Surgical Management of Menetrier's DiseaseWith Protein-losing Gastropathy

H. WILLIAM SCOTT, JR.,

Three patients with Menetrier's disease and protein-losing gas-tropathy who were studied during a 12 year period have beenpresented. The characteristic findings which differentiate themfrom patients with hypertrophic hypersecretory gastropathy, in-cluding the Zollinger-Ellison syndrome, are: 1) hypertrophy ofgastric mucosa with giant rugal folds involving the fundus, cardiaand body of the stomach but sparing the antrum; 2) muscosalhypertrophy consisting of gastric mucus-secreting cells whileparietal cells and chief cells are diminished in number and may beabsent from many microscopic sections; 3) gastric secretion oflarge volume containing excess mucus, low to absent hydrochloricacid and protein concentration 5 or 6 times normal (1.7 mg/ml); 4)hypoalbuminemia and hypoglobulinemia due to loss of serum pro-teins from gastric mucosa into the gastric lumen; 5) rare associa-tion with gastric ulcer. Unlike the Zollinger-Ellison syndrome noneof our patients had duodenal ulcer or multiple endocrineadenomatosis or a family history of these conditions. We havefound no authenticated reports in the literature which document arelationship ofMenetrier's disease (as defined above) with multipleendocrine adenomatosis. Menetrier's disease with protein-losinggastropathy is a potentially lethal disorder of unknown cause withno specific treatment. Resection of the site of gastric protein lossesas first done by Waugh' is logical and effective. One of our threepatients died in hospital before gastrectomy was done. Two othershave done well for 11 months and 12 years, respectively, aftertotal gastrectomy with Roux-en-Y esophagojejunostomy andHunt-Lawrence jejunal pouch.

THE ETIOLOGY of giant hypertrophy of the mucosalfolds of the stomach, which is sometimes associated

with severe protein losses and hypoproteinemia, is under-stood no better today than when described by Menetrier"in 1888. In Menetrier's lucid article he pointed out thatadenomatous transformation of the gastric glands couldpresent in two distinct forms: first, as circumscribedpolyps of the stomach to which, when multiple, he appliedthe term polyadenomes polypeux; second, adenomatoustransformation could present in the form of hypertrophiedplaques of mucosa either limited or diffuse to which heapplied the term polyadenomes en nappe.

M.D., HARRISON J. SHULL, M.D., DAVID H. LAW, IV, M.D.,HENRY BURKO, M.D., DAVID L. PAGE, M.D.

From the Departments of Surgery, Medicine, Radiology andPathology, Vanderbilt University Medical Center,

Nashville, Tennessee 37232

Today the eponymous term, Menetrier's disease, isusually applied to giant hypertrophy of the mucosal foldsof the stomach which may or may not be associated withloss of protein from the mucosa. 10 In Menetrier's diseasethe mucosal hypertrophy involves the fundus and body ofthe stomach and excludes the antrum. The gross appear-ance ofthe thickened gastric rugae resembles the convolu-tions of the brain. This disease must be distinguished fromthe mucosal hypertrophy of the Zollinger-Ellison syn-drome and from the form of hypertrophic gastritis towhich Schindler17 gave the name hypertrophic glandulargastritis and which Stempien22 classified as hypertrophichypersecretory gastritis. In addition, gastric lymphomaand carcinoma must be excluded in differential diagnosis.On a clinical basis, the differential diagnosis of Mene-trier's disease may be quite difficult. This remarkabledisease is said to have an increased incidence in somefamilies with multiple endocrine adenomatosis9'18'23 butunlike the Zollinger-Ellison syndrome it is uncommonlyassociated with peptic ulcer.3'12'15 The exudative gastricprotein losses which may occur can cause life-threateningprofound hypoproteinemia despite large increases in al-bumin synthesis and turnover rate.4'19During the last 12 years, three patients with this combi-

nation of Menetrier's hypertrophic gastropathy and se-vere protein-losing syndrome have been identified,studied and treated at Vanderbilt University MedicalCenter. Experience with these patients has promptedthis report.

Case ReportsN.B., a 36-year-old Caucasian tile plant foreman, was admitted to the

Vanderbilt University Hospital for the first time in January, 1962 com-plaining of generalized edema.Present illness. Two weeks prior to admission the patient developed a

cold with myalgia, weakness and non-productive cough and received

765

Presented at the Annual Meeting of the Southen Surgical Association,December 9-1 1, Boca Raton, Florida.

mcg%; bromsulphthalein retention was 10%o when the patient had se-vere edema with a serum glutamic oxaloacetic transaminase of 52karmen units. D-xylose tolerance test was normal. Stool examinationswere negative for blood, fat, ova and parasites.The most striking laboratory abnormality was a total serum protein of

3.0 gm% with 1.8 gm% albumin. On multiple repeated determinations,albumin values ranged from 1.5 to 2.1 gm%. The serum protein elec-trophoretic pattern is shown in Fig. 1. Fasting gastric analysis showedfree acid 12 degrees, total acid 27 degrees.

Electrocardiogram was normal as were x-ray examinations of theabdomen and colon. X-ray study of the chest showed a small loculatedeffusion in the right posterior pleural space. Upper gastro-intestinalx-ray series is shown in Fig. 2. Large folds of gastric mucosa were seenthroughout the body and fundus of the stomach. These were mostprominent along the greater curvature. Gastric flexibility and peristalsiswere normal. Small bowel mucosa appeared slightly thickened but wasotherwise normal. The radiologic impression was hypertrophic gas-tritis.Gastroscopy showed "enlarged and bulbous folds" as well as

"numerous 0.5 to 1 cm rounded papillomata throughout the lower bodyand angular areas of the stomach." Small ulcerated areas were seen onthe tips of the papiliomata. The flexibility and distention of the stomachagain appeared normal. Per oral small bowel biopsy revealed normaljejunum with slender villi and normal stroma.The patient was treated with a low salt, high protein diet and lost 29

pounds in 3 weeks. However, he continued to be nauseated, vomitedintermittently and remained edematous.Using standard isotope dilution techniques the patient's turn-

over rates, biological half-life and albumin pools were calculated after

766

13

Fio. 1. Cse1 (NB.) Seu protein elecrpoeic patr ro toE

operation Toa seu protei wa 3. gm% seu alui was1.

E 2WESgE 2~~~~Z M.orl meiato and int,ramu 1.scular penicillinand"-s>ttr|e ..ptomycin. The.

toGhis lCalhspitalN.B. Aferusevraltdayetofpaorenteafidsvomerpitingoght g H to iita

Frthermeviaation and inramu lr pecilnadsreptomycin. Th

Prast heisatiorincuehafvrandwhrmuclaeezilingeach falltomsince child

following day he complained of nausea and vomiting and was admittedto his local hospital. After several days of parenteral fluids, vomitingsubsided but diarrhea continued and he noted facial and cervical edemaprogressing to involve hi agsn and feet. There was a 15 poundweight gain. He was then referred to Vanderbilt University Hospital forfurther evaluation.

Past history included hay fever and wheezing each fall since child-hood. The patient had complained of intermittent vague periumbilicaldiscomfort for 9 or 10 years. This occasionally awakened him at nightand was usually relieved by milk. System review was otherwise nega-tive.

The family history was non-contributory.Physical examination revealed a well-developed, well nourished,

grossly edematous Caucasian man with normal vital signs. Temperaturewas 98.6, blood pressure 120/80, pulse 76, respirations 20. There was nogeneralized lymphadenopathy. Heart and lungs were normal. The ab-domen was distended with a prominent fluid wave and no organs werepalpable. There was 4+ pitting edema of the legs, the feet and the lowerhalf of the trunk.

Initial laboratory studies showed normal urinalysis with no protein innumerous specimens. White blood count ranged from 9,400 to 14,750with normal differential. Packed cell volume, icteric index, erythrocytesedimentation rate and platelet counts were normal. Sedim C02 was 34mEq/l, chloride 88 mEq/l, sodium 130 mEq/l, potassium 4.6 mEq/l.These values returned rapidly to normal after hospitalization. Serumurea nitrogen, phosphorus, alkaline phosphatase, cephalin flocculation,thymol turbidity, uric acid, bilirubin, glucose, cholesterol, serologicaltest for syphilis and anti-streptolysin-o titer were all normal. Prothrom-bin time was 87%o normal. Serum protein bound iodine measured 3.8

FIG. 2. Case 1 (N.B.) Upper gastrointestinal x-ray series before opera-tion.

SCOTT AND OTHERS Ann. Surg. * May 1975

Ann. Surg.- May 1975 MENETRIER'S DISEASE 767(Dianabol) as well as anticholinergic drugs and a phenothiazine tocontrol nausea.However, he returned to the hospital just three days after discharge

complaining of uncontrollable nausea and vomiting.Physical examination and laboratory data were as before with a

following additional information: normal serum fibrinogen and urinaryexcretion of 0.16 grams protein per 24 hours. Two 12-hour overnightgastric secretion studies showed no free acid with large volumes ofjuice, 687 to 1644 cc's and total acid of 257 degrees in 1644 cc's. Gastricjuice nitrogen content was 150 mg/100 ml (normal=52 mg/100 ml).

The patient was troubled by intermittent vomiting and diarrhea andcontinued to be edematous. A trial of gastric hypothermia was at-tempted while the patient was undergoing albumin turnover studies buthe did not tolerate the procedure over a 10 hour period at 45° Fahr-enheit outflow temperature.Because of continued weight loss, anorexia, vomiting and persistent

massive edema, nine units of albumin were administered intravenouslyin preparation for operation.At laparotomy the most striking finding was the appearance of the

stomach which was very thick walled with multiple areas of contractionand patterning which reflected the tremendous thickening of the gastricmucosa. Areas of plaque-like induration extended from the lesser cur-vature into the body of the stomach and thickening of the wall of thestomach extended from the cardia to the distal three inches of theorgan. At this point there seemed to be a rather sharp line of demarca-

: 62-5qa A tion between the greater thickened proximal stomach and the morenormal feeling and appearing antral segment. The antrum, however,

FIG. 3. Case 1 (N.B.) Photograph of resected stomach.

administration of 1311 labeled albumin.4.'1 Total exchangeable albuminpool was 151.5 gms with a turnover rate of 16.5% and a daily degrada-tion rate of 25 gms of albumin per day. The half-life of injected 1311albumin was 4.2 days. Normal is 14-23 days..iThe patient was discharged under treatment with an anabolic steroid

FIG. 5. Case 1 (N.B.) Patient 10years after total gastrectomy;I~weight 140 pounds.

I~~IEf lwwlX'b~~~~~~~~~~~~~~~~~~~~~~~~<.. ..... ......... l

FIG. 4. Case 1 (N.B.) Serum protein electrophoretic pattern 10 yearsafter total gastrectomy. Total serum protein was 7.5 gm%; serum albu-mmm was 4.4 gm%.

SCOTT AND OTHERS768%, packed cell volume 43%, MCHC 31.8. total serum Drotein 7.5grams%, serum vitamin A 67 Ag%, vitamin C 1.5 mg%, vitamin E 0.8mge, vitamin B12 355 ,u,gms/ml, serum folate 12.4 ng/ml, serum albu-min 4.4 gms%.

L.D., a 26-year-old Negro woman was admitted to Vanderbilt Uni-versity Hospital in March, 1962 complaining of nausea, vomiting,diarrhea and abdominal pain.

Present Illness. Four weeks prior to admission the patient noted"indigestion" at first relieved by antacids but progressing to constantburning, epigastric pain and vomiting. These symptoms persisted andone week later she developed diarrhea and ankle edema and was hos-pitalized elsewhere for one week. Continuous vomiting and milddiarrhea (two to three blood-free, loose watery stools per day) persistedand the patient was transferred to a second hospital (Hubbard).

Physical examination on admission to the Hubbard Hospital showedher to be a thin young woman who weighed 106 pounds with a slightlypuffy appearance and edematous extremities. The only positive physi-cal finding was presence of a 2 cm firm thickening in the left lobe of thethyroid and pitting pretibial edema. Pertinent laboratory data showedthe hemoglobin to be 16.5 gms% with a packed cell volume of 46%.Total serum protein was 3.8 gms% with an albumin of 1.7 gms% andglobulin of 2.1 gms%. X-ray studies of the upper gastrointestinal tractshowed a marked irregularity of the contour and mucosal pattern in theentire stomach with giant hypertrophy of the gastric rugae extendingfrom the cardia and fundus down to the incisura angularis. The walls of

FIG. 6A. Case 1 (N.B.) Recent barium study of esophagus and Hunt-Lawrence jejunal pouch; esophagojejunal junction lies above dia-phragm.

showed slight thickening and one could palpate individual folds ofcoarsened mucosa. There was no gross mass in the stomach to suggesta localized tumor. The nodes in the gastric mesentery were not en-larged. The spleen, however, was about twice normal size. On carefulexploration, pancreas, duodenum, small and large bowel were normal.Because of the extensive involvement of the entire stomach in thisprocess it was elected to perform a total gastrectomy with constructionof a Hunt-Lawrence jejunal food pouch.20The patient tolerated the procedure well and made an uneventful

recovery. Figure 4 shows postoperative serum protein electrophoreticpattern before discharge from the hospital. Postoperative albumin 1311half-life was 10.8 days. The patient tolerated postgastrectomy diet eas-ily and well and was discharged on the eighteenth postoperative day.

Pathologic examination of the removed stomach was initially diag-nosed hypertrophic gastritis. Figure 3 shows a photograph of the grossspecimen. The gross and microscopic findings will be discussed in thetext.

In the twelve years since the total gastrectomy the patient has had nofurther edema, has maintained a weight of 140 to 145 pounds and hasreturned to full time employment. His albumin turnover studies haveremained normal and his only dietary limitations are avoidance of fluidswith meals and avoidance of milk. Fig. 5 shows a recent postoperativephotograph of the patient and Fig. 6 shows a recent barium study of theesophagus and the jejunal pouch.

During this twelve year period the patient's nutrition has been satis-factory. He has been maintained on vitamin B12, 500 micrograms IM.,every 6 weeks. Recent blood studies showed his hemoglobin 13.8 grams

FIG. 6B. Closer view of siteof esophagojejunal junc-tion.

Ann. Surg. * May 1975

MENETRIER'S DISEASE

4g 0 2 3S1 11 12i13

FIG. 7. Case 2 (L.D.) Serum electrophoretic patteion admission tohospital (V.U.H.). Total serum protein (after treatment started) was 4.7gm%; albumin was 2.8 gm%.

the stomachwet e flexible throug though peristaltic activity wassomewhat diminished. The roentgenologist suspected lymphomatousinvolvement of the stomach or extensive granulomata.On March 9, 1a2, exploratory laparotomy was performed by Dr.

Matthew Watlmer who found large, soft gastric mucosal folds in thestomach which could be readily palpated from the exterior. On gas-trotomy the mucosa in the antral region seemed to be normal, while themucosa of the body and fundus showed extensive hypertrophy withgiant rugae extending from the cardia into the stomach down to theantrum. A small segment of the gastric wall was removed for biopsy anda feeding jejunostomy was established.The patient made a satisfactory recovery from operation and was

started on high protein jejunostomy feedings in the early postoperativeperiod. Gastric analysis during this time showed no free acidity with atotal acidity of 6.3 degrees. The gastric juice contained 1.4 grams ofprotein per 100 ml. Despite the high protein jejunostomy feedings,h'ypoproteinemia and hypoalbuminemia persisted and she was transfer-red to Vanderbilt University Hospital for further study. The patient hadlost approximately fifteen pounds during this illness.

Past history and family history were non-contributory.Physical examination on admission to Vanderbilt University Hospital

revealed a slender, asthenic Negro woman with normal vital signsexcept for a sinus tachycardia of 120 per minute. Significant findingsincluded a slightly enlarged left lobe of the thyroid and a well healedlaparotomy incision with ajejunostomy catheter in place. There was I +pitting edema of the pretibial area bilaterally.

Laboratory data included a normal urinalysis with no proteinuria.White blood count was 22,000 on admission and ranged from 16,200 to35,000 with a predominance of polymorphonuclear cells and a slightshift to the left with up to 12% band forms. Packed cell volume was 41%on admission but over a 4 day period fell to 23%. Erythrocyte sedimen-tation rate was 12 mm/hour.Serum urea nitrogen was 27 mg%, CO2 16.5 mEq/l, chloride 84 mEq/l,

sodium 124 mEq/l and potassium 3.8 mEq/l. These findings reverted tonormal with parenteral alimentation; however, she maintained an eleva-tion of serum urea nitrogen of 21 to 42 mg%o throughout her course.

Additional studies included alkaline phosphatase 5-9 Bodansky units,serum glutamic oxaloacetic transaminase 44-111 Karmen units andserum glutamic pyruvic transaminase 430-230 Karmen units. Totalserum protein was 4.7 grams% with 2.8 grams% albumin and 1.9grams% globulin. The serum protein electrophoretic pattern is seen inFig. 7. Serum cholesterol was 205 mge, bilirubin was 3 mge with 1.2mg%Y direct fraction. B.M.R. was +10%o. Protein bound iodine was 7oAg%.An electrocardiogram was interpreted as normal with a sinus

tachycardia. X-ray examination of the chest and abdomen were unre-markable on admission. Subsequent studies of the upper gastrointesti-nal tract with gastrographin showed large gastric mucosal folds and mildpartial obstruction in the region of the third portion of the duodenum.During her stay in the hospital repeated 24 hour gastric aspirations

revealed volumes of 2880, 2850, 1000 and 1855 ml with 3 to 5 degreesfree acid, 35 degrees to 60 degrees total acid and pH of 6.6 to 6.85. Totalgastric juice nitrogen was 140 mg/100 ml to 144 mg/100ml or 4.1 to 5.4gms/24 hours.131I labeled albumin studies were carried out to measurebiologic half-life and albumin turnover rate but counting errors disqual-ified the data.During hospitalization the vomiting continued and feedings were

attempted by mouth or by jejunostomy. A diagnosis of partial intestinalobstruction was made. Gastric suction and fluid replacement resulted inmoderate improvement. After hydration her packed cell volume fell toanemic levels (23%) with no evidence of blood loss. Two units of bloodwere given.Two days later while reoperation was under consideration, the pa-

tient suddenly went into ventricular fibrillation. Immediate externalcardiac massage and defibrillation were carried out but were unsuccess-

ful. Thoracotomy with massage and defibrillation was added but provedto be of no avail and the patient was pronounced dead. On the day ofdeath her serum electrolyte levels were within normal limits except fora potassium of 5.5 mEq/l and a CO. of 17 mEq/l.

Autopsy examination failed to show a satisfactory explanation for theimmediate cause of death. There was decreased turgor and dryness oftissues suggesting dehydration at the time of death. The thyroid showedno abnormality except for a 1 cm cyst in the left lobe. The heart showedno anatomic abnormality. The gastric mucosa showed markedhyperplasia and hypersecretion of the mucous neck cells with totalabsence of parietal and zymogenic cells in the body and fundus with a

quite severe, acute inflammatory reaction. The large folds did notinvolve the antrum (Fig. 8). The mucosa over the giant rugal folds was 5to 7 mm in thickness. There was no definite point of obstruction in the

FIG. 8A. Case 2 (L.D.) Photograph of stomach taken at autopsy. Thehypertrophied mucosal folds occupy body, cardia and fundus.

Vol. 181 * No. 5 769

AS

.... .:

ommw SW

.. ..,

SCOTT AND OTHERS

FIG. 8B. Closer view shows the small antrum is not involved.

duodenum, jejunum or any other portion of the gastrointestinal tract.

Gross and microscopic examination of the remaining organs showednormal findings. The pathologic diagnosis was Menetrier's disease with

protein-losing gastroenteropathy.

F.B., a 33-year-old Caucasian man, was admitted to the VanderbiltHospital in January, 1974 complaining of severe generalized abdominalpain of two hours duration.

Present Illness. The patient had had three previous admissions to theVanderbilt Hospital over the previous 2 years because of persistentepigastric burning pain of 6 years' duration with 3 episodes of upper

gastrointestinal bleeding. The pain was consistently described as burn-ing and crampy, made worse by prolonged periods of fasting or eatingspicy foods.At hls first admission in November, 1972, there were no unusual

findings on physical examination but laboratory studies showed him to

have total serum protein of 5 gms% with albumin of 3.2 gms%. Abu.ttery of additional laboratory studies were in the normal range andupper G.I. series showed giant gastric folds in the body and fundus ofthe stomach with the antrum appearing relatively normal. No ulcera-tions were identified. A diagnosis of Menetrier's disease was suggestedwith the differential diagnosis of lymphoma to be excluded. Gastro-scopic examination confirmed the presence of the giant rugal folds in thebody and fundus of the stomach while the antrum and pylorus appearedto be entirely normal. The first 15 cm of duodenum appeared, to beentirely normal. No definite site of ulceration or explanation for bleed-ing was identified. Biopsies of the hypertrophied mucosa were ob-tained. The patient was discharged on a bland diet but returned withrecurrent gastrointestinal bleeding episodes and was readmitted inMarch, 1973 with similar findings and then again in November, 1973with identical findings. On each of these occasions bleeding stoppedspontaneously and repeat upper G.I. and gastroscopic studies con-

firmed the presence of the giant gastric rugal folds but failed to de-monstrate a specific bleeding point (Fig. 9). At the third admission, fourunits of blood were transfused. At each of these admissions, the hypo-proteinemia and hypoalbuminemia were confirmed. Biopsies of the gas-

tric mucosa showed superficial acute and chronic inflammatory changesbut no specific diagnosis could be made. In the November, 1973 admis-sion, aortography was done with selective celiac and superior mesen-

teric arteriograms (Fig. 10). These studies confirmed the presence of thegiant hypertrophic gastric rugae with a large submucosal venous chan-nel underlying these but no varices or active bleeding sites were iden-tified. Gastric analysis showed no titratable acid in a 55 cc fastingspecimen with pH 7.08. There was a normal response in acid secretionto histamine (histalog) stimulation.

After the bleeding had stopped a 51 Cr labeled albumin study was

FIG. 9A. Case 3 (F.B.) Upper gastrointestinal x-ray series showinggiant rugal folds in body, cardia and fundus of stomach.

carried out which showed loss of 53% of the labeled albumin in 96 hours(normal loss should be less than 2%). After discharge from this thirdadmission the patient was maintained on a bland diet which he followedbut with persistence of epigastric burning pain. Two hours before hisfourth admission his epigastric pain became excruciatingly severe andgeneralized.

Physical examination in the Emergency Service at the VanderbiltUniversity Hospital showed him to be acutely ill with severe abdominal

_FIG. 9B. Closer view of upper G.I.

770 Ann. Surg. * May 1975

Vol. 181 * No. 5

FIG. 10. Case 3 (F.B.)Selective celiac arterio-gram. Hypertrophied gas-tric rugae are seen. No de-finite bleeding site wasidentified (left) in eitherarterial or (right) venousphases. Large submucosalveins are seen in venousphase.

MENETRIER'S DISEASE

pain. Temperature was 97.4, pulse 104, respirations 20, blood pressure120/60. Examination of the abdomen showed him to have diffusegeneralized tenderness to palpation with rigid abdominal musculature.Bowel sounds were absent. The remainder of the physical findings werenot remarkable. There was no ankle or pedal edema. A diagnosis ofMenetrier's disease with protein-losing gastropathy and perforated pep-tic ulcer was made.The patient was taken immediately to the operating room where this

diagnosis was confirmed. There was a 4 mm perforation of a gastriculcer located high on the lesser curvature about an inch below theesophagogastric junction. There was a large area of induration 2 to 3inches in diameter surrounding this perforation. The upper portion ofthe stomach was massively thick-walled with great thickening of themucosa involving the body and fundus. The antrum seemed to berelatively free of this process. There was no localized tumor mass in thestomach except for the area of induration surrounding the perforatedulcer. A biopsy of the gastric wall confirmed the diagnosis of Menetri-er's disease. Total gastric resection was then carried out and alimentaryreconstruction accomplished by Roux-en-Y esophagojejunostomy withconstruction of a Hunt-Lawrence jejunal pouch.20The patient withstood his procedure well. On the second day after

operation he was started on parenteral hyperalimentation. This was

771

maintained until the second postoperative week at which time he tookpostgastrectomy diet well. His wound healed per primam and he madean uncomplicated reovery. He was discharged on the twelfth postopera-tive day.

Pathologic examination of the removed stomach confirmed the diag-nosis of Menetrier's disease with the perforated gastric ulcer. The giantrugal folds in the formalin fixed specimen are shown in Fig. 11.The patient has been followed for 11 months during which time he has

FIG. 11. Case 3 (F.B.) Giant rugal folds in opened, formalin fixed FIG. 12. Case 3 (F.B.) Barium study of esophagojejunal anastomsis andspecimen resemble convolutions of the brain. Hunt-Lawrence jejunal poudh shortly after operation.

Ann. Surg. * May 1975SCOTT AND OTHERS

FIG. 13. Case 3 (F.B.) Photographof patient taken 11 months aftertotal gastrectomy with Roux-en-Yesophagojejunostomy and Hunt-Lawrence jejunal pouch. Weight139 pounds.

been relieved of epigastric pain. He has a normal food capacity butabstains from consuming fluids with meals and avoids milk; otherwise,he eats an unrestricted diet. A barium study of the esophagojejunalreconstruction with jejunal pouch done shortly after operation is shownin Fig. 12. Fig. 13 is a recent photograph of the patient. His weight hasbeen maintained at 138 to 140 pounds. He is 5 feet, 9 inches tall. He hasworked regularly as an automotive service worker.He has received 500 pg of vitamin B12 every 6 weeks intramuscularly.

Recent serum vitamin levels were: B12 280 jugg/ml; A 68 g%o; C 3.4mg%; E 0.7 mg%o; folate 16.7 ng/ml. Total serum protein was 7.2 gms%;albumin 4.5 gms%. Repeat 51 Cr labeled albumin measurement of gas-

trointestinal protein loss showed less than 2% loss of the labeled albu-min in 96 hours (normal loss should be less than 2%).

Pathologic Anatomy

The entire stomach of each patient was available forexamination and each revealed a remarkable increase inmucosal mass which was thrown into rich folds and small-er nodules, forcing the muscularis mucosae into peak-like prolongations supporting the increase in mucosa. Ineach case, the mucosa measured up to 6-8 mm in heightand occasionally the valleys between the giant infoldings

of mucosa measured 2-3 cm in depth. (Figs. 3, 8, 11 and14). In each case these notable changes were confined tothe regions of fundus and body which contain gastricglands and spared the antral region.

Histologically, the antral region also appeared withinnormal limits with remarkable changes confined to thegastric glands of the fundus and corpus. Although majorhistologic differences were demonstrated among thethree cases, the unifying feature was a complete absenceof identifiable parietal and chief cells which normallycompose the gastric glands. Instead, this rich epitheliumwas composed of simple mucus-secreting cells of thetype seen in the neck region of the normal gastric glandsand which contain primarily neutral muco-substancesand thus stain richly with the periodic acid Schiff stain.Case 3 (F.B.) demonstrated the most extreme degree ofmucosal hypertrophy with a mild degree of inflammatoryinfiltrate in the intervening connective tissue but did havea massive degree of interstitial edema and demonstrabledilatation of lymphatic channels in the submucosa, sub-serosa and regional lymph nodes. This case was alsounique in that two small ulcers were present along thelesser curvature: one of these measured 8 x 4 mm andwas well healed, extending into but not through the mus-

cular coat and was present in the region of antral glands.Just proximal to the demarcation between corpus andantral glands along the lesser curvature was an area ofhemorrhagic and edematous mucosa which had a tiny,centrally placed, acute perforated ulcer of 1-2 mm whichextended through the entire muscular coat and serosa ofthe mid lesser curvature and was associated with a smallamount of acute inflammatory exudate around theserosal opening.

rs)>2 3

SP C J_D,,__6DATE .

FIG. 14. Photograph of a cross-section of gastric body from Case 3(F.B.). The muscularis propria presents a curvolinear configuration atthe lower part of the picture. The mucosa appears as cobblestonescovering a submucosa which is drawn up into four folds by the increasein mucosal surface. A mucosal thickness of 5 mm is demonstrated afterfixation in buffered formalin.

772

Vol. 181 * No. 5

FIG. 15. Case I (N.B.) His-tologic section of gastricbody, Hematoxylin andEosin (x85). Muscularismucosae crosses lowerportion of photographswith simple, mucus-secreting glands above.

MENETRIER'S DISEASE 773

i. .\ <'.i\,

,. ,, .

Case 1 (N.B.) differed only slightly in appearance withno ulceration, presenting a stomach measuring almostprecisely the same as Case 3 (32 cm along the greatercurvature and 14-16 cm along the lesser curvature). Many

1iWX 4,XtFIG. 16. Case 2 (L.D.) His-tologic section of gastricEosin (x21). Muscularismucosae in lower third ofphotograph is separated bytwo large mucus lakes, thelarger one of which lacks a fcomplete mucosal cover-ing.

of the mucosal-lined abnormal glands were cystically di-lated (Fig. 15) and had varying amounts of inflammatorycells, predominantly polymorphonuclear leucocytes, inthe cystic spaces. Occasional lymphatics and venules of

Ann. Surg. * May 1975SCOTT AND OTHERS

the submucosa contained deposits of fibrin and freshthrombi. A marked interstitial edema was also present atoccasional sites.Case 2 (L.D.) demonstrated the least degree of mucosal

increase in mass leaving a definite impression that it wasin a stage of atrophy with many mucus cells appearingflattened with little cytoplasm. Chronic inflammatorycells were much more marked, and unique to this casewas the extension of mucus secreting glands and pools ofmucus into the muscularis mucosae in many sites (Fig.16).

Etiology and Pathophysiology

The cause of this condition is unknown. Many hypoth-eses have been presented including the possibility that itrepresents a congenital anomaly or the effects of chemi-cal, thermai or mechanical irritants or infectiousagents.3'022 The possibility that it represents an auto-immune mechanism has been suggested. 6 There is littleor no substantial evidence to support these ideas of etiol-ogy.

The restriction of the giant mucosal hypertrophy to thefundus, cardia and body of the stomach, sparing theantrum, is reminiscent of the Zollinger-Ellison syndromeand suggests an endocrine cause for Menetrier's disease.The enormous mucosal hyperplasia and hypertrophy inthe Zollinger-Ellison syndrome reflects a response of theparietal and chief cells to gastrin produced by the endo-crine tumor.24 In Menetrier's disease the giant mucosalhypertrophy and hyperplasia consists almost exclusivelyof gastric mucus cells. Parietal and chief cells are notablydiminished in number and indeed are absent in manysections.Although the body of literature concerning hyper-

trophic gastritis and giant gastric rugal folds has beenburdened by a great degree of terminologic proliferationand nosologic confusion, it seems that since about 1960 a

general agreement has been approached.17'22 The diag-nosis "Menetrier's disease" is now usually confined tothose cases of giant hypertrophic gastropathy in whichbasal acid secretion is low or absent and serum proteinsare commonly lost from the mucosal surface. Stempienand his associates22 emphasized that Menetrier's disease"is at the opposite end of the spectrum of the hyper-trophic gastropathies from that of hypertrophic hyperse-cretory gastropathy." The latter entity includes theZollinger-Ellison syndrome with its spectrum of high acidsecretory clinical manifestations including intractablepeptic ulcer disease and an association with multipleendocrine adenomatosis. As Stempien22 pointed out 10years ago, the hypertrophic hypersecretory gastropathiesare characterized by hypersecretion of HCL, pepsin andmucoprotein. No significant serum protein losses occurinto the gastric juice. The mucosal hypertrophy involves

all glandular elements, parietal cells, chief cells andmucus cells. On the contrary, Menetrier's disease ischaracterized by mucosal hypertrophy associated withdegenerative changes in the glandular layer, ahyperplasia involving superficial epithelium and re-mnants of the glandular layer, anacidity or markedhypo-acidity and significant losses of serum protein intothe gastric juice. Gastric ulceration is rare in associationwith Menetrier's disease, but has been reported.12'14 Thepersistent peptic ulcer symptoms coupled with recurrentupper gastrointestinal bleeding episodes and finally withperforation of a gastric ulcer as occurred in our thirdpatient (Case 3, F.B.) emphasizes this potential relation-ship. A widely varying amount of inflammatory intersti-tial change and edema has been described in reportedcases and was present in our patients. These changesevidently add to the great increase in mucosal mass.Their etiology is unknown but it has been pointed out byFrank and Kern6 that this process may proceed to at-rophy and indeed the gastric mucosa in our second pa-

tient (Case 2, L.D.) seemed to be in process of developingsuch an alteration.Hypoproteinemia with Menetrier's disease was first

shown by Citrin, et al.4 in 1957 to be associated with lossof serum proteins across the gastric mucosal barrier intothe gastric lumen. This was established by injectingradioactive albumin intravenously and recovering exces-

sive amounts of labeled protein in the gastric juice oftheir patient. The implication of these early studies was

that the protein losses consisted mostly of albumin whichresulted in low serum protein values. However, Katzkaet al.,8 in 1967 pointed out that patients with Menetrier'sdisease with protein losses had low serum globulin con-

centrations as well as hypoalbuminemia. In addition, hecited the work of Glass7 who reported that paper elec-trophoretic curves of gastric juice in Menetrier's diseaseshow a large globulin peak as well as a large albuminpeak. Katzka8 had similar findings in his patient withMenetrier's disease using starch block electrophoreto-grams. Gastric juice protein in 41 normal patients studiedby Katzka8 averaged 1.7 mg/ml. In his patient withMenetrier's disease gastric juice protein was 8 mg/ml and8.8 mg/ml on two separate occasions. A similar range wasfound in the gastric juice of our 3 patients. In the series of18 patients with protein losing gastroenteropathy re-

ported by Schwartz and Jarnum19 in 1961, the hypo-proteinemia could be explained in all by excess gastroin-testinal protein loss demonstrated by an increased fecalexcretion of radioactivity following intravenous injectionof 131I labeled albumin and/or 131I labeled polyvinylpyr-rolidine.

In Menetrier's disease the exact mechanism of trans-port of serum proteins across the gastric mucosal barrierinto the lumen of the stomach is not known. However,digestion of the proteins by proteolytic enzymes must

774

MENETRIER'S DISEASE

take place with reabsorption of the constituent peptidesand aminoacids to an unknown extent while the remain-der of these constituents is lost in the stool. Citrin et al.found that their patient with Menetrier's disease had asmall exchangeable albumin pool which was turning overrapidly. From their study they concluded that the capac-ity of the body to synthesize albumin was inadequate tocompensate for the gastric losses despite the availabilityof the constituent aminoacids of the albumin in the intes-tine. They thought that this was the probablepathogenesis of the hypoalbuminemia and the diminishedtotal pool in their patient.

Clinical Aspects

In the 1962 review of Reese, Hodgson and Dockerty,15the authors stated that only 80 cases of Menetrier's dis-ease, verified pathologically, had been reported by 1960.According to Raotma et al. 14 in 1974 only about 200 casesof Menetrier's disease have been reported since the orig-inal description in 1888. If the criteria used for the diag-nosis are those listed in the previous section, Raotma's14estimate of the frequency of Menetrier's disease shouldbe reduced considerably. Reese and his associates15 usedthe radiologic criteria for diagnosis of Menetrier's diseasedeveloped in their retrospective review of the subject andfound only 18 patients at Mayo Clinic during the period1949-1960 who met all the criteria and in whompathologic material was available. These 18 patients hadtotal or subtotal gastrectomies and in only 6 of this groupwas the pathologic diagnosis of Menetrier's disease con-firmed. The 12 other patients had tumors, principallycarcinoma or lymphoma, gastric ulcers, antral spasm orretained secretions which mimicked Menetrier's disease.Thus, the true incidence of Menetrier's disease is difficultto determine from reports in the literature, but we believeit to be much less common than the literature wouldsuggest.According to Spiro,21 patients with Menetrier's disease

may present with massive edema, with gastrointestinalbleeding, or with non-specific gastrointestinal complaintswhich have often led to a roentgenographic diagnosis ofgastric lymphoma or carcinoma. In our patients edemaand hypoproteinemia were the chief complaints in onepatient, nausea, vomiting and diarrhea in another, whilethe third clearly had persistent peptic ulcer symptomswith recurrent bleeding and eventually perforation.The disease appears to be an acquired disorder and the

clinical manifestations may develop rapidly in a fewweeks as in two of our patients or may evolve moreslowly and persist over a period of years (as in Case 3).Once it develops in adults, Menetrier's disease withprotein-losing manifestations seems to be persistent andunrelenting with a highly lethal course when untreated.

In children several reports indicate that a protein-losinggastropathy with giant gastric rugae which resemblesMenetrier's disease may develop and, after a period ofweeks of supportive treatment, undergo spontaneousremission.2'3'1f

Radiologic study of adult patients with Menetrier'sdisease shows the presence of long tortuous gastric rugalfolds which are frequently one to two centimeters inthickness on examination with barium, separated by deepsulci of equal depths. The criteria originally delineated byReese et al.15 in 1962 for radiologic diagnosis of thedisease emphasized that the folds are concentrated in thefundus, cardia and body of the stomach and end at theincisura angularis, sparing the antrum. Air contraststudies may improve the detail of examination. Fluoros-copy accompanied by palpation and compression of thestomach often demonstrates the enlarged folds to bestadvantage. The configuration of the greater curvature,according to Reese et al.,15 is quite characteristic sincebarium insinuates itself between the enlarged folds andforms coarse septal lines. Even when the giant rugaecannot be seen a rough estimate of their height can bedetermined by measuring the perpendicular lines on thegreater curvature which represent spicules of bariumtrapped by opposed folds. The lesser curvature is fre-quently spared in this process. The thickness of the gas-tric wall is often 10 mm or more and the enlarged rugalfolds are characteristically quite flexible. Lymphoma andcarcinoma can be differentiated when localized masses oftumor are present, when the gastric wall is inflexible atthe site of neoplastic infiltration and when the distalportions of the stomach are involved by tumor.Zollinger-Ellison syndrome can simulate Menetrier's dis-ease but large duodenal folds and the presence ofduodenal ulcer, single or multiple, aid in the differential.Gastroscopy can be very helpful in diagnosis by con-

firming the presence and flexibility of the large rugal foldsand the absence of antral involvement. Persistence of thefolds under distention with air helps to distinguish themfrom the occasionally normal folds which look largeradiologically.21 While gastroscopic biopsy in multipleareas should be carried out, the thickness of the gastricwall in Menetrier's disease often precludes a definitivediagnosis on the superficial bit of tissue obtained bygastroscope. Biopsy, however, is exceedingly helpful inidentifying or excluding neoplasms which must be dif-ferentiated.

Laboratory studies which contribute to the diagnosisof Menetrier's disease include measurement of gastricacid secretion which is usually absent or in thehypochlorhydric range. This helps to differentiate thedisease from hypertrophic, hypersecretory gastropathy22including the Zollinger-Ellison syndrome where acid sec-

retion is usually in the upper normal or excessively highranges. As advocated by Katzka8 measurement of pro-

775Vol. 181 * No. 5

SCOTT AND OTHERS

tein in gastric secretion, electrophoretically or chemical-ly, characteristically shows elevated protein concentra-tions in the juice of patients with Menetrier's disease andcan reach concentrations of 8 to 9 mg/ml as contrasted toa normal level of 1.7 mg/ml. The protein losing syndromeaccompanying Menetrier's disease can readily be recog-nized by subnormal levels of both albumin and globulin inthe patient's serum, as occurred in each of our 3 patients.Confirmation of diagnosis of the protein losing syndromecan be elaborated by the use of 1311 labeled albumin or51 Cr labeled albumin to demonstrate the accelerated turn-over of exchangeable albumin, its loss in gastric juiceand of its isotopic marker in stool and urine.Treatment of Menetrier's disease with protein-losing

gastropathy has obviously developed by empiricism.Since the etiology of the disease is unknown, there is nospecific therapy. Therapeutic trial of a variety of drugs,including steroids, high protein diets, repeated infusionsAf albumin and gastric irradiation have proven totallyinadequate when the clinical manifestations of Mene-trier's disease and the protein losing syndrome are severe.9Under such circumstances the gastric protein losses mustbe curtailed and resection of the site of protein loss is a

logical and effective treatment. Since the hypertrophiedgastric folds which are the site of protein loss occupy thefundus, cardia and body of the stomach and only thesmall antrum might theoretically be spared when a cura-

tive gastric resection is done, we believe that total gas-

trectomy with the several advantages of Roux-en-Yesophagojejunostomy and a jejunal food pouch20 is pref-erable to an alternative reconstruction designed to retainthe antrum. We have used the Hunt-Lawrence20 type ofjejunal pouch in our two surgically treated patients withelimination of the manifestations of Menetrier's diseaseand good rehabilitative results.

References1. Balfour, D. C., Jr., Hightower, N. C., Jr., Gambill, E. E., et al.:

Giant Hypertrophy of the Gastric Rugae (Menetrier's Disease)Associated with Severe Hypoproteinemia Relieved Only byTotal Gastrectomy: Report of a Case. Gastroenterology, 16:773,1950.

2. Burns, B. and Gay, B. B., Jr.: Menetrier's Disease of the Stomachin Children. Am. J. Roentgenol., 103:300, 1968.

3. Butz, W. C.: Giant Hypertrophic Gastritis. Gastroenterology,39:183, 1960.

4. Citrin, G., Sterling, K. and Halsted, J.: Mechansim of Hypo-proteinemia Associated with Giant Hypertrophy of Gastric Mu-cosa. N. Engl. J. Med., 257:906, 1957.

5. Cohen, S., Freenam, T. and McFarlane, A.S.: Metabolism of-I'I'labeled human albumin. Clin. Sci., 20:161, 1961.

6. Frank, B. W. and Kern, F., Jr.: Menetrier's Disease. Gastroen-terology 53:953, 1967.

7. Glass, G. B. J. and Ishimori, A.: Passage of Serum Albumin Intothe Stomach. Am. J. Dig. Dis., 6:103, 1961.

8. Katzka, I., Glicken, J. and Seckler, J.: Concentration of GastricJuice Proteins in a Patient with Menetrier's Disease. Report of aCase. Am. J. Dig. Dis., 12:98, 1967.

9. Kenney, F. D., Dockerty, M. B. and Waugh, J. M.: Giant Hyper-trophy of Gastric Mucosa: A Clinical and Pathological Study.Cancer, 7:671, 1954.

10. Maimon, S. N., Bartlett, J. P., Humphreys, E. M. and Palmer, W.L.: Giant Hypertrophic Gastritis. Gastroenterology, 8:397, 1947.

11. Menetrier, P.: Des Polyadenomes Gastriques et de Leurs Rapportsavec le Cancer de L'Estomac. Arch. Physiol. Norm. Pathol. S.4,1:32-55; 236, 1888.

12. Palumbo, L. T., Rugtiv, G. M. and Cross, K. R.: Giant Hyper-trophic Gastritis: Its Surgical and Pathological Significance.Ann. Surg., 134:259, 1951.

13. Pittman, F. E., Harris, R. C. and Barker, H. G.: Transient Edemaand Hypoproteinemia. Am. J. Dis. Child., 108:189, 1964.

14. Raotma. H., Angervall, L., Dahl, I. and Dotevall, G.: Clinical andMorphological Studies of Giant Hypertrophic Gastritis (Mene-trier's Disease). Acta Med. Scand., 195:247, 1974.

15. Reese, D., Hodson, J. and Dockerty, M.: Giant Hypertrophy of theGastric Mucosa Menetrier's Disease. A Correlation of theRoentgenographic Pathologic and Clinical Findings. Am. J.Roentgenol., 88:619, 1962.

16. Sandberg, D. H.: Hypertrophic Gastropathy (Menetrier's Disease)in Childhood. J. Pediatri., 78:866, 1971.

17. Schindler, R.: On Hypertrophic Glandular Gastritis, HypertrophicGastropathy, and Parietal Cell Mass. Gastroenterology, 45:77,1963.

18. Schlaeger, R., LeMay, M. and Wermer, P.: Upper GastrointestinalTract Alterations in Adenomatosis of Endocrine Glands. Radiol-ogy, 75:517, 1960.

19. Schwartz, M. and Jarnum, S.: Protein-losing Gastroenteropathy:Hyponroteinemia Due to Gastrointestinal Protein Loss of Vary-ing Etiology Diagnosed by Means of 131 I-albumin. Danish Med.Bull., 8:1, 1961.

20. Scott, H. W., Jr., Gobbel, W. G., Jr. and Law, D. H., IV: ClinicalExperience with a Jejunal Pouch (Hunt-Lawrence) as a Substi-tute Stomach After Total Gastrectomy. Surg. Gynecol. Obstet.,121:1231, 1965.

21. Spiro, H. M.: Clinical Gastroenterology, London, Collier-MacMillan Limited, 1970; p. 173.

22. Stempien, S. J., Dagrade, A. E., Reingold, I. M., et al.: Hyper-trophic Hypersecretory Gastropathy. Analysis of 15 Cases inReview of Pertinent Literature. Am. J. Dig. Dis., 9:471, 1964.

23. Underdahl, L. O., Woolner, L. B. and Black, B. M.: MultipleEndocrine Adenomas: Report of 8 Cases in Which Parathyroids,Pituitary and Pancreatic Islets were Involved. J. Clin. Endo-crinol., 13:30, 1953.

24. Zollinger, R. M. ano Craig, T. V.: Ulcerogenic Tumors of thePancreas. Am. J. Surg., 90:424, 1960.

DISCUSSION

PROFESSOR J. PHILIP SANDBLOM (Lausanne, Switzerland): It is interestingto speculate on other types of lesions in the gastrointestinal tract withgreat losses of protein and water. A couple of years ago I was con-fronted with a very unusual case; in fact, I have never seen any othersuch described. It was given to me by Professor Caroli in Paris, becauseit was a case of hemobilia, caused, as he thought, by polyposis in thebiliary tract.

(Slide) This patient had pronounced hemobilia. The operativecholangiogram showed multiple polyps in the biliary tract. ProfessorCaroli could only scoop out a few of these.The characteristic thing for this patient was a tremendous loss of

fluid, electrolytes and protein, and the patient died after three or fourdays, having lost between 10 and 15 L a day of protein-rich fluidthrough the T-tube. This case, I think, rather resembles the Menetrier'ssyndrome, and I wonder if they are related.One also thinks of the hypersecreting villous adenomas of the colon,

776 Ann. Surg. * May 1975