childhood ménétriér’s disease: a rare cause of exudative enteral...

Childhood Ménétriér’s disease:A rare cause of exudative

enteral protein lossMARK R OLIVER MBBS, CYNTHIA TREVENEN MD, R BRENT SCOTT MDCM

MÉNÉTRIÉR’S DISEASE IS A RARE

cause of gut-related protein lossin childhood. It was first described byMénétriér in 1888 (1), and since its ini-tial description there have been only47 pediatric cases reported (2). Thedisorder is characterized by an en-largement of gastric rugal folds andcharacteristic histological changes infull thickness biopsy specimens, and is

often associated with hypochlorhydria,hypoproteinemia and edema (2-10).Compared with the adult form of Mé-nétriér’s disease, which follows achronic pattern often requiring activetreatment, the childhood form is usu-ally self-limited. Although the etiologyof childhood Ménétriér’s disease isunclear, mainly allergic phenomenaand infection have been implicated in

the pathogenesis. Epidemiological evi-dence mainly supports cytomegalovirus(CMV), but other microorganisms in-cluding Helicobacter pylori and Myco-

plasma pneumoniae have been impli-cated (11-17). This report describes ayoung child with Ménétriér’s diseaseand provides additional evidence for anassociation between this disorder andCMV infection in childhood.

CASE PRESENTATIONA six-year-old Canadian Aboriginal

presented to Alberta Children’s Hospi-tal following a two-week illness charac-terized by colicky upper abdominalpain, increasing edema, intermittentnonbilious vomiting and self-limitingnonbloody diarrhea. There were nosymptoms to suggest an underlying car-diac, renal, hepatic or lymphatic disor-der that might have explained theedema. In addition, there was a nega-tive history for atopy and immuno-suppressive disorders. Examinationshowed him to be a well nourishedchild with mild pharyngitis and nolymphadenopathy. He had impressiveperiorbital edema, and pitting edema ofhis legs up to the knees, small bilateralpleural effusions and abdominal disten-sion with ascites. He also complainedof epigastric tenderness on deep palpa-tion. Rectal examination was normal.

Laboratory findings on admission tohospital showed hyponatremia (serumsodium 127 mmol/L), hypokalemia (se-

BRIEF COMMUNICATION

MR OLIVER, C TREVENEN, RB SCOTT. Childhood Ménétriér’s disease: Arare cause of exudative enteral protein loss. Can J Gastroenterol 1995;9(5):281-284. A six-year-old boy with Ménétriér’s disease, which developed in asso-ciation with an intercurrent cytomegalovirus (CMV) infection, is presented. Thiscase illustrates the clinical features, natural history and self-limited nature of thisrare cause of exudative protein loss in childhood and provides evidence for the as-sociation between CMV infection and the pathogenesis of this disorder.

Key Words: Cytomegalovirus, Exudative gastropathy, Hypoproteinemia

Maladie de Ménétrier chez l’enfant : Cause rare d’éliminationentérique exsudative des protéines

RÉSUMÉ : Le cas d’un garçonnet de six ans atteint d’une maladie de Ménétrierassociée à une infection à cytomégalovirus (CMV) est présenté ici. Ce cas illustreles caractéristiques cliniques, le décours naturel et la résolution spontanée decette rare cause d’élimination exsudative des protéines chez l’enfant, et décrit lesliens que l’on peut établir entre l’infection à CMV et la pathogenèse de la maladiede Ménétrier.

Departments of Pathology and Pediatrics, Alberta Children’s Hospital and University ofCalgary, Calgary, Alberta

Correspondence and reprints: Dr R Brent Scott, Department of Pediatrics, Health ScienceCentre, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1

Received for publication July 12, 1994. Accepted January 9, 1995

CAN J GASTROENTEROL VOL 9 NO 5 JULY/AUGUST 1995 281

rum potassium 2.8 mmol/L) and hypo-chloremia (serum chloride 94mmol/L). Serum albumin was 14 g/L(normal range 30 to 50 g/L) and totalprotein 26 g/L (normal range 55 to 75g/L) with normal hepatocellular en-zymes. Urine analysis was consistentlynegative for both protein and blood. Acomplete blood count demonstratednormal hemoglobin, white blood celland platelet counts. The differentialshowed no lymphopenia, but periph-eral eosinophilia with an absolutecount of 1.2x109/L (normal range 0.1to 0.7x109). Immunoglobulin G levelswere low at 3.16 g/L (normal range 6.33to 12.8 g/L), but other immunoglobulinlevels were normal. Plain x-rays of hisabdomen and chest, and an abdominalultrasound demonstrated bilateralpleural effusions and ascitic fluid with-out other significant abnormalities.

Stool cultures were positive for thetrophozoites of Entamoeba histolytica

and Entamoeba nana without any pus orred blood cells. A fluoroscopy guidedduodenal aspirate and small bowel bi-opsy performed using a Carey capsule(Precise Products Corporation, Minne-sota) excluded Giardia lamblia enteritisand bacterial overgrowth and demon-

strated normal duodenal histology. A72 h fecal �-1 antitrypsin clearance wasincreased well above the normal rangeat 0.278 g/day (normal less than 0.06 g/day), suggesting a protein losing en-teropathy. A limited colonoscopyshowed mild confluent inflammationof the distal colon that was histologi-cally confirmed as a mild acute nonspe-cific colitis. He was treated withmetronidazole for seven days and indo-quinolol for 21 days.

Despite rapid resolution of the vom-iting and diarrhea, the patient re-mained hypoproteinemic with ongoingepigastric pain. A barium upper gastro-intestinal series demonstrated diffusethickening of the gastric folds with freeflow of barium into the structurallynormal small intestine (Figure 1). Anesophagogastroduodenoscopy con-firmed marked thickening of the rugalfolds in the body of the stomach withsparing of the antrum. The thickenedfolds appeared gelatinous and hemor-rhagic. The esophagus and duodenumhad a normal macroscopic appearancethat was confirmed histologically. Bi-opsies of gastric tissue were sent for cul-ture of H pylori and for viral isolation.Superficial gastric biopsies from the

fundus demonstrated chronic gastritiswith conserved foveolar epitheliumand nonatrophic glands. The laminapropria was expanded by an inflamma-tory infiltrate including eosinophils(Figure 2). There was no evidence of H

pylori-like organisms or viral inclusionbodies on light microscopy of gastricfundal or antral biopsies.

Cultures of gastric tissue were nega-tive for H pylori. However, both fundalbiopsy specimens and urine were subse-quently shown to be positive for CMV

by an early antigen method that de-pends on a fluorescein-labelled mono-clonal antibody that is specific for CMV

and recognizes the immediate earlyprotein of CMV (18). Serology done atsix and 12 weeks was positive for com-plement fixing CMV antibodies. Immu-nohistochemical studies conducted onboth gastric and rectal tissues werenegative. Within two and a halfmonths of the onset of symptoms, andwithout additional therapy, the patientrecovered both clinically and bio-chemically. A follow-up eso-phagogastroduodenoscopy performedthree months after presentationshowed both macroscopic and micro-scopic resolution of the gastric disease.Repeat evaluation of gastric biopsies

Figure 2) Gastric mucosa focally infiltrated by lymphocytes, plasma cellsand eosinophils (original magnification x118)

Figure 1) Left Barium meal demonstrating hypertrophic gastric folds

282 CAN J GASTROENTEROL VOL 9 NO 5 JULY/AUGUST 1995

OLIVER et al

for CMV by the early antigen methodwere negative. Similarly, a repeat lim-ited colonoscopy showed macroscopicresolution of distal colonic changeswith only mild residual microscopic co-litis. Stool cultures were now negativefor Entamoeba histolytica. Eighteenmonths following initial presentationhe remains completely well.

DISCUSSIONThe diagnosis of Ménétriér’s disease

was based on the presence of gianthypertrophy of gastric folds seen bothradiologically and at endoscopy, hy-poalbuminemia with associated enteralprotein loss and a histological gastritisthat is often associated with hypo-chlorhydria. As has been previously re-ported in children with Ménétriér’sdisease, this patient’s clinical coursewas self-limited and benign (2-8,10-13). Although the microscopic appear-ance of his fundal biopsy was not classi-cal of this disorder (there was noevidence of foveolar hyperplasia andatrophied glands), there was tissue eosi-nophilia and edema which is seen his-tologically in this disease. Thisvariation may have been secondary toeither sampling error or the superficialnature of the biopsies (2,9). Or it couldbe that, as in adults, the clinical fea-tures of childhood Ménétriér’s diseasecan be divided into at least two distincthistopathological entities, one repre-senting massive foveolar hyperplasiaand the other hypertrophic lympho-cytic gastritis (19).

It is interesting to note that our pa-tient also presented with diarrhea andmild colitis, and excreted E histolytica

trophozoites in his stools. While it ispossible that amoebic colitis may havecontributed to the enteric protein loss,

severe hypoproteinemia is not reportedas a presenting factor of this infection(20,21). The marked hypoproteinemiain this patient persisted after the treat-ment of amoebiasis and after resolutionof the diarrhea. In addition, the colitiswas macroscopically and histologicallymild. It is likely that the massivegut-related protein loss observed in thispatient was secondary to Ménétriér’sdisease, which is associated not onlywith widening of the gastric mucosaltight junctions (10,22) but also withhypochlorhydria. The latter results insignificantly less degradation of �-1antitrypsin activity and hence measur-able gastric clearance in this disease.

At least four possible factors cancontribute to an increased gastric mu-cosal mass, in health or in response todisease: intraluminal substances such asnutrients or growth factors from themore proximal gut; trophic factors pro-duced locally or by infectious agents;neural stimulation; and immunologicalphenomena secondary to an autoim-mune process or allergy (9). It is likelythat in Ménétriér’s disease the irritat-ing agent initiates a significant inflam-matory reaction (as shown by the pres-ence of gastritis) which then directly orindirectly causes the observed hyper-trophic changes through the action ofunidentified mediators. It has recentlybeen shown that transforming growthfactor-�, an epithelial cell mitogenthat inhibits gastric acid secretionand increases mucin production, maybe involved in the pathogenesis of thisdisorder (23,24).

The strongest evidence for an etio-logical factor in the pediatric popula-tion is for CMV infection (2-13),although it is difficult to prove such acausative role because of the ubiquitous

nature of this organism. The viruscould be directly toxic to the gastricmucosa and allow increased macro-molecular uptake that, in turn, initiatesan allergic response with the typical pe-ripheral eosinophilia observed in thisdisease. Infection might also suppressspecific regulatory T cell subsets and al-low an allergic type of response to bemanifested (7), or stimulate a local in-flammatory response with the release ofmediators, eg, tumour necrosis factor-�,that provoke a hypertrophic responselasting only as long as the infection isactive (2). Of the 47 pediatric patientspreviously reported as having Mé-nétriér’s disease, only 27 were investi-gated for CMV infection (2). Nine ofthese patients (33%) had evidence ofgastric CMV infection by characteristicintranuclear inclusions, early antigenand/or positive gastric CMV culture.However, only two previously reportedcases had evidence of current CMV in-fection on the basis of viral culture(urine and gastric tissue) and serology(2). In our case, there is not only sup-portive evidence of current CMV infec-tion (fundal biopsy and urine positivefor CMV early antigen), but also a clini-cal, endoscopic and histological resolu-tion of Ménétriér’s disease that wastemporally related to clearance of in-fection. This suggests that CMV had arole in the pathogenesis of the disorderin our patient. A direct causal relation-ship between gastric CMV infection andMénétriér’s disease in childhood willrequire a thorough examination forCMV in subsequent patients with thisdisorder, and further study of both hostdefence mechanisms and the mannerin which they can be altered in CMV in-fection.

ACKNOWLEDGEMENTS: The authorsthank Roberta Funk for typing the manu-script. Mark Oliver is a recipient of an Al-berta Children’s Hospital FoundationFellowship.

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and review of the literature.Br J Radiol 1986;59:615-20.

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16. Bayerdorffer E, Ritter MM, Hatz R,Brooks W, Stolte M. Ménétriér’sdisease and Helicobacter pylori. N Engl JMed 1993;329:60. (Lett)

17. Lepore MJ, Smith FB, Bonanno CA.Campylobacter-like organisms inpatient with Ménétriér’s disease.Lancet 1988;1:466.

18. Gleaves CA, Lee CF, Kirsch L, MeyersJD. Evaluation of a direct fluorescein-conjugated monoclonal antibody fordetection of cytomegalovirus incentrifugation culture. J Clin Microbiol1987;25:1548-50.

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NJ. Ménétriér’s disease: A form ofhypertrophic gastropathy or gastritis.Gastroenterology 1993;104:1310-9.

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21. Patterson M, Schoppe L. Thepresentation of amoebiasis. Med ClinNorth Am 1982;66:689-704.

22. Kelly D, Miller L, Malagelada K,Huizenga K, Markowitz H. Gianthypertrophic gastropathy (Ménétriér’sdisease): pharmacological effect onprotein leakage and mucosalultrastructure. Gastroenterology1982;83:581-9.

23. Dempsey PJ, Goldering JR, Soroka CJ,et al. Possible role of transforminggrowth factor � in the pathogenesis ofMénétrier’s disease: supportiveevidence from humans and transgenicmice. Gastroenterology1992;103:1950-63.

24. Van den Berg M, Stokkers P, RingE, Buller H. Transforming growthfactor � in Ménétrier’s disease.J Pediatr Gastroenterol Nutr1993;17:230-2.

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