Digestive Disorders in Chagas Disease: Megaesophagus and Chagasic Megacolon

Abstract

Chagas disease, also known as American trypanosomiasis, caused by Trypanosoma cruzi and transmitted by hematophagous vectors, is a parasitic disease, which according to the WHO ranks fourth as a cause of loss of potential years of life due to complications that can occur in multiple body systems. According to the reports presented by the World Health Organization, there are between 16 and 18 million infected people in the world, predominantly in endemic areas of Latin America, of which only 1% receives an adequate diagnosis and full treatment, thereby that the chronic phase comes to present digestive disorders that are one of the main causes of loss in the quality of life of patients, as well as complications that can lead to life-threatening surgical emergencies.

1. Introduction

American trypanosomiasis ranks as the fourth most frequent disease-causing loss of productive years [1]. Also known as Chagas disease, this disease is a parasitic infection transmitted by hematophagous vectors [2] and is characterized by an acute period with general symptoms, which leads to a chronic phase and the development of complications at different levels of the infected organism. The reports, made by the World Health Organization (WHO), mention that in the world there are between 16 and 18 million infected people which approximately only 1% receives an early diagnosis and full treatment, being the area with the highest incidence is in the Latin American area where this infection is considered endemic. Due to the public health implications and the high percentage of complications that it presents in chronic phases, the Pan-American organization and the World Health Organization consider this disease as the most serious parasitic infection in Latin America [1].

In addition to vector transmission, this infection can be spread vertically through infected women during pregnancy, leading to gestational disease with implications for uterine or neonatal development.

Among the major complications of the chronic stage of Chagas disease, it is the development of the so-called—mega syndromes, within which megaesophagus and Chagasic megacolon are more frequently included, which develop from alterations in the neurosensory system in the muscular layers of these organs. Both scenarios present significant complication rates that condition the loss of productive years, a decrease in the quality of life, and compromise life depending on the presentation of volvulations or eating disorders.

Although the development of complications associated with the chronic stages of Chagas diseases, such as intestinal volvulations [3] in megacolon, is relatively uncommon in Western countries, it is still considered the most severe complication [4], positioning itself as the third cause of lower intestinal obstruction in some countries, only below diverticular disease and colon cancer [1]; with respect to megaesophagus, complications can occur even in patients who are considered asymptomatic, who nevertheless present motor disorders of the esophagus that can lead to the development of neoplasms.

2. Background

Chagas disease was discovered in 1909 by Dr. Carlos Chagas, he studied blood-sucking insects with a nocturnal habit called “barbeiros” (Figure 1). Chagas sent samples of Barbeiros that Dr. Cruz inoculated into monkeys. After 30 days, Chagas examined the monkeys’ blood and found parasites, which he named Trypanosoma cruzi. Together with their colleagues, from 1909 to 1917, they defined the clinical aspects of the disease. The first case described in humans was Berenice, a 2-year-old girl who presented 39.4°C, eyelid edema, adenomegaly, hepatomegaly, and the presence of T. cruzi in peripheral blood, with subsequent remission of signs and symptoms [5].

Figure 1.

Hematophagous barbeiro insect causing transmission of Chagas disease.

In a study by Aufderheide et al. with the review of mummies exhumed from archeological sites in both Peru and Chile, a carbon dating of their tissues was revealed to approximately 7000 BC. and confirmed by means of the polymerase chain reaction (PCR) the presence of DNA of the T. cruzi kinetoplast. Another historical fact dates back to 1835, when Charles Darwin was in Argentina, in the province of Luján de Cuyo in the southern district of Mendoza, he was inoculated by a triatomine insect. He studied these insects for at least 4 months. From 1835 to 1841, Darwin reported no symptoms, which could be due to the latent phase of Chagas disease. From 1841 to 1861, Darwin reported palpitations, a feeling of extreme fatigue, tremors, flatulence, and vomiting to his colleagues and doctors, however, none could identify the cause. At the age of 33, he left his job due to physical fatigue and digestive disorders, which can be explained by Chagas disease, Darwin experienced anginal attacks and was eventually diagnosed with heart failure. Darwin’s disease has caused extensive speculation in the scientific community. Two things are clear—1) he was exposed to the triatomine insect and 2) his symptoms can be explained by Chagas disease [6].

3. Epidemiological aspects

T. cruzi gets its entry into the body through its vector, the triatomines, members of the reduvius family when the insect ingests blood from an infected animal. The protozoan replicates in the intestine of the triatomine and is excreted from its feces. The main route of transmission in humans is the inoculation of feces directly on the mucous membranes, or in skin lesions that are generated by scratching or damage caused by the insect bites. It can also occur by blood transfusion or tissue transplantation (organ or bone marrow) from an infected person and by transmission from the mother to her fetus during pregnancy. There is another way of transmission, the oral route, which occurs when the ingestion of feces from triatomine infected with T. cruzi, when the consumption of meat or blood of wild animals, or contamination from utensils for prepare food. The estimated incidence has dropped from 500,000 in 1991 to 30,000 new cases of infection per year in 2010. The annual cost to an individual’s society for chronic disease care was $ 4059 (range $ 3569–4434) in Latin America, 13,580 ($ 11,340–15,003) in Europe, and $ 15,762 ($ 13,249–17,442) in the US, Canada and Australia, globally the weighted measure of the annual cost of health care and the productivity of a person with chronic disease was $ 4660, the estimated annual global burden of the disease is $ 627.46 million in health spending and 806,170 disability-adjusted life years, 10% of this burden affects non-endemic countries [7].

In the case of Latin America, 20% of its population is at risk of acquiring the infection, especially in endemic areas. In Mexico, it is considered a public health problem, since it is estimated that 1.1 million people are infected. The incidence from 2000 to 2007 remained in the range of 0.07–0.37 per 100,000 people, increasing to 0.70 in 2012. During 2018, 150 cases were registered throughout the republic. According to a 2013–2018 report, Chagas disease is the most serious parasitic disease in Latin America, since there are 110 million people at risk of infection in 21 different countries, likewise, the World Health Organization has classified it as one of the 14 lagging diseases [8].

4. Pathophysiology

The T. cruzi parasite is a heterogeneous species with a diverse phenotypic diversity, circulates between vectors and hosts, and is classified into discrete typing units a term used to describe sets of stocks that are genetically similar to each other and have “tags” a molecular marker to identify each other DTU (TcI-TcIVI and Tcbat) [9]. The life cycle consists of three different forms, metacyclic trypomastigotes, the infection form of T. cruzi, which consists of a fusiform shape and measures 10–20 m in length and 1.3 m in width. The transmitted by feces while triatomines feed on blood they defecate on the skin and T. cruzi introduces itself through the opening made by the bite and enter to the bloodstream or by rubbing on the mucosae (nasal or conjunctival). In the body, they are phagocytosed by macrophages, in the cytosol of subcutaneous cellular tissue they differentiate into amastigotes. The amastigotes measure 1.5–5 m in diameter with an ovoid shape, they replicate by binary fission and cause cell lysis to turn back to trypomastigotes to go into the blood and lymphatic circulation, they have tropism for myocardiocytes, rhabdomyocytes, and leiomyocytes. In this phase, a vector without infection can ingest it, within triatomines, trypomastigotes move to the medial segment of the gastrointestinal tract, once there they differentiate into epimastigotes, which replicate again through binary fission. Epimastigotes travel toward the distal segment of the gastrointestinal tract where they anchor themselves to colon epithelium through their flagella, they transform back to trypomastigotes to be excreted with feces during the next ingestion of blood and infect another human [8, 10]. In addition to vector transmission, T. cruzi can be transmitted by routes other than direct inoculation. These transmission routes play a greater role in non-endemic countries and a significant growth in endemic areas. It is estimated that vertical transmission reaches a frequency of 4.7% (range 3.9–5.6%) and that frequency may be higher in endemic countries than in non-endemic countries (5 vs. 2.7%). The biological determinant for congenital transmission is maternal parasitemia, which can be greater than 31% when T. cruzi is detected by PCR, likewise, transmission is also possible although it presents negative PCR [11]. The parasite can also be transmitted through blood and its products, the frequency of transmission per unit of infected blood is estimated to be 10–25%. In solid organ transplants from an infected donor, it appears to be lower for kidney recipients (0–19%) than for liver recipients (0–29%) and heart recipients (75–100%) [11].

The acute phase of Chagas disease is characterized by strong inhibition of the host’s immune response triggered by virulence factors of T. cruzi, which are crucial to create a persistent infection and establish chronic disease involving, among other things, the induction of anergy and clonal deletion in T cell compartments, together with strong polyclonal stimulation of type B cells which restrict antigen-specific lymphocytes. Membrane glycoproteins of T. cruzi are essential to dampen the host’s protective immunity. These membranes are covered by mucin-like molecules attached to their terminal galactosyl residues, sialic acid residues that are transferred from host glycoconjugates by parasite trans-sialidase. Mucin-like molecules of T. cruzi are key players in host–parasite interaction, including invasion of the host and subversion of its immune system. Its sialylated forms are capable of protecting the antigenic determinants of the parasite from host attack mediated by antigalactosyl antibodies and complement factor B. Likewise, they incapacitate dendritic cell function demonstrated by the inhibition of IL-12 production. This inhibition can occur at the transcriptional level of the IL-2 gene in T cells, which also occurs when T cell proliferation and activation are blocked in response to mitogens and antigens. Sialoglycoproteins also inhibit early events in T cell activation, particularly tyrosine phosphorylation of the adapter protein SLP-76 and tyrosine kinase ZAP-70 [12].

5. Clinical presentation

As mentioned above, Chagas disease has two phases of development, the acute and the chronic period. The acute phase can occur at any age, has an incubation period of 4–14 days, and a duration of 2–4 months. It is asymptomatic in 95% of cases when symptoms occur, these include fever (75%), inflammation in the inoculation site (inoculation chagoma, 25%), unilateral eyelid edema (Romaña-Mazza sign; when the conjunctiva is the gateway, 50%) (Figure 2), lymphadenopathy, and hepatosplenomegaly. The acute phase lasts 4–8 weeks, and parasitemia decreases substantially from day 90 onwards. A severe acute phase occurs in less than 1–5% of patients, including manifestations, such as acute myocarditis, pleural effusion, and meningoencephalitis (mortality risk 0.2–0.5% [8].

Figure 2.

Flagellated tripoamastigote causing the circulating phase of the disease.

Cases of congenital infection are generally characterized by the absence of symptoms in 70–80% of cases. The remaining 20–30% may have signs and symptoms, such as prematurity, low weight for gestational age, edema, jaundice, respiratory distress, persistent tachycardia, hepatosplenomegaly, and anemia. Occasionally sepsis, fever, hydrops fetalis, rash, petechiae, lymphadenopathy, meningoencephalitis, cerebral calcifications, fundus abnormalities, interstitial pneumonia, myocarditis. It can be classified as asymptomatic, early symptoms (<less than 30 days old), or late symptoms (> 30 days old) [8].

The specific symptoms, which occur in the chronic stage, will depend directly on the organ that is affected and the damage that has occurred during the entire period of the disease. There is an asymptomatic chronic phase. This is characterized by the absence of symptoms and the presence of parasitemia and/or positive serology. This form can persist but only 30% of the patient the rest may progress to symptomatic form over a period of 10–30 years.

The symptomatic phase consists of the presence of chronic heart disease (cardiomegaly) represents the main cause of mortality and/or gastrointestinal disease (megaesophagus, megacolon, megaileum, megastomach, megabladder, megaduodenum, and megajejunum) with fluctuating parasitemia levels.

6. Chagasic megaesophagus

The most common gastrointestinal affectation due to Chagas disease is the megaesophagus, it affects any age, sex, and stage of the disease. The initial symptoms can be quite nonspecific, such as hypersalivation, nocturnal cough, a sensation of coughing after eating, and weight loss that further complicates the diagnosis [13], is characterized by the inability of the esophagus lower esophageal sphincter (LES) to relax in response to swallowing and absence of peristalsis in the esophageal body and; both motor abnormalities determine esophageal dilation with food stasis that will produce most of the symptoms and complications of the disease [13].

In the acute phase of the disease, parasites cause invasion of muscle tissue of the heart and digestive system, causing ganglionitis and lymphocytic infiltration, which leads to neuronal degeneration in these organs. It has been observed a massive loss of myenteric neurons, while the loss of submucosal neurons is moderate [14]. The asymptomatic or indeterminate chronic phase is clinically silent and with very low parasitemia, the duration varies between 5, 10, and up to 20 years; during this stage, the diagnostic methods of choice are serological tests. After this phase, the chronic symptomatic period occurs in which approximately 27% of patients present cardiac lesions, 6% damage to the digestive system (mainly in the esophagus and colon), and 3% to the peripheral nervous system [13].

The myenteric and submucosal plexus make up the enteric nervous system in humans, where the ganglionic nerve networks are located. The myenteric or Auerbach’s plexus is located between the muscular layer and the longitudinal layer (Figure 3) and extends from the upper part of the esophagus to the internal anal sphincter. Additionally, the human submucosa contains two ganglion plexuses, the inner one is called Meissner’s plexus and is localized in the submucosal plexus, while the Schabadasch’s plexus is outer [15].

Figure 3.

Amastigote without flagellum responsible for cell invasion.

The progressive and irreversible deterioration in the enteric nervous system caused by the T. cruzi parasite is responsible for most of the gastrointestinal symptoms. Although any organ of the digestive system can be affected by Chagas disease, the esophagus and the colon are the ones that are most frequently damaged. The symptoms associated with Chagasic megaesophagus generally do not put the patient’s pathway at risk, however, they considerably reduce their quality of life, since they generate eating disorders secondary to dysphagia, odynophagia, or esophageal insufficiency [16].

Hypocontractibility, motor dyskinesia, and incomplete or absent relaxation of the lower esophageal sphincter are results of this destruction of the myenteric plexuses, which lead to the classic presentation of achalasia. In esophageal symptoms and altered motility, an increase in the diameter of the esophagus is observed in 7–10% of infected subjects (Nisimura et al., 2020). Despite the findings that have been made in relation to the loss of esophageal motility secondary to damage to nerve structures, it has been proposed that the condition in other cell groups is necessary to explain more broadly the damage caused by the parasite. Therefore, it has been proposed that the damage caused to the muscle and nerve layers is also associated with immunomodulatory mechanisms and the local inflammatory response [14].

The biomechanics of swallowing is directly related to the contraction of the suprahyoid muscles. This contraction promotes the elevation and stabilization of the laryngeal complex during swallowing. Analysis of the suprahyoid musculature by electromyography has generally included the end of the oral phase, the pharyngeal phase, and the beginning of the esophageal phase. In the oral and pharyngeal phases of swallowing in patients with Chagas disease, there is an increase in oral residues, a longer pharyngeal clearance and upper esophageal transit, and a longer opening of the upper esophageal sphincter. It has been observed that the contractile activity in the electromyography of patients with Chagas disease is lower than that of those who present motor esophageal disorders without this disease. This may be explained by decreased muscle recruitment of the suprahyoid muscles in patients with Chagasic megaesophagus and symptoms of dysphagia [16].

The diagnosis of Chagas megaesophagus is based mainly on the clinical history, symptoms, barium esophagram (Figure 4), manometry, and endoscopy [17], which could be classified as follows.

Rezende’s classification of Chagasic esophagopathy
Stage	Description
Stage 0	indeterminate phase
Stage 1	normal diameter with delayed emptying
Stage 2	Moderate esophageal dilation and hypertonia of the lower esophageal sphincter
Stage 3	Large increase in caliber with little contractile activity
Stage 4	Megaesophagus

Figure 4.

Unilateral eyelid edema, Romaña-Mazza sign.

An objective way to assess the severity of symptoms, as well as the effectiveness of treatment, is the Eckardt score, which ranges from 0 to 12 points, which classifies the stages of the disease. The score assigns from 0 to 3 for weight loss, dysphagia, chest pain, and regurgitation, the final value consisting of the sum of these elements—stage 0 (0–1 points), stage I (2–3 points), stage II (4–6 points), and stage III (> 6 points) [18].

Eckardt Clinical Scoring System for Achalasia
Score	Weightloss	Dysphagia	Retrosternal chest pain	Regurgitation
0	No	No	No	No
1	< 5 kg	Often	Often	Often
2	5-10 kg	Everyday	Everyday	Everyday
3	>10 kg	Each meal	Each meal	Each meal

The goal of treatment is to restore the ability to feed orally and alleviate all these symptoms, which can be achieved by various modalities, such as endoscopic dilation, peri-oral endoscopic myotomy, and Heller Pinotti laparoscopic cardiomyotomy, which is currently considered the standard treatment for non-advanced megaesophagus patients. These modalities eliminate resistance to the outflow of food, improving esophageal emptying [18].

Recurrence of dysphagia after cardiomyotomy is associated with gastroesophageal reflux with esophagitis, incomplete myotomy, fibrosis at the site of the gastroesophageal junction, an inappropriate indication of technique for patients with advanced megaesophagus, and intrathoracic migration of the gastric fundus. The reoperation is usually not very successful in relation to the first procedure and many patients require esophagectomy treatment, which is the option of choice when symptoms reappear or the stage is advanced but adds greater morbidity and mortality associated with thoracic esophageal dissection. An alternative to esophagectomy is esophageal mucosectomy, with less morbidity due to preservation of the esophageal muscle tunica and an intraluminal dissection of the esophageal mucosa with subsequent transposition of the gastric tube without violation of the mediastinum [18].

The appropriate choice of surgical treatment for recurrent achalasia depends on the pathophysiology of the recurrence. Therefore, for patients with incomplete myotomy or fibrosis at the esophagogastric junction, a new myotomy with partial fundoplication is still indicated, as long as the esophageal wall has not been damaged during dissection. For patients with significant reflux or dolichomegaesophagus, the indication is esophagectomy with transposition of a stomach or colonic tube [18].

7. Chagasic megacolon

As previously described, this disease occurs in two phases, an acute one characterized by cell destruction, extensive inflammatory foci, and a large number of circulating parasites, and a chronic phase that can cause potentially fatal cardiac and digestive disorders [19]. It has been described that up to 40% of people who suffer from it will develop one of these complications or a combination of both [20]. Megacolon is defined as irreversible dilation of the colonic segment, predominantly in the chronic phase of Chagas disease, where the dilated segment presents histopathological changes characterized by a significant loss of neurons of the myenteric or Auerbach and submucosal or Meissner plexus and although not the mechanisms of this destruction are well elucidated, it has been proposed that it could be due to the release of toxins during the fragmentation of the parasite, direct cellular damage, or inflammatory damage [20, 21].

Recently it has been described that the progress to the chronic phase is determined mainly by an inflammatory state, to which the virulence of the parasite and its tropism for the tissues contribute. During Chagasic cardiomyopathy, there is an extensive production of pro-inflammatory cytokines, such as interferon γ (INF γ), Tumor Necrosis Factor α (TNF α), as well as other mechanisms that cause tissue damage, such as the cytotoxic activity of CD8 T lymphocytes [10]. Similarly, in Chagasic megacolon, the myenteric plexus is severely affected by an inflammatory process that leads to neuronal degeneration, ganglionitis, peri-ganglionitis, neuritis, and peri-neuritis. The inflammatory infiltrate has been characterized by the presence of eosinophils, mast cells, CD68 + macrophages, Natural Killer CD57 + cells, and TIA-1 + cytotoxic lymphocytes that maintain the inflammatory process and neuronal destruction [21]. It has also been described that the neuronal destruction process derives from an autoimmune response mediated mainly by TNF α and INF γ. Both cytokines are involved in the control of the parasite during acute infection, however, an imbalance in the response of these cytokines can lead to progression to chronicity and eventually to the cardiac and intestinal complications characteristic of the chronic phase of the disease [21]. The role of the megacolon in the context of intestinal neoplasms is controversial. It is suggested that derived from the dilation of the organ and the presence of food stasis, there is prolonged contact between the intestinal mucosa and potentially carcinogenic agents. In this context, the role of Galectin 3, a protein whose increased expression is related to tumor progression and which is used by T. cruzi to enter cells, has been studied, which suggests that there could be a relationship between this protein and neoplastic progression [22]. However, other studies have sought to demonstrate that patients with chronic-phase Chagas disease have a lower risk of colon tumors at least in the megacolon region, probably derived from denervation in this area, since it has been proposed that neuronal invasion could promote tumor invasion [23].

According to current estimates, up to 10,000 deaths associated with this disease could occur annually [24], since between 15 and 20% of all cases will present digestive complications, including megaesophagus and megacolon [25]. The prevalence of megacolon in patients with Chagas disease may be higher in those who presented symptoms during the acute phase than in those in whom there were no manifestations in this phase [26].

Chagasic megacolon presents clinically with chronic constipation due to pathological dilation of the organ wall, mainly in the sigmoid portion of the colon, a site where T. cruzi is commonly found [27]. This is considered to be the most frequent symptom in patients with Chagasic megacolon, however, it has been reported that there are patients with normal evacuations, as well as patients with Chagas disease who present constipation not associated with megacolon.

Although this sequel is well known in the context of Chagas disease, few studies have described the clinical manifestations of its presentation, having little information on digestive visceromegaly caused by T. cruzi. In some case reports, constipation is reported as well as other associated signs and symptoms, such as bloating [28]. Likewise, it has been described those subjects with megacolon present a decrease in basal motility and wave frequency in manometry, absence of an inhibitory rectus-anal reflex, and it is noteworthy that in patients with diverticular disease and Chagasic megacolon, the diverticula appear in non-dilated portions of the colon [29].

The approach to patients with megacolon associated with Chagas disease is complex because most infected patients do not present symptoms in the acute phase; so, it is very likely that they will seek care when the typical manifestations of megacolon appear (constipation, abdominal pain, diarrhea, changes in defecatory habits, or bloody stools); in this situation, if the patient is not known to have trypanosomiasis and lives in an endemic area, it will be essential to make a proper diagnosis of this disease [30, 31]. When questioning these patients, other associated symptoms and signs should be identified, since heart disease coexists in up to 30% of cases. Likewise, it is necessary to question the patient about other digestive symptoms, since some of these are not associated with Chagas disease [30]. In the study of patients in the chronic phase, the diagnostic methods are indirect, that is, laboratory techniques that identify antigens of T. cruzi (direct hemagglutination) or antibodies against the parasite (Enzyme Immuno Assay, Indirect Immunofluorescence, Western Blot) [31].

The diagnosis of megacolon depends on clinical, radiological, endoscopic, and surgical findings. One of the most widely used radiological studies is the Barium enema or colon enema (Figure 5), with which the diagnosis can be confirmed if the rectosigmoid diameter at the pelvic border is greater than 6.5 cm or the diameter of the middle sigmoid is 10 cm or more. Computed tomography colonography can also be used as it allows measurement of the diameters and length of the colon from different views [32]. Colonoscopy is not the ideal study for the identification of megacolon, since it depends on the interpretation of the person who performs it, in this sense, the diagnosis can be made through the result of incomplete colonoscopy [32].

Figure 5.

Nervous plexuses of the digestive system.

The management of megacolon will depend on the degree of constipation of the patient, his/her nutritional status, and his/her comorbidities. Treatment options are clinical or symptomatic and surgical. There is no consensus on the surgical management of choice, however, the most widely used procedure is the Duhamel-Haddad procedure (rectosigmoidectomy with retrocecal interposition) or rectosigmoidectomy with low end-to-side colorectal anastomosis (see Figures 6–8) [30].

Figure 6.

Megaesophagus seen with barium esophagram.

Figure 7.

Barium enema showing megacolon.

Figure 8.

Intraoperative image of sigmoid volvulation in chagasic megacolon.

It has been reported that complications derived from chronic constipation such as rectal prolapse or acute volvulus may occur [32, 33] (imagen 8). Of these, the most serious complication is volvulus, which occurs when a redundant loop of the colon rotates around the mesentery, which, in turn, causes a closed-loop intestinal obstruction that generates ischemia due to hypoperfusion of the affected segment, where there is an accumulation of gas associated with fermentation of intestinal contents. When this happens, the tension of the wall increases, which worsens the ischemia and promotes perforation of the intestine, which could lead to the death of the patient [34].

The treatment of volvulus is based on the control of symptoms and resuscitation of the patient and then decompression and derotation of the intestine by endoscopy if there is no evidence of peritonitis or perforation, since, if it occurs, the treatment is invariably urgent surgical [34].

8. Conclusion

American trypanosomiasis is one of the most serious parasitic diseases in the world, it has economic implications in public health systems that condition costs for complications in the different body systems, as well as loss of working years when diagnosed mainly in asymptomatic chronic stages. Damage to the digestive system due to the destruction of neuronal plexuses is responsible for most of the symptoms in chronic stages, which condition disability and put the patient’s life at risk, so early diagnosis in acute stages is the main tool to stop this disease.