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Watery Diarrhea and Hypokalemia Associated with Pancreatic Islet Cell Adenoma
Vol. 50, No.2 Printed in U.S.A.
GASTROENTEROL OGY
Copyright © 1966 by The Williams & Wilkins Co.
CASE REPORTS WATERY DIARRHEA AND HYPOKALEMIA ASSOCIATED WITH PANCREATIC ISLET CELL ADENOMA KEN NETH K. MATS UMOTO, M .D., SCHULTZE, M.D.,
A. A.
J. B.
PETER, M.D. , PH.D. , RAYMO ND
HAKIM, M.D., AND PETER
T.
G.
FRANCK, M.D.
Department of Medicine , UCLA Center for the Health Sciences, Los Angeles, California , and the Department of Urology, Anker Hospit al, Saint Paul, Minnesota
Three distinct clinical syndromes have been described in association with islet cell tumors of the pancreas. Hypoglycemic episodes have long been recognized as manifestations of tumors of the f3 cell type. More recently the Zollinger-Ellison syndrome has been recognized as a manifestation of non-f3 islet cell tumors. The main purposes of this review are to emphasize the third and least well recognized syndrome of this group, to report our recent experiences during the care and cure of such a patient with a profuse watery diarrhea and hypokalemia, to report negative results of extracts of the tumor on water and glucose transport in an in vitro preparation of canine mucosa, and to discuss the etiology of the choleralike diarrhea. Syndromes Produced by Pancreatic Islet Cell Tumors
Hypoglycemia The concept that pancreatic tumors may have clinical significance as a result of secretory activity was advanced by Wilder et al. in 1927, who reported a case of a malignant islet cell tumor of the pancreas with associated hypoglycemia. 1 Since then, many cases of benign and malignant "functioning" islet cell tumors have been reported, with clinical cure of the hypoReceived August 24, 1965. Accepted October 11, 1965. Address requests for reprints to: Dr. K enneth K. Matsumoto, 9735 Wilshire Boulevard, Beverly Hills, California 90212. The authors gratefully acknowledge the encouragement and advice given them in preparation of this manuscript by Dr. Morton I . Grossman. 231
glycemic episodes being effected upon satisfactory extirpation of the tumor. In 1960, Howard and Jordan published an extensive review of 766 islet cell tumors reported in the world Iiterature. 2 Of these 766 benign and malignant islet cell adenomas, 549 (71.6%) were "functioning," i.e. associated with hypoglycemia, whereas 178 (23.2%) were not associated with hypoglycemia and could be classified "nonfunctioning." In 39 cases (5.2%), this distinction was not made. The Zollinger-Ellison Syndrome The idea that a smaller number of these islet cell tumors of the pancreas could be associated with an entirely different clinical syndrome was first advanced by Zollinger and Ellison in 1955.3 They reported two cases of recurrent jejunal ulceration" associated with gastric hypersecretion and the finding of a nonspecific islet cell tumor of the pancreas in each instance. Since then, the Zollinger-Ellison syndrome has been defined by the diagnostic triad of: (a) a fulminating ulcer diathesis affecting stomach, duodenum,' or proximal jej unum, which is refractory to the usual medical or surgical measures short of total gastrectomy; (b) marked gastric hypersecretion characterized by overnight volumes approaching 2000 to 3000 ml per 12 hr , and hydrochloric acid production from four to 15 times the normal overnight value of less than 18 meq per 12 hr; and (c) the demonstration at celiotomy of an islet cell tumor. 4 ,5 By 1964, Zollinger was able to review more than 250 such cases and noted that enteritis was a frequent findin g in this
232
CASE REPORTS
clinical syndrome. 6 He reports diarrhea of varying severity in 40% of all patients having an ulcerogenic tumor of the pancreas. In approximately 20% of such patients, enteritis of some degree was the initial complaint, followed in months or in years by severe ulcer diathesis. Thus he suggests that enteritis be included as part of this syndrome. 6 The nature of the ulcerogenic principle thought to be elaborated by such islet cell tumors became the subject of an intensive search by gastrointestinal physiologists. Gregory et al. in 1960 extracted a potent stimulator of acid secretion, presumably gastrin, from the tumor of a patient with the Zollinger-Ellison syndrome. 7 Confirmation of this followed a few months later by Code et al. B In 1961, Grossman and Gregory reported similar gastrinlike activity of tumor extracts derived from both primary and metastatic nodules in a Bantu woman with the Zollinger-Ellison syndrome. 9 In 1964, Gregory and Tracy reported that the active principle extracted from a Zollinger-Ellison tumor had the same physiological actions as gastrin obtained from hog antral mucosa.10 They concluded that the stimulant present in such ulcerogenic tumors is, in fa ct , gastrin. The diarrhea seen in many of the patients with the Zollinger-Ellison syndrome has been attributed to the enormous volume of hydrochloric acid. excreted by the stomach with resultant irritation of the small bowel. Experiments in the dog l l and the discovery of a marked reduction in intraduodenal pH in several such patients tend to confirm this view. 12 - 16 Several authors have noted that the diarrhea could be controlled with nasogastric suction but that it recurred when the aspiration was stopped. 15 - 19 The administration of optimal counts of the anticholinergic drug tricyclamol (Elorine chloride) controlled diarrhea in a single patient reported by Shay et al. who found that gastric secretion was diminished by the drug. 16 Recurrence of diarrhea after discontinuation of the drug and control with reinstitution of therapy was noted. Antacids were in effective. Intestinal motility was not separat ely studied.
Vol. 50, No.2
The steatorrhea of varying degree a:3sociated with the Zollinger-Ellison syndrome has been attributed to inactivation of pancreatic lipase at the low intraduodenal pH reported in these patients. pH values as low as 1.4 have been observed. Although previous authors have commented on the absence of significant abnormalities on small bowel biopsies/a. 15. 20-24 a recent report notes that small bowel mucosal abnormalities do occur in this disease, presumably as a result of the acid insult. 2 5 Roentgenographic changes consisting of irregularity and thickening of the small bowel mucosa and luminal dilation have been reported. 26 Regardless of the exact explanation , it is clear that gastric hypersecretion with resultant hyp eracidity in patients with the Zollinger-Ellison syndrome can result in diarrhea of varying severity, often with significant steatorrhea.a. 13-18.24. 27. 28 Syndrome of Watery Diarrhea and Hypokalemia
In 1958, Verner and Morrison reported two patients with profuse watery diarrhea leading to hypokalemia and ultimate death from shock and dehydration. 29 At autopsy, both were found to have benign islet cell tumors. Neither showed evidence of peptic ulc~ration at any time during his illness. These authors found two other cases in the earlier literature in whom diarrhea and hypokalemia were the cause of death. The patient reported by Moldawer et apo in 1954 was found at autopsy to have a benign i slet cell adenoma of the pancreas and renal tubular changes consistent with hypokalemia; the other patient (Priest and Alexander 31 ) had an islet cell tumor at autopsy. Neither of these two patients had a malignant ulcer diathesis, although the patient reported by Priest and Alexander developed a gastric ulcer during steroid therapy. One other pertinent case reviewed by Verner and Morrison was that of Brown et al. 32 in 1950. This patient was operated upon for intestinal obstruction some 4 months after the onset of severe diarrhea. A l arge islet cell adenoma was removed at celiotomy and the patient's
CASE REPORTS
Februa1'Y 1966
diarrhea ceased. No studies were done on serum potassium levels in this patient. Discounting Brown's 1950 cases in whom hypokalemia was not clearly documented, there a re now 15 cases in the English literature including the present patient, in whom a profuse, watery, refractory diarrhea leading to hypokalemia has been associated with a nonspecific islet cell tumor of the pancreas. 17 , 19, 21, ~9- 3 1, 33- 38 In none of these patients has evidence for peptic ulceration or hypersecretion been obta ined. Clearly, these patients represent a syndrome distinct from that described by Zollinger and Ellison. Case Report This 49-year-old white female school teacher was admitted to UCLA Medical Center in January, 1964, with a history of progressive diarrhea associated with gradual weight loss and the development of profound weakness. In retrospect, the diarrhea began in the fall of 1960, was intermittent, and consisted of t wo to four mushy stools daily. By the summer of 1962, the episodes were much more severe, consisting of 15 movements per day including one or two nocturnal passages. Such stools were composed almost exclusively of water. These episodes would terminate abruptly and the passage of "mushy" stools would resume. The patient continued to work daily, but began to note some weakness as well as increasing thirst and mild weight loss which progressed in intensity until June, 1963. At that time she was found to be potassium-depleted by her physician and placed on oral potassium supplements. In spite of this therapy, she required hospitalization elsewhere in August and in December, 1963, because of flaccid paralysis associated with serum potassium levels of 2.2 to 2.5 meq per liter. The cause of the diarrhea was sought in extensive medical investigations during her hospitalizations. The following studies were normal: upper gastrointestinal and small bowel series, barium enema, proctosigmoidoscopy, numerous stool cultures, and microscopic stool examination for ova, parasites and enteric pathogens, radioiodinated triolein uptake, 1'81 thyroid uptake, quantitative gastric analysis, fecal fat determination, urinary 5-hydroxy indoleacetic acid, and D-xylose excretion. Initially she was hypokalemic and hypophosphatemic. An abnormal glucose tolerance test (fasting, 118 mg per 100 ml ; Y2 hr, 190 mg per 100 ml;
233
1 hr, 224 mg per 100 ml; 2 hr, 185 mg per 100 ml; and 3 hr, 110 mg per 100 ml) was obtained Other blood chemistries were normal. A urinary tract infection was found. In December, 1963, her weakness worsened coincident with an increase in stool frequency and episodes of nausea and vomiting. By the time of admission to UCLA she had lost 30 lb. The only other complaint she had was that of occasional flushing sensations of the face lasting a minute or two and not associated with reddening of the skin or wheezing. Fever, abdominal p ain, muscle c ramps, or tenderness were denied . Physical examination revealed a pleasant, cooperative white woman who was alert and in no acute distress. There was evidence of recent weight loss with loose skin of poor turgor. No cheilosis or glossitis was present. Her blood pres~ur~ was 95/60; pulse rate, 96 per min; respIratIOn rate, 18 per min; and temperature, ?7.2 C. Her abdomen felt doughy, and her nght kidney was easily palpable. The remainder of her physical examination was otherwise unremarkable. Laboratory studies included a hemoglobin of 14.7 g p er 100 ml; hematocrit, 40.5% ; white blood cells, 10,000 per mm", with a normal differential count. Serum potassium was 2.2 meq per liter; sodium, 130 meq per liter; C02, 15.5 meq per liter; creatinine, 1.5 mg per 100 ml; carotene, 252 y per 100 ml; alkaline phosphatase, 15.9 King-Armstrong units; fastmg blood sugar, 120 mg per 100 ml; calcium, 5.6 meq per liter ; phosphorus, 2.4 mg per 100 ml ~ total protein, 7.0 g per 100 ml with A/G ratIO of 4.6/ 2.4; and prothrombin time, 14.3 sec (89%). Two stool cultures for enteric pathog.ens and three stool studies for ova and paraSItes were negative. With repletion of her electrolyte and water deficits her hematocrit fell to between 30% and 25% and her total protein to 5.1 g per 100 ml. A 3-day fecal fat determination was normal at 3.0 g per 24 hr. Coombs test was negative, and bone marrow ex.amination was not remarkable except for mIld erythroid hyperplasia. Sigmoidoscopy to 25.0 cm as well as a repeat barium enema were within normal limits. Electrocardiograms were compatible with hypokalemia. A gastric secretory study in the fasting s ta te performed after fluoroscopic placement of the nasogastric tube in the antrum revealed a residual volume of 76 cc, with a pH of 2.2, and a hydrochloric acid concentration of 1.6 meq per liter. One-hour basal volume was 34 cc with hydrochloric acid output of 1.2 meq p e; hr. Following betazole hydrochloride (histalog) 70 mg im, the patient produced 7.2 and 9.7
234
CASE REPORTS
The small bowel was filled with fluid and appeared slightly injected, but was otherwise normal. Embedded in the tail of the pancreas was a globular mass measuring 5.5 by 4.5 by 4.0 cm (fig. 1). The distal body and tail of the pancreas, the spleen, a thin strip of small bowel, the appendix and contiguous cecum, and a sample of skeletal muscle were removed. Complete exploration revealed no other abnormalities. The pancreatic tumor weighed 85 g. Microscopic examination revealed a well encapsulated tumor composed of broad sheets of cells separated by numerous vascular channels with eosinophilic amorphous material within and around their lumina. The nuclei were relatively uniform, plump, and vesicular. Most contained a chromatin granule peripherally placed. There was no vascular invasion and no attempt at gland formation. The surrounding pancreas had well developed acinar and islet tissue. This histopathology is consistent with a benign non-f3 islet cell adenoma of the pancreas. Sections of spleen, small intestine, appendix, cecum, and skeletal muscle were histologically normal. The tumor was sectioned and pieces were placed in plastic bags and frozen in Dry Iceacetone immediately after removal. No gastrinlike activity could be detected in the tumor by Dr. M. 1. Grossman at the Wadsworth Veterans
meq of hydrochloric acid, respectively, in the succeeding 2 hr. Analysis of the basal gastric juice revealed sodium, 51.7 meq per liter; potassium, 9.5 meq per liter; and chloride, 132 meq per liter. All of these values are normal in our laboratory. Following this procedure, the patient experienced a transient decrease in her stool frequency lasting about 36 hr. Because she was given intravenous fluids at the previous rate, she rapidly became edematous and hyponatremic. By the time the overhydration was obvious, her diarrhea resumed, and she rapidly lost all of her excess fluid during the next 12 hr. Balance studies performed on the UCLA Metabolic Research Unit prior to surgery are summarized in tables 1 and 2. The individual values for three 24-hr periods have been totaled; the individual totals for each of the 3 days were very similar. The most striking values are those for the potassium and water balances which indicate that about 340 meq of K+ and 10.7 liters of water were required daily for balancing her enormous fecal output. The creatinine clearance and low urine output indicate that despite the large intake of fluids and salts, the patient's hypovolemia was incompletely corrected. Subsequent to these studies, a celiotomy was performed by Dr. William P. Longmire. The liver, gall bladder, and stomach were normal.
1. Summary of 3-day metabolic balance
TABLE
Intake Parentera l Oral
Output
Na+
K+
HCO,-
Cl-
Ca++
Phosphorus
Nitrogen
H,o
, meq
tneq
meq
meq
mg
mg
g
ml
4103 216
1028 120
2084
2961 237
2718
3561
26.7
26,200 9,560
940 39
2540 86
3156 <3
4350 493
17.1 14.6
29,836 2,345
+127
+572
-441
-1282
-5 .0
+ 3,579
3504 17.4
Stool Urine
+798
Balance
TABLE
Serum day
,
2. Summary of 3-day metabolic balance. Other serum, stool, and urine studies
Na+
K+
HC03-
Cl-
Ca++
meq /liter
0 1 2 3
Vol. 50, No.2
130 144 136 136
4.7 4.6 4.0 5.2
10 .7 27.6 25 .0 25 .0
Phosphorus
Mg++
mg/l00 ml
139 135 119
12.4 11.0 11.3 10.9
2.3 1.3 1.8 1.7
1.1 1.1 1.2
Crea-
tinine '.,
2.2 1.5 1.5 1.3
Creatinine clearance liter/day
22 28 57
pH
Osmolarity Weight
-kg
47.1 48.7 49 .3 48.8
S tool
IUrine
Stool Urine
-
milliasmal/liter
300 411 378
340 370 311
8.3 8.7 8.4
-
5.5 6.0 6.7
February 1966
CASE REPORTS
235
FIG. 1. Bisected islet cell adenoma.
Hospital, Los Angeles, California. The assay and amounts of tumor employed were similar to those which had previously detected gastrinlike activity in tumors from patients with the Zollinger-Ellison syndrome." With surgery the patient's diarrhea ceased and has not recurred. Except for a transient bout of epigastric and left shoulder pain on the 8th postoperative day without any rise in serum or urinary amylase, she had an uneventful postoperative course. An upper gastrointestinal series performed following this episode of pain was entirely normal. Transit time with indigo carmine, 7 days after the operation, was 12 hr as compared to a preoperative transit time of 48 min. The patient rapidly attained her normal weight and has been teaching school regularly since July, 1964. All of her previous biochemical abnormalities have reverted to normal, including the previously noted diabetic glucose tolerance curve. Her mouth-to-anus transit time using a charcoal marker is 18 hr, and she has one or two formed stools daily.
Discussion
Clinical Features The outstanding symptom of this group of patients is that of diarrhea of variable severity and duration, but generally of
progressive nature. The diarrheal stool in its fulminant form has the appearance of weak tea and contains very little form ed substance, while in the more quiescent form, the stools take on a mushy consistency. The stool is inoffensive, and no blood is present. Abdominal cramping is sometimes present while weight loss is inevitably seen. Nausea and vomiting may occur during the more fulminant episodes of diarrhea. As the diarrhea progresses, symptoms due to hypokalemia and dehydration appear. The patient complains of generalized muscular weakness and even paralysis, and may show signs of impending stupor. The stool volumes during these exacerbations can attain prodigious and frightenin g levels ; repletion of fluids and electrolytes cannot be delayed. The term pancreatic "cholera" seems appropriate in its emphasis on this violent and devastating phase of the disease, which if left untreated at this point inevitably results in progressive dehydration, hypokalemia, and death. In general, roentgenographic studies, stool cultures, sigmoidoscopy, stool fat determin ations, and minary 5-hydroxy
236
CASE REPORTS
indoleacetic acid determinations have been within normal limits. Although a slightly elevated urinary 5-hydroxy indoleacetic acid value has been reported in one patient by Espiner and Beaven, no particular significance was attributed to this finding.36 Steatorrhea, if present at all, is mild. 22 Table 3 outlines the important features of previously reported patients with this syndrome. Of the 15 patients, eight were women and seven were men. The age range was 19 to 67 with the greatest number, five, reported during the fifth decade. Diarrhea with or without symptoms of hypokalemia and weight loss were the presenting complaints in all and in some nausea and vomitihg were noted. Duration of symptoms varied from several months to as long as 15 years. Hypokalemia was documented in all cases. Neither peptic ulceration nor gastric hypersecretion was described. (The case of Charles and Cochrane had an esophageal ulceration which was thought to be due to protracted vomiting. 33 ) Indeed, histamine fast achlorhydria was documented in three instances 17, 36, 37 and "no free acid" reported in twO. 34 ,38 Low basal acid secretory rates were found by Parkins35 and in our patient. Satisfactory resection of a benign tumor with prompt and dramatic cessation of the diarrhea was accomplished in four cases including the ptesent patient. 21 , 34, 38 Surgery was performed in six other patients. One had a temporary remission following apparently complete removal of an islet cell tumor. However, 3 weeks later diarrhea recurred, and a second operation revealed metastases in the liver.36 The second patient died of pancreatitis following removal of an islet cell carcinoma and tumor-containing lymph ~odes.17 No tumor was found in a third patient at celiotomy, and diarrhea continued. Ultimately she died of a gangrenous small bowel obstruction and, at autopsy, a 2-cm benign islet cell adenoma was found buried in the head of the pancreas. 35 Two patients had metastases already present at celiotomy.22,37 The sixth patient had a pancreatic tumor removed 5 years prior to onset of diarrhea. Eighteen months after the onset of diarrhea exploration was negative.
Vol. 50, No.2
At necropsy following death from hypo~ kalemia an islet cell tumor was found in the tail of the pancreas. 31 In the remaining five cases operation was not performed. 19 , 29, 30, 33 These patients, as well as those patients with unresectable tumors,22, 37 died of intractable watery diarrhea, hypokalemia, dehydration, and shock. Thus, of 15 patients with this syndrome, six had malignant tumors and a seventh, the patient of Priest and Alexander, probably belongs in this category. Of the eight patients with benign adenomas, four were successfully resected with cure of the diarrhea. Five of the 15 patients in the present group showed a mildly to moderately elevated glucose tolerance curve. 21 , 22, 33, 36 Two of these five had successful resections with return of glucose tolerance to normal, concomitant with cessation of diarrhea and restoration of total body potassium. 21 Biological assay for glucagon activity in a Zollinger-Ellison tumor has been negative,39 and it seems unnecessary to ascribe impaired glucose tolerance to glucagon activity when other factors such as chronic potassium depletion exist. Indeed, impairment of glucose tolerance has been previously demonstrated with experimental potassium depletion. 40 Singleton et a1. 25 suggest that subtotal loss or destruction of f3 cells could produce hyperglycemia inpatients with islet cell tumors of the pancreas, but such was evidently not the case in these two patients. Unfortunately, glucose tolerance was not repeated in our patient prior to surgery after potassium repletion. An abnormal glucose tolerance test has been reversed to normal in primary aldosteronism following potassium repletion therapy.41 In three of the 15 patients more than one endocrine adenoma was found. Brown's patient had a pancreatic and a parathyroid adenoma ;38 Moldawer's patient a pancreatic, thyroid, and parathyroid adenoma ;30 and Verner and Morrison's first case a pancreatic ahd chromophobe adenoma. 29 The presence of multiple endocrine adenomas in three of 15 patients in this group corresponds roughly to the estimate that between 20 and 40% of patients with the Zollinger-Ellison syndrome have shown evidence of multiple
February 1966
CASE REPORTS
endocrine adenomatosis. 42 , 43 Four patients had hypercalcemia associated with the diarrhea, but only one of these, that of Brown and Crile,38 had a proved parathyroid adenoma. The patient of Verner and Morrison underwent a surgical procedure on the neck which revealed no parathyroid tumor and subsequent autopsy confirmed this fact. The patient reported by Chears et a1. 21 and our patient had a return of serum calcium and phosphorus to normal following successful resection of the islet cell tumor and cessation of diarrhea. Thus it is apparent that the hypercalcemia and hypophosphatemia occasionally seen in patients with this syndrome is not invariably due to a parathyroid adenoma and that neck exploration can be postponed until the effect of the resection of the pancreatic tumor on these electrolytes can be assessed. There appears to be no satisfactory explanation for the hypercalcemia and hypophosphatemia observed in these patients. An interesting complaint of our patient and of the patient of Murray et al,34 was a flushing sensation about the face and neck with no discernible reddening of the skin. Urinary 5-hydroxy indoleacetic acid was normal in both and the flushing disappeared following resection of the tumor. The histopathology of these tumors did not resemble that of carcinoid tissue. The use of corticosteroids has been reported by some to bring about a dramatic slowing of the diarrhea,21, 31, 37 but this has not been the experience of othersY, 19, 22, 33, 35 A trial of this medication may be justified while the patient is being prepared for surgery. Other factors reported to have ameliorated the diarrhea include nasogastric suction, vomiting, and pregnancy. Parkins reports that his patient enjoyed remission from diarrhea during each of three pregnancies, but he was unable to maintain remission with estrogenic or adrenocortical steroids. 35 Etiology of Diarrhea
The circumstantial evidence available strongly suggests that there is a hormonelike substance produced by the islet cell tumor which causes diarrhea. Telling and Smiddy in 1961 first made the suggestion
237
that more than one hormone may be elaborated by noninsulin-secreting islet cell tumors.22 As previously noted, the most common syndrome is that produced by a gastrin-secreting tumor with hypersecretion of hydrochloric acid and peptic ulcer diathesis, as originally described by Zollinger and Ellison. Another syndrome is characterized by watery diarrhea and hypokalemia, without hypersecretion of hydrochloric acid. This syndrome is exemplified by the present case and those reviewed in table 3. Assay of tumor tissue from two such patients (our patient by Dr. M. 1. Grossman and Hindle's patient by Prof. R. A. Gregory) was negative for gastrin activity. These negative findings show that the postulated hormone that produces the syndrome is not gastrin. A third group of patients has manifestations of both syndromes, i.e. hypersecretion, peptic ulceration, watery diarrhea, and hypokalemia. In these patients secretion of both gastrin and a diarrheogenic hormone by the islet cell tumor may be postulated (fig. 2). The mechanism of production of diarrhea remains obscure. l7 , 22, 36, 44 An excessive secretion of succus entericus would seem the most appealing theory. The excessive secretion of potassium into gut lumen as shown by Espiner and Beaven without a change in reabsorption would seem indirectly to support this idea. 36 A portion of the tumor from our patient after storage at -20 C for 5 months was lyophilized and then shipped as a dry powder to Prof. Nathan Lifson at the University of Minnesota. Utilizing the technique of Hakim et al.,45 no effect on water or glucose transport could be demonstrated by the addition of aqueous extracts of lyophilized tumor tissue to either the serosal or both compartments of canine small bowel mucosal preparations. Certain aspects of net N a + movement were different in the presence of tumor extracts but the N a + studies are of preliminary nature. Dr. Charles Edwards of the University of Minnesota found no effect on short circuit current when lyophilized tissue was added to the inside bathing solution of a frog skin preparation. Nonetheless, it is apparent from the
~
00
56
F
M
M
Priest and Alexander, 1957
Verner and Morrison, 1958
Verner and Morrison, 1958
34
60
49
47
26
F
F
M
F
F
Charles and Cochr ane, 1960
Chears et a!., 1960
Murray et aI., 1961
T elling and Smiddy, 1961
P arkins, 1961
19
67
57
Age
F
--
Sex
Moldawer et a!., 1954
Author
yr
8
Diarrhea
No
13 mo
Diarrhea, weight loss
Diabetic
15 mo
15%
Diarrhea, weight loss , vomiting
Diabetic
2
No data Diarrhea, Bushing
Diarrhea, weight loss, vomiting
Absent acid)
Low
Absent ("low" free acid)
Low
-
Absent
Low
(no free
Blood-streaked emesis. Noul cer
Esophageal ul ce r due to vomiting (?). N o other ulcer
Absent
Absent
Gastric ulc er during steroid Rx
Low
Low
Low
3
No data Diarrhea, weight loss
Low
Low
Diabetic
Peptic ulcer
LowK Absent nephropathy
Serum K
10 mo
6 mo
4
Duration of symptoms
No data Diarrhea, weight loss
No d ata .Diarrhea, weight loss
N o data Diarrhea, weight loss
test
Presenting symptoms
No findings
P ancreatic tumor (lCT) nonresec table
ICT (excised)
rCT (excised)
Not done
Not done
Not done
Pancreatic tumor excised 5 yr earlier. 2nd laparotomy negative
Not done
Laparotomy
Small bowel obstruction with ga ngrene
Hypok alemia
Hypokalemia
Hypokalemia
Hypokalemia
Hypokalemia
Hypokalemia
Cause of death
3. A summary of previously reported cases of islet cell tumors (leT) with diarrhea and hypokalemia
Oral glucose tolerance
TABLE
ICT
Not done
ICTwith pleural metastases
lCT
rCT
lCT
ICT
Autopsy
Non-a or /3
non-/3
a or A
Non-/3
Non-/3
non-/3
? a,
N on-/3
?
N on-/3
?
B
M
B
B
M
B
B
Not stated
B
(M)
Benign (B) vs. Cell type malignant
"'co"""
M
Brown et a!., 1964
F
34
M
Hindle et a!., 1964
Matsumoto et a!., 1966
29
M
Deleu et a!., 1964
49
59
53
M
E;dmeads, 1962
49
F
E;spiner and Beaven, 1962
Diabetic
No
No
No
No
Diabetic
Diarrhea, weight loss
Diarrhea, vomiting, lethargy
Diarrhea, backache, weight loss
Diarrhea, stupor
Diarrhea, vomiting, weight loss
(a) Diarrhea (b) Diarrhea, weight loss
2
10 rna
9 rna
4
3
12 rna 4 rna
Low
Low
Low
Low
Low
Low
Absent
Absent (no free acid)
Absent (achlorhydric)
Absent (achlorhydric)
Absent
Absent (achlorhydric)
rCT (excised)
2 parathyroid adenoma. Pancreatic ICT (excised)
Pancreatic tumor with metastases
Pancreatic tumor with metastases
Not done
(a) Retroperitoneal mass (b) Pancreatic tumar. No gross metastases
Hypokalemia
Postoperative pancreatitis
Hypokalemia
Hypokalemia
ICTwith metastases
ICT
rCT with metastases
Non-(3
Non-a or (3
?
Non-a or (3
Non-a or (3
Metastatic Non-a or (3 ICT
B
B
M
M
M
M
CASE REPORTS
240 ISLET
INSULIN
'fJ
Vol. 50, No.2
CELL TUMOR OF PANCREAS
SECRETING CELL'
r - - - - I I
HYPOGLYCEMIA
- - - - -,
DIARRHEOGENIC PRINCIPLE PRODUCTION
---- . . . 1 ---- ----,
L---r
IH YPERSECRETION SUCCUS?I I INCREASED MOTILITY? I I DECREASED ABSORPTION?I L. .J
GASTRIN PRODUCTION
1
I ATION F C ENZYMES
I STEATO RRHEA
HYPERSECRETION OF HC I
SEVERE PEPTIC ULCER DIATHESIS
•
ZOLLINGER ELLISON SYNDROME
I I I
---r----
l
IRRITATION OF SMALL BOWEL INCREASED MOTILITY
•
NONSPECIFIC DIARRHEA
PROFUSE WATERY DIARRHEA
t HYPOKALEMIA DEHYDRATION
•
PANCREATIC "CHOLERA"
FIG. 2. Syndromes produced by islet cell tumors of the pancreas.
metabolic balance data (table 1) that there was an enormous loss of water, sodium, and potassium in the patient's stool. Under normal conditions, the daily fecal sodium and potassium loss is less than 10 meq each. 46 • 47 The data also indicate that, as is normally the case, the patient's stool was approximately isotonic; this would suggest that the primary problem was one of oversecretion of normal intestinal fluids, but diminished intestinal absorption might also be a factor. Obviously the negative in vitro studies are subject to several interpretations and should not be construed as strong evidence against a hormonal etiology of the diarrhea. A less appealing explanation for the
cause of the diarrhea is increased intestinal motility. Indeed, the mouth-to-anus transit time of indigo carmine was 48 min in our patient prior to surgery. Espiner and Beaven demonstrated increased contractions in a strip of guinea pig ileum exposed to their patient's serum, but not to a saline extract of the tumor, to normal human serum, or to an extract of endometrium. 36 However, we are unaware of any evidence that increased intestinal motility'per se can result in electrolyte hypersecretion. Conclusion
A patient with an islet cell adenoma of the pancreas was seen with symptoms of
CASE REPORTS
February 1966
protracted watery diarrhea, weight loss, hypokalemia, and dehydration. She underwent successful resection of the tumor with dramatic cessation of symptoms. Metabolic balance data are presented to document the enormous fecal loss of water, sodium, and potassium. Clinical features of the syndrome are discussed, and a diarrheogenic hormone is postulated to account for the clinical manifest ations which apparently may exist in a pure form as in the cases reviewed, or in combination with the more common and familiar Zollinger-Ellison syndrome as originally defined. Assay studies of the resected tumor failed to show the presence of gastrin. No effect of an extract of the tumor on water or glucose transport across isolated in vitro preparations of canine small intestinal mucosa could be demonstrated. A review of similar cases reported previously indicates the importance of early recognition and prompt surgical removal of the tumor. In those instances where the tumor is benign, the outlook for a permanent cure is excellent. REFERENCES 1. Wilder, R. M., F. N. Allan, M. H. Power, and H. E. Robertson. 1927. Carcinoma of the islands of the pancreas. Hyperinsulinism and hypoglycemia. J. A. M. A. 89: 348-355. 2. Howard, J. M., and G. L. Jordan. 1960. Surgical diseases of the pancreas, p. 321--447. J. B. Lippincott Company, Philadelphia. 3. Zollinger, R. M., and E. H. Ellison. 1955. Primary peptic ulcerations of the jejunum associated with islet-cell tumors of the pancreas. Ann. Surg. 14B: 709-728. 4. Zollinger, R. M., and E. H. Ellison. 1959. Pancreatic endocrine function and peptic ulceration. Gastroenterology 37: 401--411. 5. Zollinger, R. M ., and T. V. Graig. 1960 Endocrine tumors and peptic ulcer. Amer. J. Med. 29: 761-768. 6. Zollinger, R. M., and G. N. Grant. 1964. Ulcerogenic tumor of the pancreas. J. A. M. A.190: 181-184. 7. Gregory, R. A., H. J. Tracy, J. M. French, and W. Sircus. 1960. Extraction of a gastrin-like substance from a pancreatic tumor in a case of Zollinger-Ellison syndrome. Lancet 1: 1045-1048. 8. Code, C. F., G. A. Hallenbeck, and W. H. J.
241
Summerskill. 1963. Extraction of a gastric secretagogue from primary and metastatic islet cell tumors in three cases of the Zollinger-Ellison Syndrome. J. Surg. Res. 2: 136-140.
9. Grossman, M. I., H. J. Tracy, and R. A. Gregory. 1961. Zollinger-Ellison Syndrome in a B antu woman, with isolation of a gastrinlike substance from the primary and secondary tumors. II. Extraction of gastrinlike activity from tumors. Gastroenterology
41: 87-91. 10. Gregory, R. A., and H. J. Tracy. 1964. Constitution and properties of two gastrins extracted from hog antral mucosa. Gut 5: 103-117. 11. Parker, P. E., K. Soergel, and E. H. Ellison. 1963. Effects of excessive hydrochloric acid on canine GI tract. In American College of Surgeons Surgical Forum, Chicago . Amer. ColI. Surg. 14: 333. 12. Summerskill, W. H . J . 1959. Malabsorption and jejunal ulceration due to gastric hypersecretion with pancreatic islet-cell hyperplasia. Lancet 1 : 120-123. 13. Maynard, E . P., III, and W. W. Point. 1958. Steatorrhea associated with ulcerogenic tumor of pancreas. ArneI'. J. Med. 25: 456--459. 14. Rawson, A. B., M. T. England, G. G. Gilliam, J. M. French, and F. A. R. Stammers. 1960. Zollinger-Ellison Syndrome with diarrhea and malabsorption. Lancet 2: 131-134. 15. Spencer, S. S., and W. H. J. Summerskill. 1963. Malabsorption induced by gastric hypersecretion due to ectopic islet cell adenoma. Amer. J. Gastroent. 39 : 26-30. 16. Shay, H ., W. Y. Chey, S. M. Koide, and W. E. Burnett. 1962. Mechanism of the disordered physiology involved in the Zollinger-Ellison Syndrome. Amer. J. Dig. Dis. 7: 401--419. 17. Deleu, J., H. Tytgat, and G. E. Van Goidsenhoven. 1964. Diarrhea associated with pan-
creatic islet-cell tumors. Amer. J. Dig. Dis. 9: 97-108. 18. Donaldson, R. M ., P. R. vom Eigen, and R. W. Dwight. 1957. Gastric hypersecretion,
peptic ulceration, and islet cell tumor of the pancreas (the Zollinger-Ellison Syndrome): report of a case and review of the literature. New Eng. J. Med. B57: 965-970. 19. Edmeads, J. G., R. E. Matthews, N. T. M cPhedran, and C. Ezrin. 1962. Diarrhea caused by pancreatic islet-cell tumors. Canad. Med. Ass. J. 86: 847-851. 20. Kabler, J. D. 1960. Rare malabsorption syndromes. Ann. Intern. Med. 52: 1221-1235. 21. Cheal'S, W. C., Jr., J . E. Thompson, J . B. Hutcheson, and C. O. Patterson. 1960.
242
22.
23.
24.
25.
CASE REPORTS
Pancreatic islet cell tumor with severe diarrhea. Amer. J. Med. 29: 529-533. Telling, M., and F. G. Smiddy. 1961. Islet cell tumors of the pancreas with intractable diarrhea. Gut 2: 12-17. Haubrich, W. S., F. S. O'Neil, and M. A. Block. 1962. Observations on steatorrhea associated with gastric hypersecretion and pancreatic islet cell neoplasm. Ann. Intern. Med. 56: 302-307. Shafer, W. H. 1964. Nonbeta islet-cell carcinoma of the pancreas presenting as diarrea. Ann. Intern. Med. 61: 539-543. Singleton, J. W., F. Kern, Jr., and W. R Waddell. 1965. Diarrhea and pancreatic islet cell tumor. Gastroenterology 49: 197-
208. 26. Amberg, J. R, E. H. Ellison, S. D. Wilson, and F. F. Zboralske . 1964. Roentgenography
27.
28.
29.
30.
31.
32.
33.
34.
and the Zollinger-Ellison syndrome. J. A. M. A.190: 185-187. Cooke, W. T., D. 1. Fowler, R Gaddie, E. V. Cox, M. J. Meynell, and D. Brewer. 1960. Multiple endocrine adenoma syndrome. Gut 1 : 71-75. Forty, F., and G. M . Barrett. 1952. Peptic ulceration of the third part of the duodenum, associated with islet-cell tumors of the pancreas. Brit. J. Surg. 40: 60-63. Verner, J. V., and A. B. Morrison. 1958. Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Amer. J. Med. 25 : 374-380. Moldawer, P. M., G. L. Nardi, and J. W. Raker. 1954. Concomitance of multiple adenomas of· the parathyroids and pancreatic islets with tumor of the pituitary: a syndrome with familial incidence. Amer. J. Med . Sci. 228: 190-206. Priest, W. M., and M . K. Alexander. 1957. Islet-cell tumor of the pancreas with peptic ulceration, diarrhea, and hypokalemia. Lancet 2: 1145-1147. Brown, C. H ., W. E. Neville, and J . B. Hazard. 1950. I slet cell adenoma, with hypoglycemia, causing duodenal obstruction. Surgery 27 : 616-620. Charles, B., and W. A. Cochrane. 1960. Islet cell tumor of pancreas with chronic diarrhea and hypokalemia. Canad. Med. Ass. J . 82: 579-586. Murray, J. S., R . R. Paton, and C . E . Pope, II. 1961. P ancreatic tumor associated with
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
Vol. 50, No.2
flushing and diarrhea. New Eng. J. Med. 264: 436-439. Parkins, R A. 1961. Severe watery diarrhea and potassium depletion associated with an islet cell tumor of the pancreas. Brit. Med. J. 2: 356-357. Espiner, E. A., and D. W. Beaven. 1962. Nonspecific islet cell tumor of the pancreas with diarrhea. Quart. J. Med. 31: 447-471. Hindle, W., D. J. McBrien, and B. Creamer. 1964. Watery diarrhea and an islet cell tumor. Gut 5: 359-362. Brown, C. H., and G. Crile, Jr. 1964. Pancreatic adenoma with intractable diarrhea, hypokalemia, and hypercalcemia. J. A. M. A.190: 30-34. Eiseman, B., and R. M. Maynard. 1956. A non-insulin producing islet cell adenoma associated with progressive peptic ulceration (the Zollinger-Ellison Syndrome). Gastroenterology 31: 296-304. Sagild, U., V. Andersen, and P. B. Andreasen. 1961. Glucose tolerance and insulin responsiveness in experimental potassium depletion. Acta Med. Scand. 169: 243-251. Horton, R, J. P. Kane, E. G. Biglieri, G. M. Grodsky, and P. H. Forsham. 1963. Carbohydrate metabolism in primary aldosteronism. Clin. Res. 11: 83. Ballard, H. S., B. Frame, and R J. Hartsock. 1964. Familial multiple endocrine adenomapeptic ulcer complex. Medicine 43: 481-516. Huizenga, K. A., W. 1. M . Goodrick, and W. H . J . Summerskill. 1964. Peptic ulcer with islet cell tumor; a reappraisal. Amer. J. Med. 37: 564-577. Morrison, 'A. B., A. J . Rawson, and W. T. Fitts, Jr. 1962. The syndrome of refractory watery diarrhea and hypokalemia in patients with non-insulin secreting islet cell tumor. Amer. J. Med. 32: 119-127. Hakim, A., R. G. Lester, and N. Lifson. 1963. Absorption by an in vitro preparation of dog intestinal mucosa. J. Appl. Physiol. 18:
409-413. 46. Dempsey, E. F ., E. L. Carroll, F. Albright, and P. H. Henneman. 1958. A study of
factors determining fecal electrolyte excretion. Metabolism 7: 108-111. 47. Shamblin, J. R, J. F. Huff, J. M. Waugh, and C. G. Moertel. 1962. Villous adenocarcinoma of the colon with pronounced electrolyte distu'rbance. Ann. Surg. 156: 318-326.
GASTROENTEROL OGY
Copyright © 1966 by The Williams & Wilkins Co.
CASE REPORTS WATERY DIARRHEA AND HYPOKALEMIA ASSOCIATED WITH PANCREATIC ISLET CELL ADENOMA KEN NETH K. MATS UMOTO, M .D., SCHULTZE, M.D.,
A. A.
J. B.
PETER, M.D. , PH.D. , RAYMO ND
HAKIM, M.D., AND PETER
T.
G.
FRANCK, M.D.
Department of Medicine , UCLA Center for the Health Sciences, Los Angeles, California , and the Department of Urology, Anker Hospit al, Saint Paul, Minnesota
Three distinct clinical syndromes have been described in association with islet cell tumors of the pancreas. Hypoglycemic episodes have long been recognized as manifestations of tumors of the f3 cell type. More recently the Zollinger-Ellison syndrome has been recognized as a manifestation of non-f3 islet cell tumors. The main purposes of this review are to emphasize the third and least well recognized syndrome of this group, to report our recent experiences during the care and cure of such a patient with a profuse watery diarrhea and hypokalemia, to report negative results of extracts of the tumor on water and glucose transport in an in vitro preparation of canine mucosa, and to discuss the etiology of the choleralike diarrhea. Syndromes Produced by Pancreatic Islet Cell Tumors
Hypoglycemia The concept that pancreatic tumors may have clinical significance as a result of secretory activity was advanced by Wilder et al. in 1927, who reported a case of a malignant islet cell tumor of the pancreas with associated hypoglycemia. 1 Since then, many cases of benign and malignant "functioning" islet cell tumors have been reported, with clinical cure of the hypoReceived August 24, 1965. Accepted October 11, 1965. Address requests for reprints to: Dr. K enneth K. Matsumoto, 9735 Wilshire Boulevard, Beverly Hills, California 90212. The authors gratefully acknowledge the encouragement and advice given them in preparation of this manuscript by Dr. Morton I . Grossman. 231
glycemic episodes being effected upon satisfactory extirpation of the tumor. In 1960, Howard and Jordan published an extensive review of 766 islet cell tumors reported in the world Iiterature. 2 Of these 766 benign and malignant islet cell adenomas, 549 (71.6%) were "functioning," i.e. associated with hypoglycemia, whereas 178 (23.2%) were not associated with hypoglycemia and could be classified "nonfunctioning." In 39 cases (5.2%), this distinction was not made. The Zollinger-Ellison Syndrome The idea that a smaller number of these islet cell tumors of the pancreas could be associated with an entirely different clinical syndrome was first advanced by Zollinger and Ellison in 1955.3 They reported two cases of recurrent jejunal ulceration" associated with gastric hypersecretion and the finding of a nonspecific islet cell tumor of the pancreas in each instance. Since then, the Zollinger-Ellison syndrome has been defined by the diagnostic triad of: (a) a fulminating ulcer diathesis affecting stomach, duodenum,' or proximal jej unum, which is refractory to the usual medical or surgical measures short of total gastrectomy; (b) marked gastric hypersecretion characterized by overnight volumes approaching 2000 to 3000 ml per 12 hr , and hydrochloric acid production from four to 15 times the normal overnight value of less than 18 meq per 12 hr; and (c) the demonstration at celiotomy of an islet cell tumor. 4 ,5 By 1964, Zollinger was able to review more than 250 such cases and noted that enteritis was a frequent findin g in this
232
CASE REPORTS
clinical syndrome. 6 He reports diarrhea of varying severity in 40% of all patients having an ulcerogenic tumor of the pancreas. In approximately 20% of such patients, enteritis of some degree was the initial complaint, followed in months or in years by severe ulcer diathesis. Thus he suggests that enteritis be included as part of this syndrome. 6 The nature of the ulcerogenic principle thought to be elaborated by such islet cell tumors became the subject of an intensive search by gastrointestinal physiologists. Gregory et al. in 1960 extracted a potent stimulator of acid secretion, presumably gastrin, from the tumor of a patient with the Zollinger-Ellison syndrome. 7 Confirmation of this followed a few months later by Code et al. B In 1961, Grossman and Gregory reported similar gastrinlike activity of tumor extracts derived from both primary and metastatic nodules in a Bantu woman with the Zollinger-Ellison syndrome. 9 In 1964, Gregory and Tracy reported that the active principle extracted from a Zollinger-Ellison tumor had the same physiological actions as gastrin obtained from hog antral mucosa.10 They concluded that the stimulant present in such ulcerogenic tumors is, in fa ct , gastrin. The diarrhea seen in many of the patients with the Zollinger-Ellison syndrome has been attributed to the enormous volume of hydrochloric acid. excreted by the stomach with resultant irritation of the small bowel. Experiments in the dog l l and the discovery of a marked reduction in intraduodenal pH in several such patients tend to confirm this view. 12 - 16 Several authors have noted that the diarrhea could be controlled with nasogastric suction but that it recurred when the aspiration was stopped. 15 - 19 The administration of optimal counts of the anticholinergic drug tricyclamol (Elorine chloride) controlled diarrhea in a single patient reported by Shay et al. who found that gastric secretion was diminished by the drug. 16 Recurrence of diarrhea after discontinuation of the drug and control with reinstitution of therapy was noted. Antacids were in effective. Intestinal motility was not separat ely studied.
Vol. 50, No.2
The steatorrhea of varying degree a:3sociated with the Zollinger-Ellison syndrome has been attributed to inactivation of pancreatic lipase at the low intraduodenal pH reported in these patients. pH values as low as 1.4 have been observed. Although previous authors have commented on the absence of significant abnormalities on small bowel biopsies/a. 15. 20-24 a recent report notes that small bowel mucosal abnormalities do occur in this disease, presumably as a result of the acid insult. 2 5 Roentgenographic changes consisting of irregularity and thickening of the small bowel mucosa and luminal dilation have been reported. 26 Regardless of the exact explanation , it is clear that gastric hypersecretion with resultant hyp eracidity in patients with the Zollinger-Ellison syndrome can result in diarrhea of varying severity, often with significant steatorrhea.a. 13-18.24. 27. 28 Syndrome of Watery Diarrhea and Hypokalemia
In 1958, Verner and Morrison reported two patients with profuse watery diarrhea leading to hypokalemia and ultimate death from shock and dehydration. 29 At autopsy, both were found to have benign islet cell tumors. Neither showed evidence of peptic ulc~ration at any time during his illness. These authors found two other cases in the earlier literature in whom diarrhea and hypokalemia were the cause of death. The patient reported by Moldawer et apo in 1954 was found at autopsy to have a benign i slet cell adenoma of the pancreas and renal tubular changes consistent with hypokalemia; the other patient (Priest and Alexander 31 ) had an islet cell tumor at autopsy. Neither of these two patients had a malignant ulcer diathesis, although the patient reported by Priest and Alexander developed a gastric ulcer during steroid therapy. One other pertinent case reviewed by Verner and Morrison was that of Brown et al. 32 in 1950. This patient was operated upon for intestinal obstruction some 4 months after the onset of severe diarrhea. A l arge islet cell adenoma was removed at celiotomy and the patient's
CASE REPORTS
Februa1'Y 1966
diarrhea ceased. No studies were done on serum potassium levels in this patient. Discounting Brown's 1950 cases in whom hypokalemia was not clearly documented, there a re now 15 cases in the English literature including the present patient, in whom a profuse, watery, refractory diarrhea leading to hypokalemia has been associated with a nonspecific islet cell tumor of the pancreas. 17 , 19, 21, ~9- 3 1, 33- 38 In none of these patients has evidence for peptic ulceration or hypersecretion been obta ined. Clearly, these patients represent a syndrome distinct from that described by Zollinger and Ellison. Case Report This 49-year-old white female school teacher was admitted to UCLA Medical Center in January, 1964, with a history of progressive diarrhea associated with gradual weight loss and the development of profound weakness. In retrospect, the diarrhea began in the fall of 1960, was intermittent, and consisted of t wo to four mushy stools daily. By the summer of 1962, the episodes were much more severe, consisting of 15 movements per day including one or two nocturnal passages. Such stools were composed almost exclusively of water. These episodes would terminate abruptly and the passage of "mushy" stools would resume. The patient continued to work daily, but began to note some weakness as well as increasing thirst and mild weight loss which progressed in intensity until June, 1963. At that time she was found to be potassium-depleted by her physician and placed on oral potassium supplements. In spite of this therapy, she required hospitalization elsewhere in August and in December, 1963, because of flaccid paralysis associated with serum potassium levels of 2.2 to 2.5 meq per liter. The cause of the diarrhea was sought in extensive medical investigations during her hospitalizations. The following studies were normal: upper gastrointestinal and small bowel series, barium enema, proctosigmoidoscopy, numerous stool cultures, and microscopic stool examination for ova, parasites and enteric pathogens, radioiodinated triolein uptake, 1'81 thyroid uptake, quantitative gastric analysis, fecal fat determination, urinary 5-hydroxy indoleacetic acid, and D-xylose excretion. Initially she was hypokalemic and hypophosphatemic. An abnormal glucose tolerance test (fasting, 118 mg per 100 ml ; Y2 hr, 190 mg per 100 ml;
233
1 hr, 224 mg per 100 ml; 2 hr, 185 mg per 100 ml; and 3 hr, 110 mg per 100 ml) was obtained Other blood chemistries were normal. A urinary tract infection was found. In December, 1963, her weakness worsened coincident with an increase in stool frequency and episodes of nausea and vomiting. By the time of admission to UCLA she had lost 30 lb. The only other complaint she had was that of occasional flushing sensations of the face lasting a minute or two and not associated with reddening of the skin or wheezing. Fever, abdominal p ain, muscle c ramps, or tenderness were denied . Physical examination revealed a pleasant, cooperative white woman who was alert and in no acute distress. There was evidence of recent weight loss with loose skin of poor turgor. No cheilosis or glossitis was present. Her blood pres~ur~ was 95/60; pulse rate, 96 per min; respIratIOn rate, 18 per min; and temperature, ?7.2 C. Her abdomen felt doughy, and her nght kidney was easily palpable. The remainder of her physical examination was otherwise unremarkable. Laboratory studies included a hemoglobin of 14.7 g p er 100 ml; hematocrit, 40.5% ; white blood cells, 10,000 per mm", with a normal differential count. Serum potassium was 2.2 meq per liter; sodium, 130 meq per liter; C02, 15.5 meq per liter; creatinine, 1.5 mg per 100 ml; carotene, 252 y per 100 ml; alkaline phosphatase, 15.9 King-Armstrong units; fastmg blood sugar, 120 mg per 100 ml; calcium, 5.6 meq per liter ; phosphorus, 2.4 mg per 100 ml ~ total protein, 7.0 g per 100 ml with A/G ratIO of 4.6/ 2.4; and prothrombin time, 14.3 sec (89%). Two stool cultures for enteric pathog.ens and three stool studies for ova and paraSItes were negative. With repletion of her electrolyte and water deficits her hematocrit fell to between 30% and 25% and her total protein to 5.1 g per 100 ml. A 3-day fecal fat determination was normal at 3.0 g per 24 hr. Coombs test was negative, and bone marrow ex.amination was not remarkable except for mIld erythroid hyperplasia. Sigmoidoscopy to 25.0 cm as well as a repeat barium enema were within normal limits. Electrocardiograms were compatible with hypokalemia. A gastric secretory study in the fasting s ta te performed after fluoroscopic placement of the nasogastric tube in the antrum revealed a residual volume of 76 cc, with a pH of 2.2, and a hydrochloric acid concentration of 1.6 meq per liter. One-hour basal volume was 34 cc with hydrochloric acid output of 1.2 meq p e; hr. Following betazole hydrochloride (histalog) 70 mg im, the patient produced 7.2 and 9.7
234
CASE REPORTS
The small bowel was filled with fluid and appeared slightly injected, but was otherwise normal. Embedded in the tail of the pancreas was a globular mass measuring 5.5 by 4.5 by 4.0 cm (fig. 1). The distal body and tail of the pancreas, the spleen, a thin strip of small bowel, the appendix and contiguous cecum, and a sample of skeletal muscle were removed. Complete exploration revealed no other abnormalities. The pancreatic tumor weighed 85 g. Microscopic examination revealed a well encapsulated tumor composed of broad sheets of cells separated by numerous vascular channels with eosinophilic amorphous material within and around their lumina. The nuclei were relatively uniform, plump, and vesicular. Most contained a chromatin granule peripherally placed. There was no vascular invasion and no attempt at gland formation. The surrounding pancreas had well developed acinar and islet tissue. This histopathology is consistent with a benign non-f3 islet cell adenoma of the pancreas. Sections of spleen, small intestine, appendix, cecum, and skeletal muscle were histologically normal. The tumor was sectioned and pieces were placed in plastic bags and frozen in Dry Iceacetone immediately after removal. No gastrinlike activity could be detected in the tumor by Dr. M. 1. Grossman at the Wadsworth Veterans
meq of hydrochloric acid, respectively, in the succeeding 2 hr. Analysis of the basal gastric juice revealed sodium, 51.7 meq per liter; potassium, 9.5 meq per liter; and chloride, 132 meq per liter. All of these values are normal in our laboratory. Following this procedure, the patient experienced a transient decrease in her stool frequency lasting about 36 hr. Because she was given intravenous fluids at the previous rate, she rapidly became edematous and hyponatremic. By the time the overhydration was obvious, her diarrhea resumed, and she rapidly lost all of her excess fluid during the next 12 hr. Balance studies performed on the UCLA Metabolic Research Unit prior to surgery are summarized in tables 1 and 2. The individual values for three 24-hr periods have been totaled; the individual totals for each of the 3 days were very similar. The most striking values are those for the potassium and water balances which indicate that about 340 meq of K+ and 10.7 liters of water were required daily for balancing her enormous fecal output. The creatinine clearance and low urine output indicate that despite the large intake of fluids and salts, the patient's hypovolemia was incompletely corrected. Subsequent to these studies, a celiotomy was performed by Dr. William P. Longmire. The liver, gall bladder, and stomach were normal.
1. Summary of 3-day metabolic balance
TABLE
Intake Parentera l Oral
Output
Na+
K+
HCO,-
Cl-
Ca++
Phosphorus
Nitrogen
H,o
, meq
tneq
meq
meq
mg
mg
g
ml
4103 216
1028 120
2084
2961 237
2718
3561
26.7
26,200 9,560
940 39
2540 86
3156 <3
4350 493
17.1 14.6
29,836 2,345
+127
+572
-441
-1282
-5 .0
+ 3,579
3504 17.4
Stool Urine
+798
Balance
TABLE
Serum day
,
2. Summary of 3-day metabolic balance. Other serum, stool, and urine studies
Na+
K+
HC03-
Cl-
Ca++
meq /liter
0 1 2 3
Vol. 50, No.2
130 144 136 136
4.7 4.6 4.0 5.2
10 .7 27.6 25 .0 25 .0
Phosphorus
Mg++
mg/l00 ml
139 135 119
12.4 11.0 11.3 10.9
2.3 1.3 1.8 1.7
1.1 1.1 1.2
Crea-
tinine '.,
2.2 1.5 1.5 1.3
Creatinine clearance liter/day
22 28 57
pH
Osmolarity Weight
-kg
47.1 48.7 49 .3 48.8
S tool
IUrine
Stool Urine
-
milliasmal/liter
300 411 378
340 370 311
8.3 8.7 8.4
-
5.5 6.0 6.7
February 1966
CASE REPORTS
235
FIG. 1. Bisected islet cell adenoma.
Hospital, Los Angeles, California. The assay and amounts of tumor employed were similar to those which had previously detected gastrinlike activity in tumors from patients with the Zollinger-Ellison syndrome." With surgery the patient's diarrhea ceased and has not recurred. Except for a transient bout of epigastric and left shoulder pain on the 8th postoperative day without any rise in serum or urinary amylase, she had an uneventful postoperative course. An upper gastrointestinal series performed following this episode of pain was entirely normal. Transit time with indigo carmine, 7 days after the operation, was 12 hr as compared to a preoperative transit time of 48 min. The patient rapidly attained her normal weight and has been teaching school regularly since July, 1964. All of her previous biochemical abnormalities have reverted to normal, including the previously noted diabetic glucose tolerance curve. Her mouth-to-anus transit time using a charcoal marker is 18 hr, and she has one or two formed stools daily.
Discussion
Clinical Features The outstanding symptom of this group of patients is that of diarrhea of variable severity and duration, but generally of
progressive nature. The diarrheal stool in its fulminant form has the appearance of weak tea and contains very little form ed substance, while in the more quiescent form, the stools take on a mushy consistency. The stool is inoffensive, and no blood is present. Abdominal cramping is sometimes present while weight loss is inevitably seen. Nausea and vomiting may occur during the more fulminant episodes of diarrhea. As the diarrhea progresses, symptoms due to hypokalemia and dehydration appear. The patient complains of generalized muscular weakness and even paralysis, and may show signs of impending stupor. The stool volumes during these exacerbations can attain prodigious and frightenin g levels ; repletion of fluids and electrolytes cannot be delayed. The term pancreatic "cholera" seems appropriate in its emphasis on this violent and devastating phase of the disease, which if left untreated at this point inevitably results in progressive dehydration, hypokalemia, and death. In general, roentgenographic studies, stool cultures, sigmoidoscopy, stool fat determin ations, and minary 5-hydroxy
236
CASE REPORTS
indoleacetic acid determinations have been within normal limits. Although a slightly elevated urinary 5-hydroxy indoleacetic acid value has been reported in one patient by Espiner and Beaven, no particular significance was attributed to this finding.36 Steatorrhea, if present at all, is mild. 22 Table 3 outlines the important features of previously reported patients with this syndrome. Of the 15 patients, eight were women and seven were men. The age range was 19 to 67 with the greatest number, five, reported during the fifth decade. Diarrhea with or without symptoms of hypokalemia and weight loss were the presenting complaints in all and in some nausea and vomitihg were noted. Duration of symptoms varied from several months to as long as 15 years. Hypokalemia was documented in all cases. Neither peptic ulceration nor gastric hypersecretion was described. (The case of Charles and Cochrane had an esophageal ulceration which was thought to be due to protracted vomiting. 33 ) Indeed, histamine fast achlorhydria was documented in three instances 17, 36, 37 and "no free acid" reported in twO. 34 ,38 Low basal acid secretory rates were found by Parkins35 and in our patient. Satisfactory resection of a benign tumor with prompt and dramatic cessation of the diarrhea was accomplished in four cases including the ptesent patient. 21 , 34, 38 Surgery was performed in six other patients. One had a temporary remission following apparently complete removal of an islet cell tumor. However, 3 weeks later diarrhea recurred, and a second operation revealed metastases in the liver.36 The second patient died of pancreatitis following removal of an islet cell carcinoma and tumor-containing lymph ~odes.17 No tumor was found in a third patient at celiotomy, and diarrhea continued. Ultimately she died of a gangrenous small bowel obstruction and, at autopsy, a 2-cm benign islet cell adenoma was found buried in the head of the pancreas. 35 Two patients had metastases already present at celiotomy.22,37 The sixth patient had a pancreatic tumor removed 5 years prior to onset of diarrhea. Eighteen months after the onset of diarrhea exploration was negative.
Vol. 50, No.2
At necropsy following death from hypo~ kalemia an islet cell tumor was found in the tail of the pancreas. 31 In the remaining five cases operation was not performed. 19 , 29, 30, 33 These patients, as well as those patients with unresectable tumors,22, 37 died of intractable watery diarrhea, hypokalemia, dehydration, and shock. Thus, of 15 patients with this syndrome, six had malignant tumors and a seventh, the patient of Priest and Alexander, probably belongs in this category. Of the eight patients with benign adenomas, four were successfully resected with cure of the diarrhea. Five of the 15 patients in the present group showed a mildly to moderately elevated glucose tolerance curve. 21 , 22, 33, 36 Two of these five had successful resections with return of glucose tolerance to normal, concomitant with cessation of diarrhea and restoration of total body potassium. 21 Biological assay for glucagon activity in a Zollinger-Ellison tumor has been negative,39 and it seems unnecessary to ascribe impaired glucose tolerance to glucagon activity when other factors such as chronic potassium depletion exist. Indeed, impairment of glucose tolerance has been previously demonstrated with experimental potassium depletion. 40 Singleton et a1. 25 suggest that subtotal loss or destruction of f3 cells could produce hyperglycemia inpatients with islet cell tumors of the pancreas, but such was evidently not the case in these two patients. Unfortunately, glucose tolerance was not repeated in our patient prior to surgery after potassium repletion. An abnormal glucose tolerance test has been reversed to normal in primary aldosteronism following potassium repletion therapy.41 In three of the 15 patients more than one endocrine adenoma was found. Brown's patient had a pancreatic and a parathyroid adenoma ;38 Moldawer's patient a pancreatic, thyroid, and parathyroid adenoma ;30 and Verner and Morrison's first case a pancreatic ahd chromophobe adenoma. 29 The presence of multiple endocrine adenomas in three of 15 patients in this group corresponds roughly to the estimate that between 20 and 40% of patients with the Zollinger-Ellison syndrome have shown evidence of multiple
February 1966
CASE REPORTS
endocrine adenomatosis. 42 , 43 Four patients had hypercalcemia associated with the diarrhea, but only one of these, that of Brown and Crile,38 had a proved parathyroid adenoma. The patient of Verner and Morrison underwent a surgical procedure on the neck which revealed no parathyroid tumor and subsequent autopsy confirmed this fact. The patient reported by Chears et a1. 21 and our patient had a return of serum calcium and phosphorus to normal following successful resection of the islet cell tumor and cessation of diarrhea. Thus it is apparent that the hypercalcemia and hypophosphatemia occasionally seen in patients with this syndrome is not invariably due to a parathyroid adenoma and that neck exploration can be postponed until the effect of the resection of the pancreatic tumor on these electrolytes can be assessed. There appears to be no satisfactory explanation for the hypercalcemia and hypophosphatemia observed in these patients. An interesting complaint of our patient and of the patient of Murray et al,34 was a flushing sensation about the face and neck with no discernible reddening of the skin. Urinary 5-hydroxy indoleacetic acid was normal in both and the flushing disappeared following resection of the tumor. The histopathology of these tumors did not resemble that of carcinoid tissue. The use of corticosteroids has been reported by some to bring about a dramatic slowing of the diarrhea,21, 31, 37 but this has not been the experience of othersY, 19, 22, 33, 35 A trial of this medication may be justified while the patient is being prepared for surgery. Other factors reported to have ameliorated the diarrhea include nasogastric suction, vomiting, and pregnancy. Parkins reports that his patient enjoyed remission from diarrhea during each of three pregnancies, but he was unable to maintain remission with estrogenic or adrenocortical steroids. 35 Etiology of Diarrhea
The circumstantial evidence available strongly suggests that there is a hormonelike substance produced by the islet cell tumor which causes diarrhea. Telling and Smiddy in 1961 first made the suggestion
237
that more than one hormone may be elaborated by noninsulin-secreting islet cell tumors.22 As previously noted, the most common syndrome is that produced by a gastrin-secreting tumor with hypersecretion of hydrochloric acid and peptic ulcer diathesis, as originally described by Zollinger and Ellison. Another syndrome is characterized by watery diarrhea and hypokalemia, without hypersecretion of hydrochloric acid. This syndrome is exemplified by the present case and those reviewed in table 3. Assay of tumor tissue from two such patients (our patient by Dr. M. 1. Grossman and Hindle's patient by Prof. R. A. Gregory) was negative for gastrin activity. These negative findings show that the postulated hormone that produces the syndrome is not gastrin. A third group of patients has manifestations of both syndromes, i.e. hypersecretion, peptic ulceration, watery diarrhea, and hypokalemia. In these patients secretion of both gastrin and a diarrheogenic hormone by the islet cell tumor may be postulated (fig. 2). The mechanism of production of diarrhea remains obscure. l7 , 22, 36, 44 An excessive secretion of succus entericus would seem the most appealing theory. The excessive secretion of potassium into gut lumen as shown by Espiner and Beaven without a change in reabsorption would seem indirectly to support this idea. 36 A portion of the tumor from our patient after storage at -20 C for 5 months was lyophilized and then shipped as a dry powder to Prof. Nathan Lifson at the University of Minnesota. Utilizing the technique of Hakim et al.,45 no effect on water or glucose transport could be demonstrated by the addition of aqueous extracts of lyophilized tumor tissue to either the serosal or both compartments of canine small bowel mucosal preparations. Certain aspects of net N a + movement were different in the presence of tumor extracts but the N a + studies are of preliminary nature. Dr. Charles Edwards of the University of Minnesota found no effect on short circuit current when lyophilized tissue was added to the inside bathing solution of a frog skin preparation. Nonetheless, it is apparent from the
~
00
56
F
M
M
Priest and Alexander, 1957
Verner and Morrison, 1958
Verner and Morrison, 1958
34
60
49
47
26
F
F
M
F
F
Charles and Cochr ane, 1960
Chears et a!., 1960
Murray et aI., 1961
T elling and Smiddy, 1961
P arkins, 1961
19
67
57
Age
F
--
Sex
Moldawer et a!., 1954
Author
yr
8
Diarrhea
No
13 mo
Diarrhea, weight loss
Diabetic
15 mo
15%
Diarrhea, weight loss , vomiting
Diabetic
2
No data Diarrhea, Bushing
Diarrhea, weight loss, vomiting
Absent acid)
Low
Absent ("low" free acid)
Low
-
Absent
Low
(no free
Blood-streaked emesis. Noul cer
Esophageal ul ce r due to vomiting (?). N o other ulcer
Absent
Absent
Gastric ulc er during steroid Rx
Low
Low
Low
3
No data Diarrhea, weight loss
Low
Low
Diabetic
Peptic ulcer
LowK Absent nephropathy
Serum K
10 mo
6 mo
4
Duration of symptoms
No data Diarrhea, weight loss
No d ata .Diarrhea, weight loss
N o data Diarrhea, weight loss
test
Presenting symptoms
No findings
P ancreatic tumor (lCT) nonresec table
ICT (excised)
rCT (excised)
Not done
Not done
Not done
Pancreatic tumor excised 5 yr earlier. 2nd laparotomy negative
Not done
Laparotomy
Small bowel obstruction with ga ngrene
Hypok alemia
Hypokalemia
Hypokalemia
Hypokalemia
Hypokalemia
Hypokalemia
Cause of death
3. A summary of previously reported cases of islet cell tumors (leT) with diarrhea and hypokalemia
Oral glucose tolerance
TABLE
ICT
Not done
ICTwith pleural metastases
lCT
rCT
lCT
ICT
Autopsy
Non-a or /3
non-/3
a or A
Non-/3
Non-/3
non-/3
? a,
N on-/3
?
N on-/3
?
B
M
B
B
M
B
B
Not stated
B
(M)
Benign (B) vs. Cell type malignant
"'co"""
M
Brown et a!., 1964
F
34
M
Hindle et a!., 1964
Matsumoto et a!., 1966
29
M
Deleu et a!., 1964
49
59
53
M
E;dmeads, 1962
49
F
E;spiner and Beaven, 1962
Diabetic
No
No
No
No
Diabetic
Diarrhea, weight loss
Diarrhea, vomiting, lethargy
Diarrhea, backache, weight loss
Diarrhea, stupor
Diarrhea, vomiting, weight loss
(a) Diarrhea (b) Diarrhea, weight loss
2
10 rna
9 rna
4
3
12 rna 4 rna
Low
Low
Low
Low
Low
Low
Absent
Absent (no free acid)
Absent (achlorhydric)
Absent (achlorhydric)
Absent
Absent (achlorhydric)
rCT (excised)
2 parathyroid adenoma. Pancreatic ICT (excised)
Pancreatic tumor with metastases
Pancreatic tumor with metastases
Not done
(a) Retroperitoneal mass (b) Pancreatic tumar. No gross metastases
Hypokalemia
Postoperative pancreatitis
Hypokalemia
Hypokalemia
ICTwith metastases
ICT
rCT with metastases
Non-(3
Non-a or (3
?
Non-a or (3
Non-a or (3
Metastatic Non-a or (3 ICT
B
B
M
M
M
M
CASE REPORTS
240 ISLET
INSULIN
'fJ
Vol. 50, No.2
CELL TUMOR OF PANCREAS
SECRETING CELL'
r - - - - I I
HYPOGLYCEMIA
- - - - -,
DIARRHEOGENIC PRINCIPLE PRODUCTION
---- . . . 1 ---- ----,
L---r
IH YPERSECRETION SUCCUS?I I INCREASED MOTILITY? I I DECREASED ABSORPTION?I L. .J
GASTRIN PRODUCTION
1
I ATION F C ENZYMES
I STEATO RRHEA
HYPERSECRETION OF HC I
SEVERE PEPTIC ULCER DIATHESIS
•
ZOLLINGER ELLISON SYNDROME
I I I
---r----
l
IRRITATION OF SMALL BOWEL INCREASED MOTILITY
•
NONSPECIFIC DIARRHEA
PROFUSE WATERY DIARRHEA
t HYPOKALEMIA DEHYDRATION
•
PANCREATIC "CHOLERA"
FIG. 2. Syndromes produced by islet cell tumors of the pancreas.
metabolic balance data (table 1) that there was an enormous loss of water, sodium, and potassium in the patient's stool. Under normal conditions, the daily fecal sodium and potassium loss is less than 10 meq each. 46 • 47 The data also indicate that, as is normally the case, the patient's stool was approximately isotonic; this would suggest that the primary problem was one of oversecretion of normal intestinal fluids, but diminished intestinal absorption might also be a factor. Obviously the negative in vitro studies are subject to several interpretations and should not be construed as strong evidence against a hormonal etiology of the diarrhea. A less appealing explanation for the
cause of the diarrhea is increased intestinal motility. Indeed, the mouth-to-anus transit time of indigo carmine was 48 min in our patient prior to surgery. Espiner and Beaven demonstrated increased contractions in a strip of guinea pig ileum exposed to their patient's serum, but not to a saline extract of the tumor, to normal human serum, or to an extract of endometrium. 36 However, we are unaware of any evidence that increased intestinal motility'per se can result in electrolyte hypersecretion. Conclusion
A patient with an islet cell adenoma of the pancreas was seen with symptoms of
CASE REPORTS
February 1966
protracted watery diarrhea, weight loss, hypokalemia, and dehydration. She underwent successful resection of the tumor with dramatic cessation of symptoms. Metabolic balance data are presented to document the enormous fecal loss of water, sodium, and potassium. Clinical features of the syndrome are discussed, and a diarrheogenic hormone is postulated to account for the clinical manifest ations which apparently may exist in a pure form as in the cases reviewed, or in combination with the more common and familiar Zollinger-Ellison syndrome as originally defined. Assay studies of the resected tumor failed to show the presence of gastrin. No effect of an extract of the tumor on water or glucose transport across isolated in vitro preparations of canine small intestinal mucosa could be demonstrated. A review of similar cases reported previously indicates the importance of early recognition and prompt surgical removal of the tumor. In those instances where the tumor is benign, the outlook for a permanent cure is excellent. REFERENCES 1. Wilder, R. M., F. N. Allan, M. H. Power, and H. E. Robertson. 1927. Carcinoma of the islands of the pancreas. Hyperinsulinism and hypoglycemia. J. A. M. A. 89: 348-355. 2. Howard, J. M., and G. L. Jordan. 1960. Surgical diseases of the pancreas, p. 321--447. J. B. Lippincott Company, Philadelphia. 3. Zollinger, R. M., and E. H. Ellison. 1955. Primary peptic ulcerations of the jejunum associated with islet-cell tumors of the pancreas. Ann. Surg. 14B: 709-728. 4. Zollinger, R. M., and E. H. Ellison. 1959. Pancreatic endocrine function and peptic ulceration. Gastroenterology 37: 401--411. 5. Zollinger, R. M ., and T. V. Graig. 1960 Endocrine tumors and peptic ulcer. Amer. J. Med. 29: 761-768. 6. Zollinger, R. M., and G. N. Grant. 1964. Ulcerogenic tumor of the pancreas. J. A. M. A.190: 181-184. 7. Gregory, R. A., H. J. Tracy, J. M. French, and W. Sircus. 1960. Extraction of a gastrin-like substance from a pancreatic tumor in a case of Zollinger-Ellison syndrome. Lancet 1: 1045-1048. 8. Code, C. F., G. A. Hallenbeck, and W. H. J.
241
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25.
CASE REPORTS
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28.
29.
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31.
32.
33.
34.
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36.
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38.
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42.
43.
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45.
Vol. 50, No.2
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factors determining fecal electrolyte excretion. Metabolism 7: 108-111. 47. Shamblin, J. R, J. F. Huff, J. M. Waugh, and C. G. Moertel. 1962. Villous adenocarcinoma of the colon with pronounced electrolyte distu'rbance. Ann. Surg. 156: 318-326.