a high incidence of changes in tonus and transit time in the duodenum, jejunum and ileum of patients with megaesophagus (26,27). Manometry of the proximal small bowel has also revealed frequent abnormalities among patients with megaesophagus and/or megacolon (28), as commented below.
Studies on small bowel motility both under fasting and postprandial conditions have demonstrated perceptible alterations due to the intramural denervation caused by Chagas' disease. Normally, during fasting the small intestine presents successive cycles of motor activity known as interdigestive migrant motor complex (IMMC). In most persons, at intervals of 80 to 120 minutes a set of repeated contractions of frequency identical to the basal local electric rhythm (12/min) arises in the duodenum. These contractions cover a segment of about 25 cm and migrate in a caudal direction, and their frequency is progressively reduced, reaching 7-8/min in the ileum. The velocity of migration of the set of contractions is about 6 to 8 cm/min in the duodenum-proximal jejunum. The duration of the sequence of contractions at the recording point is about 5 min in the proximal jejunum. This type of motor activity is phase III of the IMMC and is followed by phase I, characterized by motor quiescence and refractoriness, which lasts 15 to 60 minutes. The motor activity then reappears gradually in the form of distinct manometric patterns until it culminates in a new phase III. The motor activity of the interdigestive period has been proposed to be important to lead to the colon non-absorbed food remains, secretions and cell detritus which, if retained, would favor excessive bacterial proliferation. The pattern of contractions that characterizes the IMMC is immediately interrupted by food ingestion, with the occurrence of a motor activity comparable to phase II of the IMMC. The duration of IMMC interruption by a meal depends on the composition and the physical properties of the food ingested (29).
The main manometric abnormality detected in the proximal small bowel of fasting chagasic patients was a reduction in the velocity of propagation of phase III (Figure 1). The duration of phase III was also shown to be longer in the jejunum but not in the duodenum, and the calculated length of the intestinal segment in phase III was lower than normal. These alterations mainly occurred among patients with megaesophagus and/or megacolon (28).
Figure 1 - Velocity of
propagation of phase III of the IMMC in control individuals, in chagasic patients with no
disease of the digestive tract, in chagasic patients with megacolon (blank squares), with
megaesophagus (blank circles), and with megacolon and megaesophagus (squares with blank
circles). The arrows indicate patients with megaduodenum (28).
Another remarkable change observed was the non-interruption of the IMMC by the ingestion of a meal of approximately 530 kcal (Figure 2), which exclusively occurred in patients with megaduodenum and megajejunum (30), or an attenuation of the responses to the meal revealed by prolonged manometry of the small bowel (31). Considering that Chagas' disease may be seen as a natural human model of denervated digestive viscera (32), these findings permit a suggestion of a physiological nature: the integrity of the enteral nervous system in the small intestine is necessary for the normal migration of the IMMC as well as for its interruption by food ingestion.
Figure 2 - Phase III of the
IMMC, typical of fasting motility, arising 40 minutes after the end of a 530 kcal meal
ingested by a patient with megaduodenum and megajejunum demonstrates the faulty process
that occurred in the transformation of the interdigestive motor pattern to the digestive
pattern. The reappearance of the interdigestive pattern should occur at least 90 to 120
minutes after the end of the ingestion of a test meal. The patient also presented operated
grade I megaesophagus (cardiomyotomy) and megacolon (30).
Transit time studies using scintigraphy methods and the expired nitrogen test have shown a delayed arrival of the test meal to the cecum associated with slow transit in the distal small bowel (33).
The changes in small bowel motility caused by intramural denervation may create conditions that favor bacterial proliferation due to content stagnation. In fact, hyperproliferation of aerobic bacteria and the presence of anaerobic bacteria in the small bowel have been documented in patients with chagasic megaesophagus, with the number of colonies being as high in some cases as those occurring in patients with the clinical syndrome of bacterial overgrowth in the small bowel. Since the participation of changes in gastric secretion was excluded, the abnormality was attributed to disorders of local motility (34). In support of this hypothesis, it was observed that two cases of chagasic megajejunum with clearly detectable alterations upon manometry and with confirmed bacterial overgrowth in the small bowel developed the typical clinical syndrome of bacterial overgrowth (chronic diarrhea, evidence of malabsorption and improvement with antibacterial treatment) (35).
Intestinal absorption function has been little studied in Chagas' disease. It was first observed that chagasic patients, especially those with clear involvement of the digestive tube as revealed by megaesophagus or megacolon presented abnormal responses to an oral glucose (GTT) (36), galactose (37) and xylose (38) overload test. The abnormal response to an oral overload with these monosaccharides was characterized by a high peak of their concentration in blood 30 minutes after ingestion, followed by a rapid fall. Abnormal GTT curves were detected in about 65% of patients with digestive tube "megas" (39). On the other hand, the responses to an intravenous glucose overload did not differ between chagasic patients and controls (40). These facts suggest that rapid monosaccharide absorption may occur in Chagas' disease, explaining the abnormalities observed when an overload of these substances was administered orally. Another possibility could be that the rapid gastric emptying of the test solution immediately after ingestion may expose the proximal small bowel to an excessive amount of monosaccharide, forcing rapid absorption. Favoring this hypothesis, it was demonstrated that an accelerated emptying of the liquid contained in the gastric cavity occurs probably due to the loss of the ability of the chagasic stomach to accommodate to distention (41).
In order to test directly the absorption ability of the proximal small bowel of chagasic patients, the method of continuous intestinal perfusion with indicators of variation in dilution was used. Glucose solutions of four different increasing concentrations (0.5, 1.0, 2.5, and 5.0%) were infused at a constant flow through a tube placed in the distal duodenum or proximal jejunum over a standardized period of time, and samples were collected 30 cm downstream from the point of infusion. This permitted an estimate of the amount of glucose absorbed between the two points and the data obtained were used to construct a dose-response type of curve. The intestinal segment under study in chagasic patients with an abnormal GTT was found to show kinetic characteristics indicating a greater capacity for glucose transport (greater Vmax), but less affinity (greater Km) than controls (39,42). Thus, an epithelium with a greater absorption capacity, permitting monosaccharide hyperabsorption may explain, at least in part, the abnormal GTT of chagasic patients. It has been proposed that this dysfunction in glucose absorption may be determined by the intramural denervation of the small bowel demonstrated in Chagas' disease (39,42).
The 131I oleic acid test used at the time to study lipid absorption showed low radioactivity curves in blood after ingestion in 30% of the chagasic patients studied. Considering that most of these patients showed normal gastric emptying as evaluated by a radiological method, it was concluded that the disease may cause a slow lipid absorption but without affecting the total amount absorbed since fecal radioactivity was normal (43). Intestinal absorption was later studied in chagasic patients by the intrajejunal administration of 131I oleic acid. Since no differences in results were observed between chagasic patients and controls, it was concluded that the abnormalities observed in the oral test were probably due to delayed gastric emptying of the test meal ingested (44).
The mucosa of the small bowel contains cells whose function is to secrete peptides having the most varied regulatory actions both locally and at a distance. Intramural denervation would be expected to have some effect on this secretion. However, it was observed that chagasic patient with clear impairment of the digestive tract shown by megaesophagus, did not present any abnormality in motilin, enteroglucagon or gastric inhibitor peptide levels either under basal conditions or after stimulation by and oral or intravenous glucose overload or by insulin hypoglycemia (45). I another study on this same type of patients, no changes in cholecystokinin, motilin or enteroglucagon levels were detected in the basal state or after intravenous administration of secretin associated or not with duodenal instillation of phenylalanine (46).
IV - Clinical manifestations and diagnosis
The clinical manifestations of chagasic enteropathy occur after the development of dilatation of one or more of the anatomical segments of the small bowel, They are almost always associated with concomitant symptoms of megaesophagus and/or megacolon. The presence of only motor or absorptive dysfunction of the small bowel, detectable by special tests, does not seem to be sufficient to provoke symptoms or signs of significance to the patient. There is no systematic description of the manifestations of small bowel "megas". Investigators of the digestive form of Chagas' disease have reported only few personally observed cases (18,47,48); particularly outstanding in this respect is the report by Raia et al. (17) on 11 cases of megaduodenum.
There is a wide gamut of clinical expressions of ectasic chagasic enteropathy, ranging from the absence of symptoms, with detection only by radiological examination indicated for other purposes, to signs and symptoms belonging to at least three types of syndromes: dyspeptic syndrome, intestinal pseudo-obstruction syndrome, and bacterial overgrowth syndrome of the small bowel. It may be stated that clinical manifestations tend to be more expressive and severe the greater the extent of dilation of the small bowel.
Within the dyspeptic picture, patients with "megas" of the small bowel may present a sensation of postprandial fullness and discomfort in the epigastrium (18,48). Pain, which is not always present, may vary in intensity and type and may occur during the early or late postprandial period. Raia et al. (17,47) pointed out that the clinical picture of megaduodenum can be that of gastric stasis of a progressive nature, characterized by vomiting of food ingested many hours before, dehydration, epigastric pain and visible gastric peristalsis, and lesions of the duodenal and gastric mucosa, and includes the possibility of bleeding and even stomach rupture. Another important complication is represented by esophageal mucosa injuries due to prolonged contact with material stagnating in the stomach, with reflux into the esophagus. In a case observed by us, reflux disease was present in a particularly severe form since it was facilitated by a previous surgical intervention in the cardia for the treatment of megaesophagus. It should be remembered that gastric stasis in the absence of small bowel dilation in chagasic patients may be due to gastropathy of the same etiology (47,49).
As previously mentioned, cases of megajejunum are rare. In the few cases we observed, the condition was always associated with megaduodenum. Megajejunum has also been reported to occur separately or associated with megaileum (18,47,48). Patients with megajejunum may be asymptomatic or may present well defined clinical signs and symptoms such as intestinal pseudo-obstruction associated or not with syndrome of bacterial overgrowth in the small bowel. Abdominal distention, the presence of continuous pain or of cramps, the visible peristalsis, the intestinal constipation and the detection of fluid levels in small bowel loops by simple abdominal radiography in the orthostatic position are the elements composing the picture of pseudo-obstruction of the small bowel. The occurrence of continuous chronic diarrhea or of diarrhea alternating with periods of intestinal constipation or other symptoms of pseudo-obstruction suggests a diagnosis of bacterial overgrowth in the small bowel. This hypothesis is reinforced when there is evidence of intestinal malabsorption such as weight loss and clinical and laboratory signs of steatorrhea, anemia or hypocalcemia. The diagnosis of bacterial overgrowth may be confirmed by the demonstration of strictly anaerobic bacteria in the upper portions of the small bowel, where they are not normally found, or by the increased number of colonies in duodenal aspirates (35,48,50). The hydrogen test may also indicate the presence of bacterial overgrowth by the early elevation of the content of this gas in expired air collected at regular intervals after the ingestion of 180 ml of a 10% lactulose solution (35). The presence of a high hydrogen rate in expired air when the patient is still fasting also indicates the syndrome of bacterial overgrowth of the small bowel (35). Complete remission of diarrhea and general clinical improvement of the patient with antibiotic treatment may be considered a positive diagnostic test for the syndrome (35).
The patient with megaileum described by Santos et al. (25) presented chronic diarrhea, abdominal distention and signs and symptoms of intestinal subocclusion resolved by clinical treatment. In summary, clinical manifestations similar to those of megajejunum.
The diagnosis of dilation of small bowel segments due to Chagas' disease is confirmed by standard radiological examination of the stomach and duodenum or of the entire small bowel. This examination permits the identification of the megabulb or of other segmental dilations of the duodenum, the megajejunum, megaileum, and total dilation of the small bowel (Figure 3). These examinations are also useful for the obligatory differential diagnosis with organic causes of intestinal obstruction. Endoscopic examination is indicated for the diagnosis of changes in the mucosae of the esophagus, stomach and duodenum consequent to stasis, which may range from inflammation to ulcer and bleeding, and may also aid the differential diagnosis with organic causes of stomach and duodenum obstruction. It may also indicate the diagnosis of megaduodenum.
Figure 3 - Contrast radiographs of the proximal small bowel of a patient with megacolon and chronic diarrhea. The megaduodenum can be observed on the left, as well as the mark of compression exerted by the superior mesenteric artery on the third portion of the organ. Dilation of jejunal loops and contrast retention can be seen on the right, since the radiograph was taken 90 minutes after the ingestion of a barium suspension. The patient presented the bacterial overgrowth syndrome.
For an etiological diagnosis it is indispensable to confirm serologically the presence of Chagas' disease by immunofluorescence or by any other tests with good performance. The epidemiological antecedents, the concomitant presence of megaesophagus and/or megacolon or of electrocardiographic changes compatible with Chagas' heart disease are other elements that should be considered in order to establish an etiologic diagnosis.
V - Treatment
When the patient only shows dyspeptic signs and symptoms, treatment may be limited to dietary adjustments, especially with the recommendation of bland meals free of substances that irritate the mucosae, reduction of the amounts of fatty foods, meals of small volume, and good food mastication. Although the efficacy of prokinetic medications in these pathological conditions is unknown, the use of domperidone at habitual doses could be attempted. In the presence of reflux esophagitis, proton pump inhibitors are indicated even for continuous use, the same applying to the presence of marked gastritis or duodenitis.
Surgical treatment of megaduodenum is reserved for cases in which stasis is clinically important and consists of duodenojejunal anastomosis close to the duodenojejunal angle, this being the type of operation most frequently used by Raia (17). Rezende (18) pointed out that surgical treatment should be indicated only in cases in which the symptoms are unequivocally due to the megaduodenum and not only on the basis of radiological findings.
In cases of megajejunum or megaileum, partial enterectomy is indicated as long as the respective dilated segments are not extensive (18). The operations, however, should be avoided when long segments of the small bowel are dilated. In these cases, clinical treatment of the obstructive episodes should be instituted, with interruption of oral feeding, continuous gastric aspiration, correction of dehydration and of electrolyte disorders and, eventually, the use of total parenteral nutrition (18,48).
overgrowth syndrome of the small bowel should be treated with antimicrobial drugs
(tetracycline, chloramphenicol, cephalosporine, metronidazole, etc.), usually at similar
or even lower doses than those used for the treatment of infectious processes, for 3 or 4
weeks. Bacterial sensitivity tests do not always indicate the best antibiotic for each
case. Since the motor abnormality is persistent, the periodic use of antimicrobial agents
may be necessary. If the picture is not resolved with a given antibiotic, indicating
bacterial resistance, it is necessary to switch to another one. Associated nutritional
disorders due to the malabsorption provoked by bacterial overgrowth should also be
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