Gastric Mycosis Following Gastric Resection and

0. REHNBERG, M.D., A. FAXEN, M.D., U. HAGLUND, M.D., J. KEWENTER, M.D., B. STENQUIST, M.D., L. OLBE, M.D.

In a prospective five-year follow-up study of 289 consecutive From the Department of 11 and 111, University of patients subjected to antrectomy and gastroduodenostomy with Gffteborg, Sahigen's Hospital, GMteborg, Sweden or without vagotomy, 130 patients underwent gastroscopy. Gastric mycosis was present almost exclusively in patients sub- jected to combined antrectomy and vagotomy (36%). Gastric acidity seemed to be of only minor or no importance in the ach is unknown, macroscopically apparent gastric my- development of the mycosis. The residual volume in the gastric remnant was significantly higher in patients with gastric my- cosis has been claimed to be responsible for such symp- cosis. The impaired emptying of the gastric remnant is most toms as nausea, belching, vomiting, and epigastric likely a vagotomy effect and may be the main reason for the pain.7"' development of gastric mycosis. A simple but effective method The purpose of the present investigation was to study was developed to evacuate gastric yeast cell aggregates. Gastric significance of gastric mycosis in terms of mycosis seems to give rise to only slight symptoms, mainly the clinical nausea and foul-smelling belching, whereas the reflux of duo- subjective symptoms and ordinary nutritional param- denal contents that often occurred in combination with gastric eters in a series of patients subjected to surgery for mycosis was more likely to cause gastritis and substantial dis- peptic ulcer disease and to evaluate the occurrence of comfort. gastric mycosis as related to postoperative acid secre- tion, gastric emptying, and bile reflux. y EAST FUNGI are common saprophytes in the oral Material and Methods cavity in the healthy adult' and are probably pres- ent in small quantities in the entire gastrointestinal The study comprised 130 patients, including all those tract.2 The presence of yeasts has been demonstrated undergoing postoperative gastroscopy in a series of 289 in ulcerations of the and the duodenum.3'5 patients consecutively subjected to antrectomy with Sch6nebeck6 showed that yeasts were particularly com- gastroduodenostomy for duodenal or gastric ulcer. In mon in the gastric juice of patients with gastric ulcer patients with preoperative maximal acid response to or carcinoma, and after partial . Achylia betazole (Histalog®) exceeding 20 mmol/30 min (51 and/or impairment of gastric motility have been con- patients), a selective or truncal vagotomy was per- sidered the most important factors favoring overgrowth formed in addition to the antrectomy. All 94 patients of yeast,6 possibly in combination with reflux of duo- with complaints of any gastrointestinal nature received denal contents into the stomach.7 gastroscopy in the follow-up period. In addition, 36 In excessive amounts, yeast fungi may form huge asymptomatic patients were subjected to gastroscopy intraluminal colonies, appearing as filling defects at as controls. barium meal examinations.8-'0 They are often impres- The follow-up study included examination of the pa- sively demonstrated at gastroscopy as white or slightly tients at one month, and three and five years after op- bile-colored amorphous aggregates, either scattered eration. The postoperative state of the patient was over the entire mucosal surface, or appearing as a gruel graded according to the Visick scale.'2 The body weight or porridge-like substance. They may also be present five years after operation was compared with the usual as more or less homogeneous boluses. This condition is preoperative weight. The changes from three to five referred to as gastric mycosis and is often associated years after operation of blood hemoglobin and folate with obvious signs of gastritis. Although the clinical concentrations, and serum concentrations of iron, vi- significance of microscopic yeast infection in the stom- tamin B,2, albumin, calcium, and alkaline phosphatases were recorded. These assays were carried out at the Department of Clinical Chemistry at Sahlgren's Hos- Supported by grants from the Swedish Medical Research Council, routine The half-hour acid numbers 1 7X-760 and B77-1 7X-00577- 130. pital using procedures. peak Reprints will not be available from the author. output following stimulation by pentagastrin or beta- Submitted for publication: December 1, 1981. zole (PAOG) and by insulin (PAO,n,) was determined. 0003-4932/82/0700/0021 $00.75 © J. B. Lippincott Company 21 22 REHNBERG AND OTHERS Ann. Surg. - July 1982

Pentagastrin was given as an intravenous infusion of 90 were 30-day treatments by nystatin (500 000 IU X 3) and 300 ug/hr, betazole as subcutaneous injection of or metoclopramid (10 mg X 3) in six of seven patients 2 mg/kg BW, and insulin as an intravenous injection as checked by gastroscopy (unpublished observation). of 0.2 U/kg BW. Acid response to insulin was judged An effective method was designed taking advantage of positive or negative according to the Hollander cri- the low specific weight of the yeasts. Patients with gas- teria.'3 tric mycosis drank a large volume (750 ml) of ordinary The presence or absence of macroscopic yeast ag- fruit syrup (1 part syrup and 4 parts water, about 800 gregates was noted at gastroscopy after an overnight mOsm/kg), then laid on the left side for two hours, fast. If macroscopic aggregates were found, samples thus providing optimal conditions for the floating yeasts were taken for yeast culturing and microscopy. Positive to empty into the duodenum. This procedure was re- findings indicated gastric mycosis. peated four times during the day. The residual content of the stomach was aspirated at the beginning of the gastroscopy and thus did not Statistics include, for instance, regurgitations from the duodenum Statistical methods used were during the gastroscopy. In 20 antrectomized and va- chi-square, Fischer's gotomized patients, the fasting liquid gastric volume exact, Mann Whitney U, and Wilcoxon's matched pairs was determined in connection with gastroscopy, involv- signed-rank tests. ing eight consecutive and unselected patients without and 12 patients with gastric mycosis. In eight of the Results patients with gastric mycosis, the fasting liquid gastric At gastroscopy, gastric mycosis was found in 19 of volume was determined before and after evacuation of the 130 patients. On culture, ten patients had growth the mycosis. of Candida and nine patients of Torulopsis. Five pa- In five patients with gastric mycosis and Candida tients with gastric mycosis and growth of C. albicans albicans growth in the culture, serum was tested for on culture were tested for Candida antibodies in serum, Candida antibodies by complement-binding and im- with negative results in all cases. Among the yeasts, munodiffusion tests.'4 scattered fibers of fruits and vegetables were often seen Gastric emptying of a liquid meal-750 ml of 10% at microscopy. glucose solution-was studied according to George.'5 There were no significant differences in body weight Twenty-three patients were investigated following an- or blood chemistry between patients with and without trectomy and vagotomy (five patients without and 18 mycosis, provided the Visick score was taken into ac- patients with mycosis). Nine of the patients with my- count. cosis were restudied after evacuation of the gastric yeasts as checked by gastroscopy. At an in vitro control Gastric Mycosis in Relation to Operative Procedure experiment, phenol red solution was added to a mixture and of yeasts and gastric juice. Thirty minutes later, all of Postgastrectomy Complaints the dye was found in the liquid and none in the yeast Gastric mycosis was observed in one of 79 patients phase after centrifugation. in whom antrectomy without vagotomy had been per- The volume of the liquid gastric content following 12 formed. This patient had a stomal ulcer with stenosis. hours of fasting was determined by nasogastric tube Mycosis was demonstrated in 18 of the 51 patients suction in randomly chosen duodenal ulcer patients af- (36%) who had been subjected to antrectomy and va- ter antrectomy and gastroduodenostomy with (19 pa- gotomy (p < 0.001). No stenosis was found in any of tients) or without (18 patients) vagotomy. these patients. Eight patients originally operated on by The concentration of conjugated bilirubin in the fast- antrum resection and later reoperated on by vagotomy ing liquid gastric content was photometrically deter- because of a stomal ulcer were all free from gastric mined in 33 patients subjected to combined antrectomy mycosis at gastroscopic examination after the first op- and vagotomy. Immediately after aspiration of gastric eration, and four of them displayed mycosis after the juice, 2.5 mol/l sodium hydroxide were added to the vagotomy (Table 1). sample until pH 6 was reached. Following antrum resection and vagotomy, nausea and diarrhea occurred with significantly higher fre- Procedure for Evacuation of Mycosis quency (p < 0.001 and 0.025, respectively) in patients with gastric mycosis (Table 2). Epigastric pain, pyrosis, As a rule, evacuation of visible yeasts could not be and dumping had the same frequency in patients with successfully performed by repeated gastric lavage and and without mycosis. suction through a wide gastric tube. Equally inefficient Evacuation of gastric mycosis by the "float-away" VOL. I196 . NO. I GASTRIC MYCOSIS 23 method was complete in all 12 patients tested, according TABLE 1. Incidence of Gastric Mycosis in Relation to Operative to gastroscopy before and after the procedure. The Procedure and Postoperative Complaints mycosis had reappeared at gastroscopy from one to 12 Operative months later in five of six evacuated patients who did Procedure GI Symptoms Asymptomatic Total not proceed with the "float-away" method on their own. Antrectomy 1/55 = 2% 0/24 1/79 Complete evacuation of all visible yeasts did not alter Antrectomy the symptoms, including vomiting and/or nausea, in plus vagotomy 13/39 = 33% 5/12 = 40% 18/51 = 36% five of eight patients. Three patients stated that vom- iting and/or nausea had temporarily ceased or dimin- ished after the evacuation. Foul-smelling belching was lowing antrectomy and vagotomy did not differ in pa- relieved temporarily in all five patients with this symp- tients with or without gastric mycosis. tom. There was no change of symptoms in the patients The mean liquid gastric content (ml ± SEM) at the with diarrhea (three patients). end of the emptying test (120 min) was significantly larger (p = 0.02) after evacuation of the yeasts (89 Gastric Mycosis in Relation to Acid Secretion + 25) than before (30 ± 13) (Fig. 1). Similarly, in eight of the patients with gastric mycosis the mean fasting Peak acid output following stimulation with insulin liquid gastric content at gastroscopy was significantly (PAO10) and betazole or pentagastrin (PAOG) was (p < 0.01) larger after evacuation of the yeasts (95 determined in 59 antrectomized patients and in 45 pa- + 18 ml) than before (22 ± 6 ml). tients subjected to antrectomy plus vagotomy. Gastric After the evacuation of the yeasts in 12 patients sub- mycosis occurred in 16 one vagotomized patients and in jected to antrectomy and vagotomy, the mean fasting patient who had to antrectomy been subjected alone. gastric content at gastroscopy was significantly (p The PAOG did not differ in patients with and without = 0.05) larger (93 ± 12 ml) than in eight similarly op- gastric mycosis. The mean PAOG (mmol/hr ± SEM) erated patients without gastric mycosis (54 ± 18 ml). after antrectomy and vagotomy was 9.6 ± 1.4 in pa- tients with gastric mycosis and 10.0 ± 1.4 in patients Bile Reflux in Relation to Gastric and without mycosis. The median minimal pH (and range) Mycosis Post- operative Complaints during basal acid secretion was 3.0 (2.2-6.9) in vagoto- mized patients with mycosis and 2.6 (1.4-8.2) in va- Bile reflux was estimated in patients subjected to gotomized patients without mycosis. During stimulated antrectomy and vagotomy by determination of the con- secretion, the median minimal pH was 1.5 in patients centration of the conjugated bilirubin in the filtrated with mycosis. The mean PAOG in 59 patients subjected residual gastric content after more than 12 hours of to antrectomy alone was 13.2 ± 1.2 and did not signif- fasting (Table 3). The concentrations and amounts of icantly differ from that of the patients operated on by bilirubin were significantly higher in the patients with antrectomy and vagotomy in this series. mycosis (p < 0.02) and in the patients with pronounced The PAO0n, (mmol/hr ± SEM) was 1.6 ± 0.5 in 22 gastrointestinal symptoms (Visick 3-4) (p < 0.02). In vagotomized patients without mycosis and 1.2 ± 0.4 in the patients with mycosis, the concentrations and 15 patients exhibiting gastric mycosis, the increase in amounts of bilirubin were lower (p < 0.05) in those with acid output after insulin stimulation being 0.8 ± 0.4 and slight or no symptoms (Visick 1-2). In the patients with 0.3 ± 0.3, respectively. These differences were not sta- slight or no symptoms, those without mycosis had the tistically significant. Gastric mycosis occurred, how- lowest concentrations and amounts of bilirubin (p ever, in 12 of 25 patients (48%) with negative Hollander tests < and in three of 20 patients (15%) (p 0.02) with TABLE 2. Symptoms in Patients after Antrectomy and Vagotomy positive Hollander tests. Mycosis No Mycosis Gastric Emptying and Residual Gastric Content Symptoms (n = 18) (n = 29) Epigastric pain and/or The residual gastric liquid content after 12 hours of pyrosis 50% 41% fasting was significantly larger (p < 0.002) in 19 pa- Nausea 67% p < 0.001 10% tients operated on by antrectomy and vagotomy (52 Vomiting 33% 10% ± 8 ml) than in 18 patients in whom only antrectomy Diarrhea 39% p < 0.025 10% had been performed (23 ± 2 ml). In 31 patients sub- Dumping 33% 31% jected to 2-4 determinations of the residual gastric liq- Melaena 10% uid volume, the variation between tests was 22%. No symptoms 28% 21% Foul-smelling belching 67% Unknown The pattern of gastric emptying of 10% glucose fol- 24 REHNBERG AND OTHERS Ann. Surg. * July 1982 ml cretion. Gastric acidity, therefore, seems to be of minor content or no importance in the development of gastric mycosis. It appears more likely that impaired gastric motility as a consequence of vagotomy plays a major role in the development of gastric mycosis. The fasting content in the gastric remnant was larger after antrectomy with gastroduodenostomy and vagotomy than after antrec- tomy with gastroduodenostomy alone. It is thus possible that impaired gastric emptying after vagotomy may contribute to the development of gastric mycosis. In the

-4 comparison of residual gastric contents in patients with and without gastric mycosis, it is reasonable, however, 0 10 50 120 min to use the residual volume after evacuation of the yeast aggregates in the patients with gastric mycosis, since FIG. 1. Residual gastric content (ml SEM) after instillation of 750 the volume of yeasts is difficult to measure. Both the ml of 10% glucose solution in patients with gastric mycosis after an- trectomy and vagotomy (n = 9). Solid line represents before evacu- fasting gastric content and the two-hour residual vol- ation, and dashed line represents after evacuation of the yeasts. ume in the emptying test were significantly larger after evacuation, indicating that the volume of the fasting < 0.05), i.e., practically no bile reflux. In 31 patients gastric content after evacuation of the yeast aggregates subjected to 2-6 determinations of the bilirubin con- is the sum of the yeast aggregate volume and the liquid centration the variation between tests was 35%. volume prior to the evacuation. After evacuation, the antrectomized and vagotomized patients with gastric Discussion mycosis had significantly larger fasting gastric content than the patients similarly operated on without mycosis. Gastric mycosis after resection and gastroduoden- There is, thus, evidence to support the hypothesis that ostomy with or without vagotomy seems to appear gastric mycosis occurs preferentially in the vagotomized mainly when vagotomy has been performed.'6 In the gastric remnant, that the vagotomized gastric remnant present series, the only exception was an antrectomized has a relatively large residual gastric content, and that patient with gastric retention due to a stenosing stomal the largest fasting gastric content was found in patients ulcer. In the antrectomized and vagotomized patients with gastric mycosis. The fasting gastric content in an- in the present series, the gastric mycosis occurred in trectomized and vagotomized patients was a rather con- about one third of cases, and mainly in patients with stant phenomenon from day to day, suggesting that negative Hollander tests. It has previously been sug- these patients seldom have completely empty stomachs, gested that patients with hypochylia or achylia might thus allowing the yeast colonies to grow into macro- be prone to develop gastric mycosis.6 In the present scopically visible, sometimes huge masses. The fact that series, the gastric acid secretion was about the same in mycosis had reappeared at gastroscopy shortly after patients with and without gastric mycosis, and the in- evacuation of the yeast aggregates in most patients in- tragastric pH was similar in the two groups during basal dicated that mycosis, like the large residual gastric con- conditions and during maximal stimulation of acid se- tent, is a constant phenomenon in these patients.

TABLE 3. Relations Between Bile Reflux, Gastric Mycosis, and Symptoms for All Patients Operated on by Antrectomy with Gastroduodenostomy and Vagotomy Concentration (gmol/l) and Amount (umol) of Conjugated Bilirubin in Residual Gastric Content after More Than 12 Hours Fasting No Gastrointestinal Symptoms Gastrointestinal Symptoms (Visick 1-2) (Visick 3-4) Median Range N Median Range N Mycosis Concentration 5.4 0-32 7 57 0-112 9 Amount 0.42 0-1.6 5.1 0-8.4 No mycosis Concentration 0 0-1.2 10 0.6 0-157 7 Amount 0 0-0.06 0.04 0-4.7 Total Concentration 0.3 0-32 17 28.4 0-157 16 Amount 0 0-1.6 1.6 0-8.4 Vol. 196 * No. I GASTRIC MYCOSIS 25 The depicted method of evacuating yeast aggregates with incomplete gastric emptying, which may occur takes advantage of the fact that yeast floating on a occasionally in diabetics2' as a consequence of auto- liquid with a volume exceeding the residual volume nomic neuropathy22 and after partial gastrectomy,'6 but would be emptied first with the patient positioned on should be considered essentially as a vagotomy effect, the left side. It seems advisable to let the volume of the at least in gastrectomized patients. drink be large, since left-side posture is probably the most unfavorable for the emptying in conformity with Acknowledgments the emptying of liquid and solid meals in patients op- erated on by vagotomy and a drainage procedure.'7"8 The assistance by the Department of Clinical Chemistry in carrying way of clean- out the chemical assays, and by the Institute of Medical Microbiology The method is a simple, safe, and effective in carrying out the yeast cultures and the serologic tests, is gratefully ing the stomach of yeasts that interfere with adequate acknowledged. gastroscopic examination or gastric emptying test. Evacuation of the mycosis might also help in the eval- uation of symptoms suspected to be due to the yeasts. References Indirectly, the success of this method to evacuate the 1. Winner H, Hurley R. Candida Albicans. London: Churchill Ltd, yeast aggregates explains why the yeast cells, in par- 1964. 2. Akrawi YY. The biology of intestinal moniliasis. J Fac Med ticular, are left behind in the stomach of the gastric (Baghdad) 1960; 2(2):63-69. mycosis patient. 3. Askanazy M. Uber Bau und Entstehung des chron. Magengesch- se may contribute to some symptoms in wtirs, sowie Soorpilzbefunde in ihm. Virchows Arch Pathol Mycosis per Anat 1921; 234:111-178. antrectomized and vagotomized patients, mainly nau- 4. Frank P. Uber die Beziehungen des Soorpilzes zu dem runden sea, foul-smelling belching, and possibly diarrhea. The MagengeschwQr. Wien Arch Intern Med 1922; 5:39-42. serum tests for Candida antibodies seem to 5. Holmstrom B, Wallensten S, Frisk A. Presence of fungi in gastric negative and duodenal ulcers. Acta Chir Scand 1959; 117:215-220. confirm the idea that no invasion of the gastric mucosa 6. Schonebeck J. Incidence of yeast-like fungi in gastric juice under by the yeasts had taken place.'4 normal and pathologic conditions. Scand J Gastroenterol 1968; Gastritis due to reflux of duodenal contents, which 3:351-354. 7. Konok G, Haddad H, Strom B. Postoperative gastric mycosis. was a common finding in the patients with gastric my- Surg Gynecol Obstet 1980; 150:337-341. cosis, is more likely to give rise to substantial discom- 8. Borg I, Heijkenskj6ld F, Nilehn B, Wehlin L. Massive growth fort.'9'20 This is supported by the observation that of yeasts in resected stomach. Gut 1966; 1:244-249. 9. Ahnlund HO, Pallin B, Peterhoff R, Schonebeck J. Mycosis of asymptomatic patients with gastric mycosis had low bile the stomach. Acta Chir Scand 1967; 133:555-562. reflux, and that the majority of symptomatic patients 10. Jepsen OL. Uber Hefepilze im Mageninhalt nach Gastrektomie with gastric mycosis were still symptoihatic after evac- und Vagotomie. Rontgenfortschritte 1968; 109:269-279. 11. Norberg B, Tyreman NO. Intraluminal fungi infection in the uation of the yeasts. Foul-smelling belching may be the stomach. Lakartidningen 1973; 70:1855-1856. most specific and frequent symptom of gastric mycosis. 12. Visick AH. Measured radical gastrectomy. Lancet 1948; 1:505- was relieved in all patients by evacuation of the my- 510. It 13. Hollander F. Laboratory procedures in the study of vagotomy. cosis. The gastric mycosis did not seem to influence Gastroenterology 1948; 11:419-425. simple nutritional parameters in the gastrectomized 14. Holmberg K. Immunological diagnosis of severe candida infec- these it is believed that patients tions. Lakartidningen 1977; 74:2896-2900. patients. On gounds, 15. George JD. New clinical method for measuring the rate of gastric with gastric mycosis seldom need antimycotic therapy. emptying: the double sampling test meal. Gut 1968; 9:237- If therapy is needed, however, repeated wash outs by 242. be since 16. Perttala Y, Peltokallio P, Leiviska T, Sipponen J. Yeast bezoar the "float-away" method seem to preferable, formation following gastric surgery. Am J Roentgenol 1975; antimycotics given perorally are usually ineffective. 125:365-373. Whether reflux of duodenal contents is a prerequisite 17. McKelvey STD. Gastric incontinence and post-vagotomy diar- an rhoea. Br J Surg 1970; 57:741-747. for gastric mycosis is still open question. Assuming 18. Hancock BD, Bowen-Jones W, Dixon R, et al. The effect of pos- that amounts and concentrations of bilirubin in the gas- ture on the gastric emptying of solid meals in normal subjects tric juice provide a rough index of duodenogastric re- and patients after vagotomy. Br J Surg 1974; 61:326. than 19. Keighley MRB, Asquith P, Alexander-Williams J. Duodenogas- flux, the patients with mycosis had more reflux tric reflux: a cause of gastric mucosal hyperaemia and symp- those without mycosis. The most substantial reflux, toms after operations for peptic ulceration. Gut 1975; 16:28- however, occurred in symptomatic patients, irrespective 32. reflux 20. Hoare AM, McLeish A, Thompson H, Alexander-Williams J. of gastric mycosis. An increased duodenogastric Selection of patients for bile diversion surgery: use of bile acid and gastric mycosis may be independent sequelae to measurement in fasting gastric aspirates. Gut 1978; 19:163- motor disturbances by the vagotomy. It cannot be ex- 165. 21. Katz LA, Spiro HM. Medical progress. Gastrointestinal mani- cluded, however, that the reflux is a contributing factor festations of diabetes. N Engl J Med 1966; 275:1350-1361. in the development of gastric mycosis. 22. Hosking DJ, Bennet T, Hampton JR. Diabetic autonomic neu- Gastric mycosis seems prone to develop in patients ropathy. Diabetes 1978; 27:1043-1055.