progress report chagas enteropathy - gut.bmj.com · developed neuronal lesions in those ganglia...

Gut, 1973, 14, 910-919

Progress report

Chagas enteropathy

Chagas disease, the usual name given to Trypanosomiasis americana, iswidely distributed in Latin America, where it produces a high mortalityindex among young children as well as incapacity among adults. Its parasiticagent, Trypanosoma cruzi, is a flagellate protozoon discovered by CarlosChagas in 1909,1who described the clinical and pathological events caused bythe parasite, and, with remarkable foresight, pointed out the basic featuresof the disease that might usefully be investigated in the future, especially theconsequences of the lesions in the central nervous system.2 In fact the de-struction of neurones caused by the parasite is the main characteristic of thedisease. In this sense an important contribution to the quantitative study of'Chagasic denervation' has been made by Kbberle and his group. 3,4,5,6,7,8,9,10,11,12,13

The neuronal destruction determined by T. cruzi may affect both thecentral and peripheral nervous systems; the lesions in the latter are distinctlycommoner in the hollow viscera. T. cruzi has a special affinity for muscletissue although capable of selecting all types of tissue as host. Accordingto Koberle and Alcantara,7 the lesions in the autonomic nervous systemare responsible for most of the anatomical and functional disorders occur-ring in hollow muscular organs, such as the heart, oesophagus, small intestine,and colon, and sometimes the bronchi, ureters, and urinary bladder. Thedamage is more evident in the autonomic nervous system but is slight in thesympathetic nervous system compared with that inflicted upon the para-sympathetic, in smooth and cardiac muscles.The anatomical and functional disorders of Chagas disease, incurred

mainly as the direct sequelae of the acute stage, are more important clinicallythan the infestation itself, which becomes less significant in the chronicstage. Neurolysis of the acute stage follows rupture of the pseudo-cysts, theliberation and disintegration of leishmanial forms of the parasite close tothe neurones.3 The extent of this early neurolysis will determine the severityof the sequelae and the patient's future degree of clinical adaptation. Cardio-pathy and abnormalities of the digestive tract, especially mega-intestine, arethe commonest from the clinical viewpoint. As much as 80% of the cardiacnerve structure may be destroyed, and also, as will be seen later, a largeproportion of the neurones of the myenteric plexus of Auerbach.

It is worth noting that Chagasic denervation in motile organs such as theheart and digestive tract provides a neurophysiological pattern that would bedifficult to reproduce experimentally. In his thesis,14 Meneghelli sees Chagasenteropathy in the small intestine as a pattern in which neurophysiologicalchanges, associated with problems of absorption, opens up an interestingfield of study. This report is an attempt to analyse the consequences ofChagasic denervation in the small intestine in the light of recent contri-butions to the subject.

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Author Material Tissue Type of Infection Plexus Denervation

Koberle' Cat Duodenum Natural Meissner 37Koberle' Cat Jejunum-ileum Natural Meissner 30Koberle' Dog Duodenum Natural Meissner 52K6berle' Dog Jejunum Natural Meissner 61Alclntara Mouse Duodenum Experimental Meissner 38et all" and

Jejunum-ileum ExperimentalAlcAntaral" Mouse Duodenum Experimental Auerbach 50

Jejunum Experimental Auerbach 57Ileum Experimental Auerbach 54

Costa and Man Duodenum Chronic Meissner SOAlcintara"B AuerbachAlclntara and Man Jejunuml Chronic Auerbach 33Costa' Meissner 36Costa and Man Ileum Chronic Auerbach 51AlcAntaral5 Meissner 42

Table I Summary ofreported series

Denervation of the Small Intestine

Studies of Chagasic denervation in the entire gastrointestinal tract, andespecially in the small intestine, have been carried out by many workers,in man and in naturally and artificially infected animals. For example,in naturally infected dogs, Alvarengal5 noted degenerated neurones sideby side with unaffected ones in ganglions throughout the entire length of thegut. However, in some of the ganglia, the neuronal destruction was complete.G. Koberle8 made a quantitative assessment of neurones in the myentericplexus of naturally infected cats and dogs, and noted a reduction in thenumber of ganglionic neurones in the whole of the digestive tract. The dataof this author and of other quantitative studies are set out in table I.8,9,12,13,16,17,18 Alencar,19 working with experimentally infected mice, noted theinvasion of the muscular layers of the small intestine and of the plexuses ofMeissner and Auerbach in the acute stage of the disease. Under the sameexperimental conditions, Tafuri and Raso20 and Tafuri and Brener21 foundlocal or diffuse myositis in the small intestine and profound alterations in theneurones of the intestinal nervous plexus, especially the myenteric ones.These workers22 also demonstrated lesions in Meissner's and Auerbach'splexuses in the later stage of infection, irregular in site and intensity, butalways in connexion with chronic focal myositis. In the human form of thedisease, Raia et a123 have found a reduction in number or complete loss ofneurones in the myenteric plexus of patients with mega-duodenum.

Electron Microscopy of the Lesions in the Small Intestine Myenteric Plexus

Tafuri et a!24 made an electron-microscopic study of the lesions in themyenteric plexus of patients chronically ill with Chagas disease. They foundthat the lesions in the jejunum, though similar to those in the oesophagusand colon, were less serious. Together with practically unaltered neurones,they found radically changed nerve cells. The electron microscope showedswelling and vacuole formation in the mitochondria; dilatation of the in-terstitial space in the endoplasmic reticulum; and an increase in the number oflysosomes (figs 1 and 2).

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Fig. 1 Jejunum ofa chronic Chagasic patient. Auerbach ganglion. Alteredneurone (N) (swelling and vacuolization ofmitochondria (Mi) andperipheraltigrolysis) alongside part ofa normal neurone (arrow). Schwann cells (Sc) andnon-myelinic nerve fibres (Af) section at various directions. Lipofuchsin granules(Lp) in the neurone's cytoplasm, and lysosomes (Li) in the Schwann cellcytoplasm, x 7200.

In the axons of affected neurones they observed also lysis of neurotubulesand neurofilaments; swelling and vacuole formation in the axonal mito-chondria; and osmophilic granules, singly or in groups, between the neuro-filaments and neurotubule (fig 2).

In the majority of nerve fibres a large number of vesicles containingelectron-dense granules could be seen, together with other clear vesiclesdevoid of osmophil content. The Schwann cells showed little alteration inmost ganglia examined, but in others lysosomes and amorphous osmophilicgranules could be seen in the cytoplasm, together with slightly swollenmitochondria.The ultrastructural changes in surviving neurones led Tafuri and Maria25

to suggest disturbances at the level of neurosecretion and of synaptic trans-mission. The increase in size and number of the dense vesicles as an accumu-lation of neurotransmitter substances would be part of a compensatoryhypersecretion in response to denervation.

Pathogenesis of the Lesions in the Autonomic Nervous System

In the intestinal tract as in the heart, the pathogenic mechanisms of thelesions in the autonomic nervous system are not as yet fully understood.Lisboa25 described the sequence of events leading to neurolysis in the con-genital human form of Chagas disease. He reported that the process starts

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Chagas enteropathy

Fig 2 Jejunum ofa chronic Chagasic patient. Auerbach ganglion. Intenselyinjured neurone (N): vacuolization ofmitochondria (Mi); presence ofamorphousmasses (Ma) and eosinophilic granules in the cytoplasm; nuclear fibres (A f) withvacuolated mytochondria, lysis ofneurotubules, and also the presence ofdensegranular vesicles (vd). x 28,000.

with simple leishmanial infestation of the histiocytes adjacent to ganglia ofthe Auerbach plexus. The rupture of these histiocytes ('pseudo-cysts') andthe liberation of leishmanias is followed by ganglionic and periganglionicinflammation and later on by neurolysis. Koberle3 has postulated that aneurotoxin or an enzyme directly responsible for the neurolysis may be re-leased into the intercellular space by dead leishmanial stages of T. cruzi.Andrade and Andrade2 infected two groups of mice with T. cruzi and

blocked the inflammatory reaction in one group with cortisone. The mice inthis group did not develop neuronal lesions but those in the other groupdeveloped neuronal lesions in those ganglia where local inflammation wasobserved. The authors concluded that inflammation is a more importantfactor in the process of neurolysis than infestation alone.Okumura28 postulated that parasitism of the neurones themselves is the

main cause of their destruction.None of the mechanisms suggested to date are completely understood.

Furthermore, the mechanisms of Koberle3 and the Andrade,27 for example,are not eventually exclusive. A more detailed study of the neurolytic mech-anism would help to classify current ideas on this point, and might also pro-duce information that would be useful in the treatment of the acute stage ofthe disease.

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Disturbances in Motility

The motility of hollow muscular viscera, the heart, and digestive tracthas been among the different physiopathological aspects of Chagas diseaseand is that which has received most attention. In the intestine, the first effect ofneurolysis in the Auerbach plexus is the loss of muscular coordination.The consequent motor hyperactivity can be interpreted according to Cannon'slaw of denervation,30 although, within certain limits, the degree of functionaldisturbance is dependent on the extent of denervation. According to K6berle,6the denervation required to produce a disturbance varies with the organinvolved. Thus, for mega-oesophagus to occur, there must be a denervation ofat least 90%, for bronchiectasia 75%, for megacolon 55%, and for cardio-pathy only 25%. The motor incoordination of the intestine and the akinesiaof the closed sphincters, together with the physical distension produced bythe contents of the intestine, all combine in the pathogenesis of mega-intestine. The loss of coordinated peristalsis and sphincter function delays thepassage of the intestinal contents. The resulting distension of the tube andthe stretching of the muscle fibres cause hypertrophy of the intestinal musclewall. The rarity of the mega-jejunum is explained by the free transit of theliquid contents of the small intestine where the motor dysfunction is generallyuncomplicated by stasis.

Abnormalities in motility in the small intestine of patients with Chagasdisease had already been observed in x-ray studies byFonseca31,32 and Toledoand Fonseca.33 These authors described them as a 'functional dyskinesia'in which the dysrhythmia is not only connected with the tonus (hypertoniaand segmental dystonia) but also to the rate of the passage of the intestinalcontents (slow, accelerated, or uncoordinated in segments). Vieira et al34demonstrated in a group of 28 patients accelerated intestinal movement in32.1 % and delayed passage in 3.6% of the cases.Firm evidence of a functional parasympathetic denervation in the digestive

tube was obtained by Godoy and Vieira35, who studied the mega-oesophaguscondition in Chagas patients using a kymographic record of intraoesopha-geal pressure. They demonstrated a 'striking increase in tonus and reflexactivity' when mecholyl was administered. This fact was confirmed radio-graphically by Rezende and Dutra36 in the small intestine in a case ofmegaduodenum. Meneghelli et al37 documented the hyperactivity of the duo-denal and proximal jejunal muscle to direct intraluminal acetylcholine. Anincreased contractile response to various doses was noted by Menezes andOliveira38 in the duodenum of Chagasic rats. Later, Zanotto and Okumura39observed hyperexcitability to acetylcholine and bradykinin in the isolatedileum of chronically Chagasic mice. The reaction to bradykinin suggeststhat hyperexcitability of isolated muscle may be independent of the mechan-ism of neurotransmission.

Previous references to ultrastructural changes in surviving neurones ledTafuri and Maria25 to suggest disturbances of the mechanism of neuro-secretion and synaptic transmission as the basis of the motor incoordinationin the small intestine. They explain the increase in size and number of thedense vesicles as an accumulation of neurotransmitter substance as part ofa compensatory hypersecretion in response to denervation. In normalindividuals, the neurosecretory component of peripheral neurones has beendescribed as electron microscopic-dense granules contained in special types

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of large and small vesicles. These granules contain neurotransmitter sub-stances such as noradrenaline, 5-hydroxytryptamine (5-HT), and monoamines.According to Gershon's hypothesis,40 5-HT in particular acts as a neurotrans-mitter between the net formed by sensory and motor neurones, and hasan important role in the intrinsic peristaltic reflex of the intestine. Accordingto Tafuri and Maria,25 the surviving neurones of Chagasic patients are eitherunable to liberate the excess of neurotransmitter substances accumulated orthese substances would probably only reach damaged nerve terminals.

Disturbances of Absorption

Alterations in the mechanisms of absorption in the Chagasic intestine haveonly recently become the subject of investigation.One of the first observations was made by Reis,41,42 by Reis et al,43 and

by Campos and Can9ado,44 who noted abnormal blood glucose levels aftera glucose tolerance test. The curves showed an abnormally high peak 30minutes after ingestion, and returned to fasting levels only after 120 to 180minutes. While not denying the possibility of acute hyperabsorption ofglucose, Reis attempted to explain this type of glucose tolerance as due topancreatic hypersecretion of glucagon and a consequent rise in hepaticglycogenolysis. The hyperglycaemic response of Chagasic patients to smallintravenous doses of glucagon led Reis and Vichi45 to believe that the liverof these patients was hypersensitive to glucagon.The first suggestions of a change in absorption functions in Chagas

disease arose from the work of Vieira and Meneghelli,46 who attempted tolink an abnormal glucose tolerance test with plasma turbidimetry afteringestion of fat. In this study, carried out in a group of 30 patients, theauthors noted a deficit in fat absorption from the low plasma turbidimetrycurves in 27.3 % of Chagasic patients with a raised glucose tolerance test.For these authors these two observations occurring together constitute aparadoxical syndrome, ie, hyperabsorption of glucose and malabsorption offat. Later Meneghelli and Reis47 showed that a similar effect holds for oralgalactose tests. Eight out of 15 patients showed higher galactosaemia thannormal individuals, and there was a close correlation between the raisedgalactosaemia and the increased level of blood glucose by the glucosetolerance test. Meneghelli et a148 also pointed out that the glucose tolerancetest was normal for parenteral glucose in these patients, independently ofthe type of test after oral loading, strongly supporting the hypothesis thataccelerated absorption is the explanation for the raised glucose tolerance.The most recent contributions to the study of absorption in Chagas

disease can be found in the work of Meneghelli14 and Meneghelli et al.49'50In 22 of 40 patients examined the blood glucose was above normal limits30 minutes after loading, and in some cases three times the fasting level. Inthree cases where the glycaemia reached extremely high levels it later droppedbelow normal, even less than 50 mg. This sudden drop is explained by anincrease in insulin secretion in response to the initial abnormal hyper-glycaemia.The abnormal acute hyperglycaemia in oral tolerance tests could be

explained by gastric dysrhythmia, the gastric contents being passed to theduodenum more rapidly than normally. However, Meneghelli carried out adirect continuous perfusion of a segment of the small intestine of Chagasic



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patients, using the technique of Fordtran et al,5' and measured absorption ofglucose at four different rates of infusion, namely, 0.5, 0.25, 0 1, and 0.05g/minute. The results showed that patients with raised blood glucose levelshave a greater capacity to absorb glucose than people used as controls.When the rate of infusion was more than 0.25 g/min, the rate of absorptionby Chagasic patients was proportional to the excess of glucose administered,suggesting that facilitated diffusion rather than an active transport mechan-ism was responsible for the raised absorption. Indirect support for thisconclusion comes from the results of oral xylose tolerance tests in whichdoses of 25 and 50 g were used. Chagasic patients showed a raised xylosaemiaat 30 minutes.50

In contrast to the carbohydrate absorption tests, patients with abnormalglucose tolerance tests showed low fat absorption, as measured by a bloodradioactivity count after an oral dose of '31I labelled oleic acid (Meneghelli'4).The faecal excretion of fat was normal, though Meneghelli combined thesedata in the suggestion that the velocity of fat absorption is reduced in Chagasdisease, without affecting the total fat uptake. More data are required toclarify the disturbed absorption of carbohydrate and fat in Chagas disease,paradoxically raised for carbohydrate and reduced for fat, which comprisewhat Meneghelli has termed 'Chagas enteropathy'.

Meneghelli14 and Meneghelli et a!49 believe that the functional disturbancesof absorption, already mentioned, are specifically connected with para-sympathetic denervation. This is supported by the swift increases in glycaemiclevels in vagotomy and atropinization reported respectively by Horneet a152 in rabbits and also by Hasting-James53 in vagotomy in map. A numberof authors have also reported defective fat absorption in surgical or pharma-cological vagotomy (Inglefinger et a154; Fox and Grimson55; Tucker eta156; and Butler and Eastham57), in connexion with intestinal absorption.The experimental work of Anastas'eva and Skliarov,58 quoted by Mene-ghelli,'4 merits a special mention: they studied the absorption of fat inThiry loops whose intramural nervous plexuses had been destroyed, andconcluded that this destruction disorganizes the absorption mechanisms.

Conclusions

The facts reported here open up a way for interesting speculations on theneurophysiological interrelations with the absorption mechanisms due toChagasic denervation. Research in this area involves a complex methodologynecessary to inquire particularly into the myogenic regulation, the propagationof the basic electrical rhythm, and how the rhythmic alterations in length andtension along the smooth intestinal musculature occur. Moreover, it wouldbe interesting to ascertain the behaviour of the duodenal pacemaker in theChagasic intestine, as well as the 'spike' pattern discharges which occur

during depolarization of the membrane, either spontaneously or under theinfluence of acetylcholine or epinephrine. Secondly, the basic electricalrhythm should be studied as well as the rhythmic function of the metabolicactivity of the intestinal mucosa during the absorption phases. Accordingto Prosser and Bortoff,59 various biochemical processes may be held respon-sible for oscillatory alterations in the ionic conductances which appear in thepacemaker's potentials. The interrelation between metabolism and electricalrhythm, according to these authors, is suggested by: the increase of rhythmic

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frequency which is related to temperature; metabolic inhibitors, such asdinitrophenol, which inhibit the activity of the slow waves of the smallintestine, probably by decreasing the quantity of available energy for themembrane oscillator; hypoxia, cyanides, and azide also decrease rhythmicfrequency; adrenaline which may allow some activation after the admini-stration of metabolic inhibitors.

It should be remembered that Rougerau and Thouvenot00'61 and Thouvenotand Rougerau62,63 reported that the metabolic factor connected with absorp-tion may cause momentary alterations in the rhythmic electrical activityof the small intestine. They noticed that galactose, ribose, manose, glucose,or glycerine, when put inside jejunal or duodenal loops in rats, causeda prompt decrease in the amplitude of the basic electrical rhythm, followed bya continuous discharge of the 'spike' type potentials. The basic electricalrhythm remained unaltered when the absorption of glucose was blocked byfluorizine and also during the passive absorption of xylose and saccharose.Thus, electrical activity of the intestine seems to be affected by the metabolicalterations which occur during active absorption.The recent works by Levin et al,64 performed in the everted mucosa of the

jejunum of human foetuses, confirmed the findings mentioned above andshowed that the addition of certain hexoses and amino acids to the fluidthat bathes the mucosa during absorption causedan increase intheendogenousintramural potentials.

Applying these known facts to the phenomena which occur in Chagasicenteropathy, one could search for better explanations for the correlationsbetween electrogenesis and intestinal absorption, particularly in the case ofthe hyperabsorption of glucose as reported by Meneghelli.'4 In this instance,the neuronal injuries caused by Chagas disease in the small intestine sketcha neurophysiological 'pattern' which might be a starting point for stimulatingresearch in the area of enterophysiology. Investigations performed alongthis line might shed some light on the influence of denervations on thedisturbance of absorption as well as on the consequences of alterations inabsorption over electromyogenesis.

J. V. MARTINS CAMPOS AND W. L. TAFURI

Brazilian Institute of Studies and Research in Gastroenterology, Sao Paulo,Brazil, and the Department of Pathology, Minas Gerais Federal UniversityMedical School, Belo Horizonte, Brazil.

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