- Email: [email protected]
Prevalence of endocrine abnormalities in patients with the Zollinger-Ellison syndrome and in their families
Prevalence of Endocrine Abnormalities in Patients with the Zollinger-Ellison Syndrome and in Their Families
CORNELIS B. LAME%,
M.D.
Nijmegen, The Netherlands FLEMMING STADIL, M.D. Copenhagen, Denmark JAN H. VAN TONGEREN, M.D Nilmegen, The Netherlands
From the Division of Gastroenterology, St. Radboud Hospital, Nijrnqen, The Netherlands; and the Department of Surgical Gastroenterology D, Herlev Hospital, Copenhagen, Denmark. Requests for reprlnts should be addressed to Dr C. Lamer% Division of Gastroenterology, St. Radboud Hospital, Nljmegen, The Netherlands. Manuscript accepted August 23, 1977.
To evaluate the frequency of associated and heredltary endocrinopathles in the Zolllnger-Elllson syndrome, 10 patients with the syndrome were studied. In seven of them, coexlstlng endocrine disease was found. In six, the Zolllnger-Elllson syndrome was probably a feature of multlple endocrine adenomatosls type I, whereas Cushlng’s syndrome In the remaining patient may have been caused by the production of an ACTH-llke substance by a mlxed pancreatic tumor. A total of 109 family members, Including all living first degree relatlves over 15 years of age, were screened for endocrine abnormalltles. All SIX patlents wlth evidence of multlple endocrine adenomatosls type I had relatlves with endocrlnopathles. In the famllles of the four other patients with the Zolllnger-Elllson syndrome, no endocrine abnormalltles were found. During thls study four new cases of pltultary tumor, 17 of hyperparathyroldlsm, seven of the Zolllnger-Elllson syndrome and one of lnsullnoma were detected. Although most of the disorders were asymptomatic, thls clearly Indicates that patlents suffering from Zolllnger-Elllson syndrome and also thelr families should undergo detailed endocrine studles. The Zollinger-Ellison syndrome is characterized by peptic ulcers, diarrhea, hypersecretion of gastric acid and by gastrin-producing tumors, usually originating in the pancreas [ 1,2]. Tumors of extrapancreatic endocrine glands are found in up to 48 per cent of the patients with the Zollinger-Ellison syndrome [3]; this syndrome has been called multiple endocrine adenomatosis or neoplasia type 1 [4,5]. Hyperparathyroidism, pituitary tumors and pancreatic islet cell tumors are the most frequent manifestations of this entity [5-71. Apart from multiple endocrine adenomatosis, endocrinopathies may also be caused by mixed pancreatic tumors which secrete two or more hormones [8-121. An increased incidence of endocrine abnormalities has also been found in the families of some patients with the Zollinger-Ellison syndrome [5,13], and a number of families with multiple endocrine adenomatosis have been recorded [4,8,13-201. However, not all family members were investigated in these earlier studies, and this may have resulted in an inaccurate estimation of the incidence of abnormalities. Moreover, the selection of probands or family members to be examined was often made only when a history suggestive of endocrine disease was elicited. Since endocrinopathies may be asymptomatic, the incidence of endocrine involvement might have been underestimated. In this report the results of endocrine studies in 10 patients with the Zollinger-Ellison syndrome and in all their first degree relatives over
April 1979
The American Journal of Medicine
Volume 94
697
ENDOCRINE
ABNORMALITIES
IN ZCLLINGER-6LLISON
SYNDROME-LAMER.9
15 years of age are recorded. The only criterion of selection was the willingness of the patient and his relatives to participate in the study.
serum gastrin level, the gastric acid secretion was also measured. Provocation tests with calcium, secretin and food were performed on hypergastrinemic subjects before a diagnosis of Zollinger-Ellison syndrome was made and also to exclude hypergastrinemia of antral origin [21-231. These tests were carried out using 15 mg calcium/kg body weight given over 3 hours, 1 Clinical Unit (CU) secretin/kg body weight within 30 seconds and a standard test meal containing 30 g of protein, 20 g of fat and 25 g of carbohydrate [21]. If a family member had died, the medical history and the autopsy reports were reviewed. The diagnosis of pituitary tumor was based on roentgenographic or autopsy findings. The diagnosis of hyperparathyroidism was made on the combination of an increased plasma calcium concentration (at least 2.65 mmol/liter) and a low inorganic phosphate level (less than 0.85 mmol/liter) found on at least two occasions. In patients coming to surgery, the diagnosis of Zollinger-Ellison syndrome was confirmed by histologic examination of the tumors or by persistent hypergastrinemia after total gastrectomy. In Jnoperated patients, the diagnosis of Zollinger-Ellison syndrome was made if the following criteria were confirmed: (1) basal gastric acid output above 10 mmol/hour (normal value 2 3 f 2.6 mmol/hour; SD, n = 20); (2) fasting serum gastrin concentrations above 150 pg/ml (normal value 66 f 18 pg/ml; SD, n = 100); (3) an increase in serum gastrin of more than 50 per cent of the basal value both after infusion of calcium and after intravenous administration of secretin; and (4) a postprandial increase in serum gastrin of less than 50 per cent of fasting concentration. Those deceased subjects, in whom no tumors had been found and serum gastrin levels were not available, were regarded as having suffered from a Zollinger-Ellison syndrome if they had shown evidence of the characteristic features of the disease. These patients were designated as having suspected Zollinger-Ellison syndrome. The diagnosis of insuli-
PATIENTS AND METHODS Eight of 10 probands with the Zollinger-Ellison syndrome had histologically proved gastrinoma and one (Case 8, Table I) had persistently raised serum gastrin levels after total gastrectomy. The remaining patient (Case 6, Table I) had a basal gastric hypersecretion of 67 mmol/hour; fasting hypergastrinemia ranging from 400 to 1,300 pg/ml; marked increases in serum gastrin following provocation with calcium and secretin (138 and 174 per cent of basal value): and a 10 per cent postprandial increase in serum gastrin over the fasting level. At laparotomy a nodular pancreas was found in this patient, but a biopsy specimen was not taken. Seven of the patients with the Zollinger-Ellison syndrome died. Their deaths were attributed to complications of peptic ulcers in four, to tumor growth in two and to renal failure in one. All the living first degree relatives of these 10 patients with the Zollinger-Ellison syndrome over 15 years of age (n = 69) were studied. If an endocrine disease was detected in first degree relatives, the study was then extended to all the family members over 15 years old. It was not possible to investigate two non-first degree relatives. Seven first degree relatives younger than 15 years were examined at their parents’ request. In total, 109 family members were studied. The investigation consisted of taking a full history, a roentgenogram of the sella turcica and measurement of plasma or serum growth hormone, prolactin, thyroxine, calcium, inorganic phosphate, parathormone, gastrin, glucose, insulin and cortisol levels. Blood samples were taken after an overnight fast. In those subjects found to have a raised
TABLE I
Results of Endocrine Studies in 10 Patients with the Zollinger-Ellison
PllultaryGland Pro 9ellar Growth Case No.
Enlarge ment
10 2 0 3 0 40 50 6 0 7 0 8 0 90 10 $ Normal values
ET AL.
Hormone (~U/ml)
lactin @/ml)
7 9
(mmoll Ilter)
(mm@/ liter)
0
2.20 2.05 2 20 2.10 2.64 2.60 3.05 2 67 2.60 2.91 2.202 60
0 so 1.24 1.00 0.76 0.62 0.63 0 60 0.68 0 70 0 93t 0.651.30
0 0 -
5 7 66 <20
106.5 <20
PancreaticIslets lnstdln Gland Glucose Glucose P-Islet
ParalhyroldGlands InorganIc Tumor Calcium Phosphate (IIssue dlagnssls)
0 +
Syndrome
PTH @g/ml)
<25 65 265
Enlargement 0 0 0 + +
330
-
445 <200
+ +
(mmoll Ilk) 4.8 4.5 68 6.0 54 66 4.5 50 4.9 4.5-5.5
Ratlo (mU/mmol) 45 5.6 15 3.8 24 <7.3t
@ = equivocal. PTH = parathormone NOTE: + = present; 0 = absent; - = not determined; ‘Normal suppression by dexamethasone. t This figure has been calculated from the criterion for insulinoma described by Grunt et al. [31]. t Value obtained during renal insufficiency. Serum thyroxine levels were normal in all patients.
606
April 1978
The American Journal of Medicine
Volume 64
call Tumor 0 0 0 0 0 0 0 0 0 0
AdrenalCorlex Corllssl (rmol/ liter) 050 043 106 046 048 0.50’ 047 0.47 0.35 0 350.80
Nodular Hyprplada
MEA Idvldsnce
0 0 + + 0 +
0 0 0 0 + + + + + +
ENDOCRINE ABNORMALITIES IN ZOLLINBER-ELLISON SYNDROME-LAMER3
noma and nodular adrenocortical hyperplasia was made by histologic findings. Plasma concentrations of calcium were measured by atomic absorption spectrophotometry. Inorganic phosphate was determined using a modification of the FisksSubbarow technic [24]. Cottisol was estimated by a fluorimetric assay [25] and glucose by the ferricyanide method [26]. The plasma or serum concentration of growth
hormone, prolactin, thyroxine, parathormone, gastrin and insulin was measured by radioimmunoassay. Normal values are recorded in Table I or mentioned in the text. In the gastrin assay, a rabbit antibody was used with almost equimolar potency to gastrin components II and Ill [27]. RESULTS Endocrine Studies in Patients with the Zollinger-Ellison Syndrome. Endocrine studies in 10 patients with the Zollinger-Ellison syndrome revealed endocrinopathies in seven of them (Table I). One of these seven patients (Case 4, Table I) had clinical evidence of Cushing’s syndrome, with elevated cortisol levels in plasma and high urinary excretion of 17-hydroxycorticoids (12.6 ~mol/mmol creatinine) and 17-ketosteroids (10.4 ~mol/mmol creatinine). Enlargement of the sella turcica was not found in this patient; at autopsy, bilateral
ET AL.
adrenocorticai hyperplasia without pituitary tumor was found. The other six patients with the Zollinger-Ellison syndrome with coexisting endocrinopathies had signs of multiple endocrine adenomatosis type I. Endocrine Studies In Relatives of Patients with Zollinger-Ellison Syndrome. In none of 31 first degree relatives of four patients with the Zollinger-Ellison syndrome without signs of multiple endocrine adenomatosis type I was an endocrine disease diagnosed. Overt diabetes mellitus was the only abnormal finding in one of these family members. All six patients who had a Zollinger-Ellison syndrome as a component of multiple endocrine adenomatosis type I had relatives with an endocrine abnormality. Of 78 family members, 27 had proved and three suspected abnormalities of the endocrine system. None of seven relatives younger than 15 years of age had endocrine disease. Figure 1 shows the types and numbers of endocrine abnormalities in the members of the six families with multiple endocrine adenomatosis type 1. Features of Endocrine Abnormalities in Affected Members of SIX Families with Niultlple Endocrine Adenomatosis Type 1. The endocrine abnormalities in the affected family members were often asymp-
1
F/gum 1. Pedigrees of six families (A through f) with multiple endocrine adenomatosis type 1. Squares represent male an circles female subjects. Oblique lines represent deceasedsubjects. An asterisk refers to newly found endocrkwpathies. AtrOws indicate probands. 7 = insufficient data; 2 = not affected; 3 = hyperparathyroidism; 4 = Zollinger-Ellison syndrome; 5 = SUSpetted Zollinger-Ellison syndrome; 6 = insulinoma; 7 = pituitary tumor; 8 = nodular adrenocortical hyperplasia.
April 1978
The American Journal of Medicine
Volume 64
609
ENDOCRINE ABNORMALITIES IN ZOLLIN(YR+LLISON SYNDROME-LAMERS ET AL.
TABLE II
The RatiosBetweenAsymptomatkEndocrbw Abnormalities and Newly Diagnosed Endocrinopathles, and Between Asymptomatic Forms and the Total Number of Endocrine Disorders in 36 Affected Members of Six Families wlth Multlple Endocrine Adenomatosls Type I.
Dlsofdsr Pituitary tumor Hyperparathyroidism Zollinger-Ellison syndrome Suspected ZollingerEllison syndrome lnsulinoma Nodular adrenocortical hyperplasia
Newl) Diagnosed
Total
414 12117 317 o/o
5/S 14130 3115 o/5
l/i o/o
l/3 414
tomatic; in 69 per cent of the newly diagnosed endocrinopathies, the subjects were without symptoms (Table II). Of the eight patients with pituitary tumors one had amenorrhea, one had both amenorrhea and a high degree of visual loss, and one showed evidence of growth retardation. The five other patients had no clinical symptoms. The four patients with newly diagnosed pituitary tumor were all asymptomatic, but a temporal defect in the visual field was found in three of them. In the fourth, two pituitary adenomas were found at autopsy. Growth hormone levels were elevated in one and prolactin levels in three of five patients studied. Hyperparathyroidism was diagnosed in 30 members of the six families with multiple endocrine adenomatosis. All 14 patients who came to operation were found to have enlarged parathyroid glands. Two patients died from renal failure due to hypercalcemic nephrocalcinosis. Sixteen of the 30 patients with hyperparathyroidism had a history of renal stones and one had severe osteitis fibrosa cystica. In only five of 17 newly diagnosed cases of hyperparathyroidism was the disease symptomatic. Peripheral parathormone levels were increased in 13 of 21 hypercalcemic patients studied. Fifteen subjects were found to be suffering from the Zollinger-Ellison syndrome. Non-&islet cell tumors were demonstrated in eight patients, and one had persistent hypergastrinemia after total gastrectomy. In the seven patients without tissue diagnosis, the Zollinger-Ellison syndrome was verified by basal gastric hypersecretion and stimulation tests as stated earlier. According to the criteria mentioned, all patients with serum gastrin levels above 150 pg/ml were found to have a Zollinger-Ellison syndrome. Moreover, the diagnosis of Zollinger-Ellison syndrome was suspected but could not be verified in five deceased subjects. These patients all suffered from complicated and re-
610
April 1978
The American Journal of Medicine
Volume 64
current peptic ulcer disease. Ulcers or diarrhea occurred in only four of the seven patients with newly diagnosed Zollinger-Ellison syndrome. The complaints were rather mild and had led to gastric surgery in only one of these patients. However, in 10 of the 12 patients from these six families who died as a result of endocrine disease, proved or suspected Zollinger-Ellison syndrome was the cause of death. In one patient, an increased insulin-glucose ratio was found and insulinoma was histologically proved at a later date. This patient did not suffer from symptoms of hypoglycemia. The two other patients with insulinoma had been operated upon because of severe hypoglycemic attacks. These attacks disappeared after resection of the pancreatic P-islet cell tumors. Nodular adrenocortical hyperplasia was found at autopsy in four members of the families of patients with multiple endocrine adenomatosis, but the condition seemed asymptomatic in all four. Serum thyroxine levels were normal in all subjects studied. Thyroid nodules were palpable in four. COMMENTS The present study revealed coexisting endocrine disease in seven of 10 patients with the Zollinger-Ellison syndrome. One of these seven patients had Cushing’s syndrome, probably caused by the ectopic production of an ACTH-like substance by the pancreatic tumor as has been previously described [9,10]. The other six patients had evidence of multiple endocrine adenomatosis type I. The incidence of associated endocrinopathies in this study was higher than the 15 to 48 per cent previously described in patients with the Zollinger-Ellison syndrome [3,28,29]. The explanation for this is uncertain but might be related to the thoroughness of the endocrinologic screening. All our six patients with the Zollinger-Ellison syndrome and evidence of multiple endocrine adenomatosis type I had affected relatives. These results are at variance with the studies by Stocks [ 181 and Croisier et al. [7], who mainly collected their data from the literature and reported that multiple endocrine adenomatosis type I was a hereditary disorder in only 21 to 45 per cent of the cases. We believe that the main reason for this difference was the incomplete study of asymptomatic family members in the earlier reports. Indeed, we found that endocrinopathies were often asymptomatic as did Johnson et al.
[171. The family history was suggestive of multiple endocrine adenomatosis in only three of the six families studied. In the families of four patients with the Zollinger-Ellison syndrome without evidence of multiple endocrine adenomatosis type I, no endocrine abnormalities were found in first degree relatives. The results
ENDOCRINE ABNORMAUTIES IN ZOLL~NGER-ELL~SON SYNDROME-LAMERS ET AL.
of the family studies give addiiional support to Wermer’s hypothesis that the Zollfnger-Ellison syndrome exists in two forms: (1) the Zollinger-Ellison syndrome as a component of multiple endocrine adenomatosis type I, a hereditary disease for which the name ZollingerEllison syndrome should be retained, and (2) the ZolIingerIllison syndrome without evidence of multiple endocrine adenomatosis type I, a nonhereditary disorder, for which the name Zollinger-Ellison disease is proposed However, to verify this hypothesis more families of patients with the Zollinger-Ellison syndrome should be studied systematically. According to Wermer [4,5], multiple endocrine adenomatosis type I is inherited as an autosomal dominant disorder with high penetrance and some variability in expressivity. If this is true, a new dominant mutation had probably occurred in family F (Figure l), as indicatedby the lack of endocrine disorders in the parents, brother and sister of patient F II 1 and the presence of hyperparathyroidism in the son. In our study, multiple endocrine adenomatosis type I tended to show some interfamilial variability. All three patients with insulinoma, for example, were members of family C, whereas in the other five families no cases of insulinoma were found.
[s].
From the results of this study it can be concluded that detailed endocrine studies should be undertaken in all patients with the Zollinger-Ellison syndrome and also in their families. Although endocrinopathies have been described in children [5,16.30], the incidence is probably very low [ 171 and in this study none of seven children younger than 15 years of age were affected. The endocrinopathies are frequently asymptomatic, and laboratory and roentgenologic investigations have to be undertaken. The pituitary and parathyroid glands and the pancreatic islets should be carefully investigated. These investigations should be repeated at regular intervals as the occurence of endocrine disorders increases with age [51. ACKNOWLEDGMENT We are indebted to Drs. J. A. ten Bokkel Huinink, J. F. Hansen, U. A. Termote and Th. Thien for their participation in the investigation of the patients. The hormone assays were performed by Drs. Th. J. Benraad, W. H. L. Hackeng, C. B. Lamers, R. M. Lequin and H. A. Ross. The manuscript was corrected by Dr. J. R. Murray.
REFERENCES 1.
6
10.
11
12
13
Zollinger RM, Ellison EH: Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann Surg 142: 709, 1955. lsenberg JI, Walsh JH, Grossman MI: Zollinger-Ellison syndrome. Gastroenterology 65: 140, 1973. Way L, Goldman L. Dunphy JE: Zollinger-Ellison syndrome. An analysis of 25 cases. Am J Surg 116: 293, 1966. Wermer P: Genetic aspects of adenomatosis of endocrine glands Am J Med 16: 363, 1954. Wermer P: Multiple endocrine adenomatosis; multiple hormone-producing tumours, a familial syndrome, chap 13. Endocrine-Secreting Tumours of the GI Tract (Bonfils S, ed), London-Philadelphia-Toronto, W.B. Saunders, 1974. Ballard HS, Frame B, Hartso& RI: Famlllll multlple endocrine adenoma-peptic ulcer complex. Medicine (Baltimore) 43: 461. 1964. Croisier JC, Azerad E, Lubetzki J: L’adenomatose polyendocrinienne (syndrome de Wermer) Sem H6p Paris 47: 494, 1971. Shleber W: Insulin-producing Zollinger-Elllsson syndrome. Surgery 54: 446,1963. Geokas MC, Youl Chun J. Dinan JJ, et al.: Islet-cell carc~norna (Zolllnger-Elllson syndrome) wlth fulminating abenocortlcal hvoetfunction and hypokalemia. Can Med Assoc J 93: 137, . 1965 Law DH, Liddle GW, Scott HW, et al.: Ectopic production of multiole hormones (ACTH. MSH and gastrln) by a single malignant tumor. N Engl J Med 273: 292, 1965: _ Mwaylyon IM, Eddleston ALWF, Williams R, et al.: Treatment of multiple-hormone-producing malignant Isletcell turnour with streptozotocin. Lancet 2: 695, 1968. Larson LI, Grlmelius L, Hakanson R, et al.: Mixed endocrine pancreatic tumors producing several peptlde hormones. Am J Pathol79: 271, 1975. Friesen SR, Schltie RN, Pearse AGE Genetic aspects of the ZE-syndrome: prospective studies in two kindred; antral
14.
15
16.
17.
18. 19 20.
21.
22.
23.
24. 25.
April 1979
gastrin cell hyperplasia. Ann Surg 176: 370, 1972 Underdahl LO, Woolner LB, Black BM: Multiple endocrine adenomas: report of 8 cases in which the parathyroids, pituitary and pancreatic islets were involved. J Clin Endocrinol Metab 1: 20, 1953. Schmid JR, Labhart A, Rossier PH: Relationship of multiple endocrine adenomas to the syndrome of ulcerogenic islet cell adenomas (Zollinger-Ellison). Occurrence of both syndromes in one family Am J Med 3 1: 343, 1961. Moldawer M: Multiple endocrine tumors and ZolllngerIlllson syndromes in families: one or two syndromes? A report of two new families. Metabolism 11: 153, 1962. Johnson 61, Summerskill WHJ, Anderson VE, et al.: Clinical and genetic investigation of a large kindred with multiple endocrine adenomatosis. N Engl J Med 277: 1379, 1967. Stocks AE: Problems of the syndrome of familial multiple endocrine adenomas. Aust Ann Med 16: 278. 1967 Snyder N, Scurry MT, Deiss WP: Five families with multiple endocrine adenomatosls. Ann Intern Med 76: 53, 1972. Vance JE, Stall RW, Kitabchi AE, et al.: Familial nesidioblastosis as the predomlnant manifestation of multlple endocrine adenomatosis. Am J Med 52: 211, 1972. Lamers CBH, van Tongeren JHM: Comparative study of the value of the calcium, secretin and meal stimulated increase in serum gastrin to the diagnosis of the Zollinger-Elllson syndrome. Gut 18: 128, 1977. Ganguli PC, Polak JM, Pearse AGE, et al : Antralgastrln-cell hyperplasia in peptic-ulcer disease. Lancet 1: 583. 1974 Straus E, Yalow RS: Dlfferentttl dlagnosis of hypergastrinemla. Gastrolntestlnal Hormones (Thompson JC, ed), AustinLondon, Unlversity of Texas Press, 1975, p 99. Fiske CH, Subbarow Y: The colorlmetric determination of phosphorus. J Blol Chem 66: 375, 1925. Mattingly D: A simple fluorimetric method for the estimation of free 1 l-hydroxycortlcoids in human plasma. J Clln Pathol
The American Journal of Medclne
Volume 64
611
26.
27.
28.
812
15: 374, 1962. Hoffman WS: A rapid photoelectric method for the determination of glucose in blood and urine. J Biol Chem 120: 51, 1937. Rehfeld JF, Stadil F, et al.: Gastrin heterogeneity in serum and tissue. Gastrointestinal Hormones (Thompson JC, ed), Austin-London, University of Texas Press, 1975, p 43. Ellison EH, Wilson D: The Zollinger-Ellison syndrome: reappraisal and evaluation of 260 registered cases. Ann Surg 180: 512, 1964.
April 1978
The American Journal of Medicine
Volume 64
29.
30. 31.
Bonfils S, Bader JP: The diagnosis of Zollinger-Ellison syndrome with special reference to the multiple endocrine adenomas, chap 19. Progress in Gastroenterology (Glass GBJ, ed). New York, Grune 8 Stratton, 1970 Pender B: Isletcell tumour of pancreas associated with peptic ulceration. Lancet 1: 123, 1959. Grunt JA, Pallotta JA, Soeldner JS: Blood sugar, serum insulin and free fatty acid interrelationships during intravenous tolbutamide testing in normal young adults and in patients with insulinoma. Diabetes 19. 122, 1970.
CORNELIS B. LAME%,
M.D.
Nijmegen, The Netherlands FLEMMING STADIL, M.D. Copenhagen, Denmark JAN H. VAN TONGEREN, M.D Nilmegen, The Netherlands
From the Division of Gastroenterology, St. Radboud Hospital, Nijrnqen, The Netherlands; and the Department of Surgical Gastroenterology D, Herlev Hospital, Copenhagen, Denmark. Requests for reprlnts should be addressed to Dr C. Lamer% Division of Gastroenterology, St. Radboud Hospital, Nljmegen, The Netherlands. Manuscript accepted August 23, 1977.
To evaluate the frequency of associated and heredltary endocrinopathles in the Zolllnger-Elllson syndrome, 10 patients with the syndrome were studied. In seven of them, coexlstlng endocrine disease was found. In six, the Zolllnger-Elllson syndrome was probably a feature of multlple endocrine adenomatosls type I, whereas Cushlng’s syndrome In the remaining patient may have been caused by the production of an ACTH-llke substance by a mlxed pancreatic tumor. A total of 109 family members, Including all living first degree relatlves over 15 years of age, were screened for endocrine abnormalltles. All SIX patlents wlth evidence of multlple endocrine adenomatosls type I had relatlves with endocrlnopathles. In the famllles of the four other patients with the Zolllnger-Elllson syndrome, no endocrine abnormalltles were found. During thls study four new cases of pltultary tumor, 17 of hyperparathyroldlsm, seven of the Zolllnger-Elllson syndrome and one of lnsullnoma were detected. Although most of the disorders were asymptomatic, thls clearly Indicates that patlents suffering from Zolllnger-Elllson syndrome and also thelr families should undergo detailed endocrine studles. The Zollinger-Ellison syndrome is characterized by peptic ulcers, diarrhea, hypersecretion of gastric acid and by gastrin-producing tumors, usually originating in the pancreas [ 1,2]. Tumors of extrapancreatic endocrine glands are found in up to 48 per cent of the patients with the Zollinger-Ellison syndrome [3]; this syndrome has been called multiple endocrine adenomatosis or neoplasia type 1 [4,5]. Hyperparathyroidism, pituitary tumors and pancreatic islet cell tumors are the most frequent manifestations of this entity [5-71. Apart from multiple endocrine adenomatosis, endocrinopathies may also be caused by mixed pancreatic tumors which secrete two or more hormones [8-121. An increased incidence of endocrine abnormalities has also been found in the families of some patients with the Zollinger-Ellison syndrome [5,13], and a number of families with multiple endocrine adenomatosis have been recorded [4,8,13-201. However, not all family members were investigated in these earlier studies, and this may have resulted in an inaccurate estimation of the incidence of abnormalities. Moreover, the selection of probands or family members to be examined was often made only when a history suggestive of endocrine disease was elicited. Since endocrinopathies may be asymptomatic, the incidence of endocrine involvement might have been underestimated. In this report the results of endocrine studies in 10 patients with the Zollinger-Ellison syndrome and in all their first degree relatives over
April 1979
The American Journal of Medicine
Volume 94
697
ENDOCRINE
ABNORMALITIES
IN ZCLLINGER-6LLISON
SYNDROME-LAMER.9
15 years of age are recorded. The only criterion of selection was the willingness of the patient and his relatives to participate in the study.
serum gastrin level, the gastric acid secretion was also measured. Provocation tests with calcium, secretin and food were performed on hypergastrinemic subjects before a diagnosis of Zollinger-Ellison syndrome was made and also to exclude hypergastrinemia of antral origin [21-231. These tests were carried out using 15 mg calcium/kg body weight given over 3 hours, 1 Clinical Unit (CU) secretin/kg body weight within 30 seconds and a standard test meal containing 30 g of protein, 20 g of fat and 25 g of carbohydrate [21]. If a family member had died, the medical history and the autopsy reports were reviewed. The diagnosis of pituitary tumor was based on roentgenographic or autopsy findings. The diagnosis of hyperparathyroidism was made on the combination of an increased plasma calcium concentration (at least 2.65 mmol/liter) and a low inorganic phosphate level (less than 0.85 mmol/liter) found on at least two occasions. In patients coming to surgery, the diagnosis of Zollinger-Ellison syndrome was confirmed by histologic examination of the tumors or by persistent hypergastrinemia after total gastrectomy. In Jnoperated patients, the diagnosis of Zollinger-Ellison syndrome was made if the following criteria were confirmed: (1) basal gastric acid output above 10 mmol/hour (normal value 2 3 f 2.6 mmol/hour; SD, n = 20); (2) fasting serum gastrin concentrations above 150 pg/ml (normal value 66 f 18 pg/ml; SD, n = 100); (3) an increase in serum gastrin of more than 50 per cent of the basal value both after infusion of calcium and after intravenous administration of secretin; and (4) a postprandial increase in serum gastrin of less than 50 per cent of fasting concentration. Those deceased subjects, in whom no tumors had been found and serum gastrin levels were not available, were regarded as having suffered from a Zollinger-Ellison syndrome if they had shown evidence of the characteristic features of the disease. These patients were designated as having suspected Zollinger-Ellison syndrome. The diagnosis of insuli-
PATIENTS AND METHODS Eight of 10 probands with the Zollinger-Ellison syndrome had histologically proved gastrinoma and one (Case 8, Table I) had persistently raised serum gastrin levels after total gastrectomy. The remaining patient (Case 6, Table I) had a basal gastric hypersecretion of 67 mmol/hour; fasting hypergastrinemia ranging from 400 to 1,300 pg/ml; marked increases in serum gastrin following provocation with calcium and secretin (138 and 174 per cent of basal value): and a 10 per cent postprandial increase in serum gastrin over the fasting level. At laparotomy a nodular pancreas was found in this patient, but a biopsy specimen was not taken. Seven of the patients with the Zollinger-Ellison syndrome died. Their deaths were attributed to complications of peptic ulcers in four, to tumor growth in two and to renal failure in one. All the living first degree relatives of these 10 patients with the Zollinger-Ellison syndrome over 15 years of age (n = 69) were studied. If an endocrine disease was detected in first degree relatives, the study was then extended to all the family members over 15 years old. It was not possible to investigate two non-first degree relatives. Seven first degree relatives younger than 15 years were examined at their parents’ request. In total, 109 family members were studied. The investigation consisted of taking a full history, a roentgenogram of the sella turcica and measurement of plasma or serum growth hormone, prolactin, thyroxine, calcium, inorganic phosphate, parathormone, gastrin, glucose, insulin and cortisol levels. Blood samples were taken after an overnight fast. In those subjects found to have a raised
TABLE I
Results of Endocrine Studies in 10 Patients with the Zollinger-Ellison
PllultaryGland Pro 9ellar Growth Case No.
Enlarge ment
10 2 0 3 0 40 50 6 0 7 0 8 0 90 10 $ Normal values
ET AL.
Hormone (~U/ml)
lactin @/ml)
7 9
(mmoll Ilter)
(mm@/ liter)
0
2.20 2.05 2 20 2.10 2.64 2.60 3.05 2 67 2.60 2.91 2.202 60
0 so 1.24 1.00 0.76 0.62 0.63 0 60 0.68 0 70 0 93t 0.651.30
0 0 -
5 7 66 <20
106.5 <20
PancreaticIslets lnstdln Gland Glucose Glucose P-Islet
ParalhyroldGlands InorganIc Tumor Calcium Phosphate (IIssue dlagnssls)
0 +
Syndrome
PTH @g/ml)
<25 65 265
Enlargement 0 0 0 + +
330
-
445 <200
+ +
(mmoll Ilk) 4.8 4.5 68 6.0 54 66 4.5 50 4.9 4.5-5.5
Ratlo (mU/mmol) 45 5.6 15 3.8 24 <7.3t
@ = equivocal. PTH = parathormone NOTE: + = present; 0 = absent; - = not determined; ‘Normal suppression by dexamethasone. t This figure has been calculated from the criterion for insulinoma described by Grunt et al. [31]. t Value obtained during renal insufficiency. Serum thyroxine levels were normal in all patients.
606
April 1978
The American Journal of Medicine
Volume 64
call Tumor 0 0 0 0 0 0 0 0 0 0
AdrenalCorlex Corllssl (rmol/ liter) 050 043 106 046 048 0.50’ 047 0.47 0.35 0 350.80
Nodular Hyprplada
MEA Idvldsnce
0 0 + + 0 +
0 0 0 0 + + + + + +
ENDOCRINE ABNORMALITIES IN ZOLLINBER-ELLISON SYNDROME-LAMER3
noma and nodular adrenocortical hyperplasia was made by histologic findings. Plasma concentrations of calcium were measured by atomic absorption spectrophotometry. Inorganic phosphate was determined using a modification of the FisksSubbarow technic [24]. Cottisol was estimated by a fluorimetric assay [25] and glucose by the ferricyanide method [26]. The plasma or serum concentration of growth
hormone, prolactin, thyroxine, parathormone, gastrin and insulin was measured by radioimmunoassay. Normal values are recorded in Table I or mentioned in the text. In the gastrin assay, a rabbit antibody was used with almost equimolar potency to gastrin components II and Ill [27]. RESULTS Endocrine Studies in Patients with the Zollinger-Ellison Syndrome. Endocrine studies in 10 patients with the Zollinger-Ellison syndrome revealed endocrinopathies in seven of them (Table I). One of these seven patients (Case 4, Table I) had clinical evidence of Cushing’s syndrome, with elevated cortisol levels in plasma and high urinary excretion of 17-hydroxycorticoids (12.6 ~mol/mmol creatinine) and 17-ketosteroids (10.4 ~mol/mmol creatinine). Enlargement of the sella turcica was not found in this patient; at autopsy, bilateral
ET AL.
adrenocorticai hyperplasia without pituitary tumor was found. The other six patients with the Zollinger-Ellison syndrome with coexisting endocrinopathies had signs of multiple endocrine adenomatosis type I. Endocrine Studies In Relatives of Patients with Zollinger-Ellison Syndrome. In none of 31 first degree relatives of four patients with the Zollinger-Ellison syndrome without signs of multiple endocrine adenomatosis type I was an endocrine disease diagnosed. Overt diabetes mellitus was the only abnormal finding in one of these family members. All six patients who had a Zollinger-Ellison syndrome as a component of multiple endocrine adenomatosis type I had relatives with an endocrine abnormality. Of 78 family members, 27 had proved and three suspected abnormalities of the endocrine system. None of seven relatives younger than 15 years of age had endocrine disease. Figure 1 shows the types and numbers of endocrine abnormalities in the members of the six families with multiple endocrine adenomatosis type 1. Features of Endocrine Abnormalities in Affected Members of SIX Families with Niultlple Endocrine Adenomatosis Type 1. The endocrine abnormalities in the affected family members were often asymp-
1
F/gum 1. Pedigrees of six families (A through f) with multiple endocrine adenomatosis type 1. Squares represent male an circles female subjects. Oblique lines represent deceasedsubjects. An asterisk refers to newly found endocrkwpathies. AtrOws indicate probands. 7 = insufficient data; 2 = not affected; 3 = hyperparathyroidism; 4 = Zollinger-Ellison syndrome; 5 = SUSpetted Zollinger-Ellison syndrome; 6 = insulinoma; 7 = pituitary tumor; 8 = nodular adrenocortical hyperplasia.
April 1978
The American Journal of Medicine
Volume 64
609
ENDOCRINE ABNORMALITIES IN ZOLLIN(YR+LLISON SYNDROME-LAMERS ET AL.
TABLE II
The RatiosBetweenAsymptomatkEndocrbw Abnormalities and Newly Diagnosed Endocrinopathles, and Between Asymptomatic Forms and the Total Number of Endocrine Disorders in 36 Affected Members of Six Families wlth Multlple Endocrine Adenomatosls Type I.
Dlsofdsr Pituitary tumor Hyperparathyroidism Zollinger-Ellison syndrome Suspected ZollingerEllison syndrome lnsulinoma Nodular adrenocortical hyperplasia
Newl) Diagnosed
Total
414 12117 317 o/o
5/S 14130 3115 o/5
l/i o/o
l/3 414
tomatic; in 69 per cent of the newly diagnosed endocrinopathies, the subjects were without symptoms (Table II). Of the eight patients with pituitary tumors one had amenorrhea, one had both amenorrhea and a high degree of visual loss, and one showed evidence of growth retardation. The five other patients had no clinical symptoms. The four patients with newly diagnosed pituitary tumor were all asymptomatic, but a temporal defect in the visual field was found in three of them. In the fourth, two pituitary adenomas were found at autopsy. Growth hormone levels were elevated in one and prolactin levels in three of five patients studied. Hyperparathyroidism was diagnosed in 30 members of the six families with multiple endocrine adenomatosis. All 14 patients who came to operation were found to have enlarged parathyroid glands. Two patients died from renal failure due to hypercalcemic nephrocalcinosis. Sixteen of the 30 patients with hyperparathyroidism had a history of renal stones and one had severe osteitis fibrosa cystica. In only five of 17 newly diagnosed cases of hyperparathyroidism was the disease symptomatic. Peripheral parathormone levels were increased in 13 of 21 hypercalcemic patients studied. Fifteen subjects were found to be suffering from the Zollinger-Ellison syndrome. Non-&islet cell tumors were demonstrated in eight patients, and one had persistent hypergastrinemia after total gastrectomy. In the seven patients without tissue diagnosis, the Zollinger-Ellison syndrome was verified by basal gastric hypersecretion and stimulation tests as stated earlier. According to the criteria mentioned, all patients with serum gastrin levels above 150 pg/ml were found to have a Zollinger-Ellison syndrome. Moreover, the diagnosis of Zollinger-Ellison syndrome was suspected but could not be verified in five deceased subjects. These patients all suffered from complicated and re-
610
April 1978
The American Journal of Medicine
Volume 64
current peptic ulcer disease. Ulcers or diarrhea occurred in only four of the seven patients with newly diagnosed Zollinger-Ellison syndrome. The complaints were rather mild and had led to gastric surgery in only one of these patients. However, in 10 of the 12 patients from these six families who died as a result of endocrine disease, proved or suspected Zollinger-Ellison syndrome was the cause of death. In one patient, an increased insulin-glucose ratio was found and insulinoma was histologically proved at a later date. This patient did not suffer from symptoms of hypoglycemia. The two other patients with insulinoma had been operated upon because of severe hypoglycemic attacks. These attacks disappeared after resection of the pancreatic P-islet cell tumors. Nodular adrenocortical hyperplasia was found at autopsy in four members of the families of patients with multiple endocrine adenomatosis, but the condition seemed asymptomatic in all four. Serum thyroxine levels were normal in all subjects studied. Thyroid nodules were palpable in four. COMMENTS The present study revealed coexisting endocrine disease in seven of 10 patients with the Zollinger-Ellison syndrome. One of these seven patients had Cushing’s syndrome, probably caused by the ectopic production of an ACTH-like substance by the pancreatic tumor as has been previously described [9,10]. The other six patients had evidence of multiple endocrine adenomatosis type I. The incidence of associated endocrinopathies in this study was higher than the 15 to 48 per cent previously described in patients with the Zollinger-Ellison syndrome [3,28,29]. The explanation for this is uncertain but might be related to the thoroughness of the endocrinologic screening. All our six patients with the Zollinger-Ellison syndrome and evidence of multiple endocrine adenomatosis type I had affected relatives. These results are at variance with the studies by Stocks [ 181 and Croisier et al. [7], who mainly collected their data from the literature and reported that multiple endocrine adenomatosis type I was a hereditary disorder in only 21 to 45 per cent of the cases. We believe that the main reason for this difference was the incomplete study of asymptomatic family members in the earlier reports. Indeed, we found that endocrinopathies were often asymptomatic as did Johnson et al.
[171. The family history was suggestive of multiple endocrine adenomatosis in only three of the six families studied. In the families of four patients with the Zollinger-Ellison syndrome without evidence of multiple endocrine adenomatosis type I, no endocrine abnormalities were found in first degree relatives. The results
ENDOCRINE ABNORMAUTIES IN ZOLL~NGER-ELL~SON SYNDROME-LAMERS ET AL.
of the family studies give addiiional support to Wermer’s hypothesis that the Zollfnger-Ellison syndrome exists in two forms: (1) the Zollinger-Ellison syndrome as a component of multiple endocrine adenomatosis type I, a hereditary disease for which the name ZollingerEllison syndrome should be retained, and (2) the ZolIingerIllison syndrome without evidence of multiple endocrine adenomatosis type I, a nonhereditary disorder, for which the name Zollinger-Ellison disease is proposed However, to verify this hypothesis more families of patients with the Zollinger-Ellison syndrome should be studied systematically. According to Wermer [4,5], multiple endocrine adenomatosis type I is inherited as an autosomal dominant disorder with high penetrance and some variability in expressivity. If this is true, a new dominant mutation had probably occurred in family F (Figure l), as indicatedby the lack of endocrine disorders in the parents, brother and sister of patient F II 1 and the presence of hyperparathyroidism in the son. In our study, multiple endocrine adenomatosis type I tended to show some interfamilial variability. All three patients with insulinoma, for example, were members of family C, whereas in the other five families no cases of insulinoma were found.
[s].
From the results of this study it can be concluded that detailed endocrine studies should be undertaken in all patients with the Zollinger-Ellison syndrome and also in their families. Although endocrinopathies have been described in children [5,16.30], the incidence is probably very low [ 171 and in this study none of seven children younger than 15 years of age were affected. The endocrinopathies are frequently asymptomatic, and laboratory and roentgenologic investigations have to be undertaken. The pituitary and parathyroid glands and the pancreatic islets should be carefully investigated. These investigations should be repeated at regular intervals as the occurence of endocrine disorders increases with age [51. ACKNOWLEDGMENT We are indebted to Drs. J. A. ten Bokkel Huinink, J. F. Hansen, U. A. Termote and Th. Thien for their participation in the investigation of the patients. The hormone assays were performed by Drs. Th. J. Benraad, W. H. L. Hackeng, C. B. Lamers, R. M. Lequin and H. A. Ross. The manuscript was corrected by Dr. J. R. Murray.
REFERENCES 1.
6
10.
11
12
13
Zollinger RM, Ellison EH: Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann Surg 142: 709, 1955. lsenberg JI, Walsh JH, Grossman MI: Zollinger-Ellison syndrome. Gastroenterology 65: 140, 1973. Way L, Goldman L. Dunphy JE: Zollinger-Ellison syndrome. An analysis of 25 cases. Am J Surg 116: 293, 1966. Wermer P: Genetic aspects of adenomatosis of endocrine glands Am J Med 16: 363, 1954. Wermer P: Multiple endocrine adenomatosis; multiple hormone-producing tumours, a familial syndrome, chap 13. Endocrine-Secreting Tumours of the GI Tract (Bonfils S, ed), London-Philadelphia-Toronto, W.B. Saunders, 1974. Ballard HS, Frame B, Hartso& RI: Famlllll multlple endocrine adenoma-peptic ulcer complex. Medicine (Baltimore) 43: 461. 1964. Croisier JC, Azerad E, Lubetzki J: L’adenomatose polyendocrinienne (syndrome de Wermer) Sem H6p Paris 47: 494, 1971. Shleber W: Insulin-producing Zollinger-Elllsson syndrome. Surgery 54: 446,1963. Geokas MC, Youl Chun J. Dinan JJ, et al.: Islet-cell carc~norna (Zolllnger-Elllson syndrome) wlth fulminating abenocortlcal hvoetfunction and hypokalemia. Can Med Assoc J 93: 137, . 1965 Law DH, Liddle GW, Scott HW, et al.: Ectopic production of multiole hormones (ACTH. MSH and gastrln) by a single malignant tumor. N Engl J Med 273: 292, 1965: _ Mwaylyon IM, Eddleston ALWF, Williams R, et al.: Treatment of multiple-hormone-producing malignant Isletcell turnour with streptozotocin. Lancet 2: 695, 1968. Larson LI, Grlmelius L, Hakanson R, et al.: Mixed endocrine pancreatic tumors producing several peptlde hormones. Am J Pathol79: 271, 1975. Friesen SR, Schltie RN, Pearse AGE Genetic aspects of the ZE-syndrome: prospective studies in two kindred; antral
14.
15
16.
17.
18. 19 20.
21.
22.
23.
24. 25.
April 1979
gastrin cell hyperplasia. Ann Surg 176: 370, 1972 Underdahl LO, Woolner LB, Black BM: Multiple endocrine adenomas: report of 8 cases in which the parathyroids, pituitary and pancreatic islets were involved. J Clin Endocrinol Metab 1: 20, 1953. Schmid JR, Labhart A, Rossier PH: Relationship of multiple endocrine adenomas to the syndrome of ulcerogenic islet cell adenomas (Zollinger-Ellison). Occurrence of both syndromes in one family Am J Med 3 1: 343, 1961. Moldawer M: Multiple endocrine tumors and ZolllngerIlllson syndromes in families: one or two syndromes? A report of two new families. Metabolism 11: 153, 1962. Johnson 61, Summerskill WHJ, Anderson VE, et al.: Clinical and genetic investigation of a large kindred with multiple endocrine adenomatosis. N Engl J Med 277: 1379, 1967. Stocks AE: Problems of the syndrome of familial multiple endocrine adenomas. Aust Ann Med 16: 278. 1967 Snyder N, Scurry MT, Deiss WP: Five families with multiple endocrine adenomatosls. Ann Intern Med 76: 53, 1972. Vance JE, Stall RW, Kitabchi AE, et al.: Familial nesidioblastosis as the predomlnant manifestation of multlple endocrine adenomatosis. Am J Med 52: 211, 1972. Lamers CBH, van Tongeren JHM: Comparative study of the value of the calcium, secretin and meal stimulated increase in serum gastrin to the diagnosis of the Zollinger-Elllson syndrome. Gut 18: 128, 1977. Ganguli PC, Polak JM, Pearse AGE, et al : Antralgastrln-cell hyperplasia in peptic-ulcer disease. Lancet 1: 583. 1974 Straus E, Yalow RS: Dlfferentttl dlagnosis of hypergastrinemla. Gastrolntestlnal Hormones (Thompson JC, ed), AustinLondon, Unlversity of Texas Press, 1975, p 99. Fiske CH, Subbarow Y: The colorlmetric determination of phosphorus. J Blol Chem 66: 375, 1925. Mattingly D: A simple fluorimetric method for the estimation of free 1 l-hydroxycortlcoids in human plasma. J Clln Pathol
The American Journal of Medclne
Volume 64
611
26.
27.
28.
812
15: 374, 1962. Hoffman WS: A rapid photoelectric method for the determination of glucose in blood and urine. J Biol Chem 120: 51, 1937. Rehfeld JF, Stadil F, et al.: Gastrin heterogeneity in serum and tissue. Gastrointestinal Hormones (Thompson JC, ed), Austin-London, University of Texas Press, 1975, p 43. Ellison EH, Wilson D: The Zollinger-Ellison syndrome: reappraisal and evaluation of 260 registered cases. Ann Surg 180: 512, 1964.
April 1978
The American Journal of Medicine
Volume 64
29.
30. 31.
Bonfils S, Bader JP: The diagnosis of Zollinger-Ellison syndrome with special reference to the multiple endocrine adenomas, chap 19. Progress in Gastroenterology (Glass GBJ, ed). New York, Grune 8 Stratton, 1970 Pender B: Isletcell tumour of pancreas associated with peptic ulceration. Lancet 1: 123, 1959. Grunt JA, Pallotta JA, Soeldner JS: Blood sugar, serum insulin and free fatty acid interrelationships during intravenous tolbutamide testing in normal young adults and in patients with insulinoma. Diabetes 19. 122, 1970.