Intractable Watery Diarrhea, Hypokalemia, and Malabsorption in a Patient with Mediterranean Type of Abdominal Lymphoma

Vol. 55, No.1 Printed in U.S.A.

GASTRO ENTEROLOGY

Copyright © 1968 by The Williams & Wilkins Co.

INTRACTABLE WATERY DIARRHEA, HYPOKALEMIA, AND MALABSORPTION IN A PATIENT WITH MEDITERRANEAN TYPE OF ABDOMINAL LYMPHOMA MAX

J.

SEIJFFERS, M .D., MICHA LEVY, M.D., AND GEORGE HERMANN, M.D.

Unit of Gastroenterology, Department of Medicine "A" and Department of Roentgenology, The Hebrew University-Hadassah Hospital and Medical School, Jerusalem, Israel

The combination of intractable watery diarrhea, hypokalemia, and malabsorption was recently observed in a patient with lymphomatous involvement of the small intestine and mesenteric lymph nodes.

Case Report A 21-year-old Jewish male, born in Iraq, who came to Israel at the age of 2, was referred to our department from Afulah. His present illness started in August 1963 with diarrhea of up to 20 watery bowel movements daily. From then on he continued to suffer from diarrhea which fluctuated markedly in intensity. In 1964 and again in 1965 he was hospitalized in a regional hospital. A diagnosis of "chronic colitis" was made, and treatment with Salazopyrin and corticosteroids brought temporary improvement. In March 1966 he was hospitalized in Afulah. Physical examination revealed a poor nutritional state and diffuse abdominal tenderness, but was otherwise noncontributory. Laboratory findings were consistent with a diagnosis of malabsorption syndrome. A small bowel X-ray was interpreted as showing a "deficiency pattern"; a barium enema was normal. During this hospitalization, the condition of the patient deteriorated rapidly and the number of bowel movements reached 30 per day. Received August 31, 1967. Accepted February 12, 1968.

Address requests for reprints to: Max J. Seijffers, M.D., Department of Medicine "A," Hebrew University-Hadassah Hospital, P.O.B. 499, Jerusalem, Israel. The authors wish to acknowledge the help and advice received from Professors J. J . Groen and D. Birnbaum and from Drs. J. Ben-Bassat , M. I. Sacks, J. Menczel, and J. W. Czaczkes. Thanks are also due to the dieticians of the Metabolic Unit and the nursing staff of the Department of Medicine "A" for their skilled assistance.

Therapeutic trials with Salazopyrin, tetracyclines, a gluten-free diet, and a milk-free diet did not produce any improvement. Finally therapy with large doses of steroids was instituted. He was transferred to our department on May 1, 1966. At that time he was receiving 200 mg of hydrocortisone intravenously daily, penicillin, and streptomycin. Physical examination on admission revealed an ill and emaciated patient, weighing only 40 kg, as against 66 kg before the start of his illness. His temperature was 36.5 C. Muscle wasting and weakne~s were pronounced. Mucous membranes reflected only slight clinical dehydration and chilosis was present. No enlarged lymph nodes could be detected. There was slight diffuse tenderness on abdominal palpation ; the spleen and liver were not enlarged and no masses were felt. Tendon reflexes were diminished. The fingernails were watchglass shaped. Laboratory examinations . The erythrocyte sedimentation rate was 7/ 19, hematocrit was 42%, and leukocytes were 15,200 per mm3 (subsequent counts were mostly in the normal range) . Urea, glucose, serum amylase, bilirubin, liver function tests, a bromsulfalein test, calcium, serum vitamin B,. , and serum folate were normal. Serum potassium was 1.2 (!), sodium 129, chloride 79, and CO, combining power 39.4 mEq per liter. Albumin was 2.3 and globulin 2.9 g per 100 ml. Serum carotene was 15 p.g per 100 ml. The maximum rise in blood glucose after an oral lactose load of 50 g was 8 mg per 100 ml (normal> 20 mg). Routine urinalysis and a creatinine clearance were normal. The 5-hr urinary excretion of Dxylose after a 5-g oral load was 0.7 g (normal > 1.2 g). The excretion of Co 00B,, in the Schilling test was 9.5% (normal > 10%). Smears of bone marrow were interpreted as normal. Measurement of gastric acid secretion, urinary excretion of 5-hydroxyindolacetic acid, and fecal excretion of 1131 -polyvinyl-pyrrolidone

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119

FIG. 1. Appearance of duodenum in the 3rd month after admission, during clinical remission, showing absence of normal mucosal pattern and presence of many polypoid filling defec ts.

after intravenous administration also gave normal rcsul t~. The daily stool fat excretion was 14.4 g on a diet cont;lining approximately 20 g of fat per day . R epeated tests revealed little or no occult blood . During the periods of diarrhea the transit time of carmin e-red marker varied from 9 to 14 hr. A small intestinal X-ray examination shortly after admission, during a period of severe diarrhea a nd hypokalemia, showed widened muco~al fold:; and dilated loops, p:trticularly in the upper part of the small intestin(•. Thr dilation of thc duod<'num wa s cspPcially striking. A sul:seqtH'nt ~ma ll howe! study was made in the 3rd month of ho ~p italiza tion during a period in which thP patient was completely free of cliarrhe:t. Thickening of mucosal folds and dilation of loops were more pronouncrd. In addition the normal mucosal pattern was not recognizable in the duodenum and there were multiple filling defects, especially in the third part of the duodenum . The duodenum appeared stretched, and peristalsis \Yfl s almost completely lacking (fig. 1). A chest X-ray wns normal. A peroral small bowel biopsy obtained from an area just past the ligament of Treitz, 10 days after institution of a gluten-free diet, during

severe diarrhea, revealed, apart from slight nonspecific changes, normal histological structures (fig. 2). A second biopsy was taken 2Y2 months later, this time during a period of normal bowel movements and while the patient was receiving a normal gluten-containing diet. It was obtnined from the third part. of the duodenum, which was roentgenologically most srvcrely involved, :mel revealed complete ab~rnce of villi, n cuboidal surfacr epithelium, spa rs it~· of crypts, and heavy cellular infiltration of mtH'.osa and submucosa (fig. 3). In the deeper part of t he mucosa and in the submucosa thrrr were a large number of reticulum cells. Thr diffusrnrss of the infiltrnte and the npp:uent destruction of the crypts were regardrd :1 ~ vrrY suggestive of n mnlignnnt lymphoma. Under the dissrcting microscope there was one small area showing four large swollen villi. The rest of the mucosa was occupied by large, bulging, dome-shaped structures devoid of any finer architectural landm:uks. Results of fecal and urinary electrolyte estimation. (Feces were collected in 2-liter bottles and assa~red at the termination of each 24-hr period. After mixing, the fecal supernatant fluid was filtered and analyzed . On several occasions

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Comparison of data from period I and II showed that, despite much higher fecal volumes in period I, the average daily fecal potassium concentration in the first period was higher, and not lower, than in period II ; the high fecal potassium concentrations during period I were associated with a particularly high oral potassium intake. Because of both high potassium concentrations and large fecal volumes, fecal potassium losses were very large, up to 378 mEq per day. Under these conditions of severe diarrhea, potassium loss in stools far exceeded urinary potassium output. A considerable discrepancy between estimated fecal ions and fecal osmolality, which persists after inclusion of osmolar values of fecal monosaccharides, was obvious. (Fecal calcium concentrations varied between 3.2 and 5.8 mEq per liter and magnesium between 5.8 and 17.2 mEq per liter.) Measurement of 12-hr urinary volumes showed the volume of night urine to be often more than twice the volume of the daily urine. Course . After admission, treatment with antibiotics was stopped and the amount of hydrocortisone gradually reduced. The patient Fro. 2. First small bowel biopsy, obtained during severe diarrhea. Villi are slightly broader and shorter than usual and an increased number of mitotic figures are seen in the depths of the crypts. Otherwise there are no abnormalities (H & E, X 110).

a mixed sample was put through a Waring blender prior to filtration, but this did not give significantly different results. Results of two fecal and urinary collection periods are given in table 1. Daily dietary intake during the first 2 weeks after the institution of a gluten-free diet (hospital day 7) was probably not significantly different from that of hospital days 17, 18, and 19, for which the available complete records show an average intake of 800 g of carbohydrate, 11 g of fat, 67 g of protein, 299 mEq of potassium, and 241 mEq of sodium; banana consumption was 2550 g. During the second collection period the patient was on a constant diet containing 522 g of carbohydrate, 27 g of fat, 99 g of protein, 158 mEq of potassium, and 162 mEq of sodium per day, including 1200 g of bananas. Dietary calculations did not include sodium and potassium in drinking water.) Fecal electrolyte composition (table 1) showed much higher potassium concentration and substantially lower sodium and chloride concentrations than electrolyte concentrations of rli:urhea.l Rtools in general (see Discussion).

FIG. 3. Second small bowel biopsy obtained during clinical remission. Note the completely flat mucosa, sparsity of crypts, and heavy cellular infiltration of mucosa and submucosa (H & E, X 50).

T ABLE

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CASE REPORTS

Jul y 1968

1. Results of analyses of 24-hr collections of f eces and U?'ine, duTing two periods i n which no other interfering examinations were peTfoTmed

I

Feces

I

Hospital day K+

Volume

Na+

o-

Osmolality

liters

Reducing

Glucose

sub-

Fructose

K+

Volume

Na+

CJ-

Osmo· Jality

stance

I

-Peri od I 7 8 9 10 11 Peri od II 25 26 27 28

Urine

mEq/liter

mosm/kg

---

--liters

g/100 ml

mEq/liter

mosm/kg

I

8.5 6 .8 7 .5 3 .9 4 .3 2 .4 2 .5 2.9 1.6

i

22 41 51 77 88

41 16 9.5 9 .0 9.0

20 5 5 7 .5 5

319 334 336 343 348

46 57 34 60

52 27 24

10 10 15 15

314 315 335 395

10

1.9 4 .3 6 .2 7 .8 5 .8

0.8 1.5

was given parenteral fluid, mainly saline supplemented with potassium chloride, and a bland but otherwise free diet. Beca use of a dramatic and progressive increase in the volume of feces on the following cla~·s, culminating in a fecal output of 14.3 liters on t he 6th day, a strict gluten-free diet was started and the amount of intravenous hydrocortisone was again increased to 200 mg per day (fig . 4) . The color of the watery feces varied from bright yellow to dark green ; they had a not unpleasant fermented banana odor. Volumes of single bowel movements reached 1 liter. During t his period of severe diarrhea from 134 to 218 mEq of potassium per day were supplied parenterally, and up to 300 mEq per day were given in the form of food, mainly banan:1s. Serum potassium rose (fig. 4). There was aft er the second day an obvious contrast between the relatively good general stat us of the patient and the cholera-like diarrhea. The patient exhibited throughout the lst month a voracious appetite, consumed up to 3500 calories per day, and maintained his weight. T he inclusion of a large amount of bananas in his gluten-free diet was partly determined by the patient's belief in their curative effect. Another striking feature was the absence of gross clinical signs of dehydration . Plasma osmolality values corroborated this (fig. 4). Moreover, the patient maintained not only a satisfactory diuresis, but even developed a striking polyuria (fig. 4). These large urine

i 0 .76 0.79 1.52 1.6

0 . 14 0 .10 0 .80 0 .26

2.3 2.1 2 .3 4 .3

I

I

18 22 25 16 21

128 90 116 66 58

165 116 128 95 95

383 268 293 213 230

15 79 73 36

140 120 145 115

153 216 232 150

427 569 656 407

GLUTEN

FREE

~ ~ ~~

HYD RO-

CO~T~SONE mg

I

da y

Paren t eral Flu id

DIET

200t 100 0

~

~~ [

liter I day

Seru m Pota ss i u m meq

I liter

Urine liter I da y

Plasm a

;[ 82~t0~ ,

Joor

Osm olality 280[ milliosmol / kg 260 Feces liter / day

;~,

12 1~

6 4

2 0 1

Days

afte r admission

FIG. 4. Graphic representation of fecal and urin ary fluid loss, serum potassium, plasma osmo la lity, and therapeutic regimen during the first 35 days after admission. Vertical arrows indi cate administration of 20 units of adrenocorticotropin .

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CASE REPORTS

volumes could not be explained on the basis of a particularly large parenteral fluid load (fig. 4), but it was noted that the patient's oral fluid intake was very high although no accurate estimation was made. Urine osmolality values varied from 758 to 187 milliosmols per liter. At the end of the 1st month the amount of steroids was progressively diminished and adrenocorticotropin was given intermittently (fig. 4). Because the gradual decrease in daily stool volume also coincided with the institution of a gluten-free diet, it was continued despite the findings in the first jejunal biopsy. Discontinuation of this diet later, after stool volume had almost returned to normal, did not cause an immediate recurrence of diarrhea. A pancreatic adenoma1 was suspected but, because of the initial severe diarrhea and cachexia and, subsequently, because of apparent progressive improvement, explorative laparotomy was postponed. Daily stool weight during the 2nd month was much reduced (daily average 910 g), and the patient gained 4 kg. During this period the patient started to complain about progressively severe epigastric pain, especially immediately after food. In the beginning of the 3rd month all drugs were discontinued and a free, gluten-containing diet was given. The patient had now from one to three formed or semiformed stools. Small intestinal X-ray studies, however, showed no improvement, and the small bowel biopsy during this period of remission finally established the diagnosis of lymphoma (fig. 3). The patient continued to stay afebrile, and his blood sedimentation rate, leukocyte counts, and liver function tests remained normal. In the 4th month diarrhea recurred and continued despite treatment with corticosteroids and nitrogen mustard. Daily stool weights renched 5.5 kg. Once more it wns noted how rapidly severe hypokalemia developed and serum potassium values of 1.5 mEq per liter were recorded . Severe epigastric pain was now the dominant complaint. Subsequently developing signs of intestinal obstruction and peritoneal irritation made a laparotomy necessary. A mass composed of omentum and adherent intestinal loops, comprising l y2 meters of jejunum, was found. The small intestine bled easily on contact and was seeded with miliary yellowish-gray nodules. Many large mesenteric lymph nodes were present. Liver and spleen appeared normal. A lymph node was excised and the abdomen was closed. A diagnosis of

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"lymphoma, most likely reticulum cell sarcoma" was made on the basis of examination of the lymph node. The subsequent course was downhill and the patient died 3 years and 4 months after the appearance of the first symptoms of his illness. At autopsy (Dr. A. Polliack) the most striking finding was a very large abdominal mass composed of adherent intestinal loops and enlarged mesenteric lymph nodes. Individual lymph nodes reached a diameter of 6 em. The lymphomatous process involved the small intestine diffusely over its whole length with the exception of the most distal part of the ileum. There was also a marked enlargement of paraaortic and mediastinal lymph nodes. (A more detailed autopsy report will be presented in a clinicopathological conference in the Israel Journal of Medical Sciences.)

Discussion Involvement of the small intestine by a lymphomatous process has been recognized as an occasional cause of the malabsorption syndrome. 2 · 3 R ecent reports have stressed the not infrequent occurrence of steatorrhea as the presenting or main symptom of lymphomata of the small intestine in young Israeli Arabs and Jews of Middle Eastern extraction 4 • 5 (S. Brandstaetter, personal communication). Ethnogeographic origin and age group distinguish these patients from patients with abdominal lymphoma elsewhere.4 • 5 The patient described belongs to this group: he was born in Iraq and presented at the age of 18 years with malabsorption and diarrhea as the main manifestations of a lymphoma involving the small intestine. Two points warrant further discussion: the diagnostic difficulties encountered and the severity and characteristics of the diarrhea. It appears that a long history of dia rrhea is the rule and that, therefore, an initial relatively benign course of several years of intermittent diarrhea does not militate against a diagnosis of this type of abdominal lymphoma. Two and a half years after the first clinical symptoms ap peared and after several months of profuse diarrhea, there were still no palpable enlarged lymph nodes; neither was there

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CASE REPORTS

hepatomegaly, splenomegaly, or evidence of enlarged mediastinal lymph nodes. The patient was afebrile, neither blood sedimentation rate nor leukocyte count was strikingly increased, and liver function tests were normal. This complete lack of signs indicating the presence of a systemic disease should not, therefore, lead to the exclusion of abdominal lymphoma as a diagnostic possibility. Abdominal pains, although frequent, 4 • 5 need not be continuously present in the course of the disease; for the 1st month in our department, at the height of the diarrhea, pain was absent, while later on, at the time of normal bowel movements, it became a conspicuous complaint. The nearly normal appearing first intestinal biopsy taken at the height of the diarrhea probably can be explained on the basis of the patchy character of the lymphomatous involvement. This biopsy, obtained after only several days of glutenfree diet, makes it most unlikely that this patient suffered from adult celiac disease6 prior to the development of a small intestinallymphoma. 7 The ethnic predilection and apparent frequency of incidence in a small geographic area of this syndrome, with an age distribution strikingly different from the abdominal lymphomas described elsewhere, are presently not understood 4 • 5 ; it is, however, possible t hat this apparently separate disease entity may not be limited to I srael and that it will be recognized with increasing frequency in other Mediterranean countries. For t he present we would, t herefore, suggest the connotat ion "Mediterranean type" for these lymphomas, in analogy to other diseases 8 occurring predominantly in patients of Mediterranean ancestry. The most striking clinical feature in this case was undoubtedly the severity of the diarrhea and consequent extreme hypokalemia. Excluding acute diarrheal diseases this occurs with any regularity only in patients with an adenoma of the pancreas. 1 Watery diarrhea is mentioned in some of the case reports of patients from Israel with small intestinal lymphoma, but it has

123

not been quantitated and was probably less severe than in the patient reported by us. Decrease in stool volume coincided with the institution of a carbohydrate rich diet and it seems, therefore, unlikely that intestinal disaccharidase deficiency contributed significantly to the severity of the diarrhea. Electrolyte composition of diarrheal stools in various diseases shows a remarkable agreement; beyond stool volumes of about 3 liters per day electrolyte concentrations approximate those found in blood plasma.9 The discrepancies between electrolyte concentration in the diarrheal stool of this patient and those reported in the literature may have been due to the high carbohydrate and high potassium diet or to the administration of hydrocortisone. Low fecal chloride may, because of existing disaccharidase deficiency, have been theresult of accommodation of organic anions in a fluid kept isosmotic by colonic mucosa. High fecal potassium concentrations, despite large fecal volumes (table 1, period I ), may have been a reflection of a concomitant very high potassium intake in this patient with extensive small bowel disease, although variations in potassium intake do not seem to affect stool potassium in normal subj ects, 10 patients with ulcerat ive colitis, 11 and idiopathic steatorrhea. 12 Whether t he rapid development of extreme hypokalemia during corticosteroid therapy, also observed in another patient with diarrhea due to abdominal lymphoma, was, partially at least, ascribable to an accentuation of fecal potassium loss could not in the absence of control data be established. Since, however, mineralocorticoids are known to affect fecal sodium-potassium ratios in normal subj ects,l 3 it also seems possible t hat the high fecal potassium and low fecal sodium concentrations were the result of hydrocortisone therapy. The slightly higher t han expected osmolalities of the stools, which are reported to be close to those of extracellular fluid , were probably a result of fermentation in the time interval between voiding and assay. These near normal osmolal values, the extremely low chloride concentrations,

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CASE REPORTS

and the identical values for electrolyte composition before and after blending all seem to exclude the possibility of artifacts, caused by electrolytes from undigested food, as an explanation for the electrolyte composition of the stool water. Rather, they point toward a state of equilibrium as a result of ion exchange through intestinal mucosa. The large daily urinary output in the 2nd week, exceeding by far parenteral fluid intake, points to a good net water absorption, which, however, was delayed as attested by the reversal of the diurnal urinary excretion rhythm. The striking polyuria which accompanied the diarrhea was probably secondary to polydipsia. High incidental urinary osmolal values, normal or below normal plasma osmolality, and clinically good hydration despite large daily fluctuations in fecal volume tend to exclude the possibility of transient primary polyuria. Oral fluid intake was not quantitated but a rough estimate can be arrived at from the values for fecal and urinary volume and parenteral intake (fig. 4). It seems most likely that the patient became accustomed to drinking these large amounts in response to prolonged diarrhea. A lag period of several days between adaptation of oral fluid intake to sudden decreases in severity of diarrhea would thus result in temporary polyuria. Summary

A case of abdominal lymphoma in a young Israeli patient of Iraqi origin is described. Diarrhea and malabsorption were the presenting features. The diarrhea was cholera-like with daily stool volumes reaching 14.3 liters and was associated with severe hypokalemia. The diagnostic difficulties encountered and the character of the diarrhea are discussed.

Vol. 55, No. 1

REFERENCES

K. K., J. B. Peter, R. G. Schultze, A. A. Hakim, and P. T. Franck. 1966. Watery diarrhea and hypokalemia associated with pancreatic islet cell adenoma. Gastroenterology 50: 231-242. 2. Sleisenger, M. H., T . P. Almy, and D . P. Barr. 1953. Sprue syndrome secondary to lymphoma of the small bowel. Amer. J. Med. 15: 666--674. 3. Kent, T. H. 1964. Malabsorption syndrome with malignant lymphoma. Arch. Path. (Chicago) 78: 97-103. 4. Ramot, B ., N. Shahin, and J . J. Bubis. 1965. Malabsorption syndrome in lymphoma of small intestine. I srael J . Med. Sci. 1: 2211. Matsumoto,

226.

5. Eidelman, S., R. A. Parkins, and C. E . Rubin. 1966. Abdominal lymphoma presenting as malabsorption. Medicine (Balt.) 45: 111-137.

6. Yardley, J . H., T. M. Bayless, J. H. Norton, and T. R. Hendrix. 1962. Celiac disease. New Eng. J. Med. 267: 1173-1179. 7. Gough, K. R., A. E. R ead, and J . M . Naish. 1962. Intestinal reticulosis as a complication of idiopathic steatorrhoea. Gut 3 : 232239. 8. Heller, H., E. Sohar, and L. Sherf. 1958.

9.

10.

11.

12.

13.

Familial Mediterranean fever. Arch. Intern Med. (Chicago) 102: 50-71. Fordtran, J. S., and J . M. Dietschy. 1966. Water and electrolyte movement in the intestine. Gastroenterology 50: 263-285. Dempsey, E . F., E. L. Carrol, F. Albright, and P. H. Henneman. 1958. A study of factors determining fecal electrolyte excretion. Metabolism 7: 108-118. Lubran, M., and P. M. McAllen. 1950. Potassium deficiency in ulcerative colitis. Quart. J . Med. 20 : 221-231. Cooks, T ., G. Thomas, D. Mangall, and H. Cross. 1953. Observations on the faecal excretion of total solids, nitrogen, sodium, potassium, water and fat in the steatorrhoea syndrome. Clin. Sci. 12: 221-234. Wrong, 0 ., and A. Metcalfe-Gibson. 1965. The electrolyte content of faeces. Proc. Roy. Soc. Med. 58: 1007-1009.