CASE REPORTS Refer to: Riddle MC, Golper TA, Fletcher WS, et al: Glucagonoma syndrome in a 19-year-old woman. West J Med 129:68-72, Jul 1978

Glucagonoma Syndrome in a 19-Year-Old Woman MATTHEW C. RIDDLE, MD THOMAS A. GOLPER, MD WILLIAM S. FLETCHER, MD Portland, Oregon JOHN W. ENSINCK, MD PHILLIP H. SMITH, PhD Seattle ABBREVIATION USED IN TEXT IRG = immunoreactive glucagon

A NEW CLINICAL SYNDROME associated with glucagon-secreting tumors has recently been described.'-3 The main features are a distinctive and disabling skin rash, weight loss, anemia and glucose intolerance. Most persons with the syndrome have been elderly and seriously ill at the time of diagnosis. We report here a case with typical and

dramatic findings of the disorder appearing in a 19-year-old woman. Because of her youth and otherwise good health, extensive metabolic studies have been possible, and several unusual features are described. Report of a Case In a previously well 19-year-old woman a pruritic vesicular skin eruption developed on the ankles. Initially it subsided after therapy with orally given prednisone. The rash recurred, however, developing into a widespread eruption, worst around the genitals, the mouth and areas of superficial trauma. Glossitis was also present, as was significant emotional depression. Findings on a skin biopsy were not diagnostic. Periodic exacerbations continued despite therapy with topically administered creams, orally given prednisone, vitamins and dietary restrictions, and avoidance of contact with metals. From the Departments of Medicine (Riddle, Golper) and Surgery (Fletcher), University of Oregon Health Sciences Center, Portland, and the Departments of Medicine (Ensinck) and Biological Structure (Smith), University of Washington, Seattle. Submitted January 16, 1978. This work was supported by grant 26.09 from the Medical Research Foundation of Oregon, and by NIH grants AM-08547, AM-16008, AM-03433 and RR-00334. Reprint requests to: Matthew C. Riddle, MD, Division of Metabolism, Department of Medicine, University of Oregon Health Sciences Center, Portland, OR 97201.

68

JULY 1978 * 129 * 1

About 11 months after onset of the rash the patient reported several new symptoms, including muscle weakness, nausea, early satiety and cessation of menses. A weight loss of ten pounds, diffuse loss of muscle mass and mild anemia were noted. Glucose tolerance, which had been normal previously, was mildly impaired. Repeat skin biopsy showed epidermal cleavage forming bullae containing acantholytic cells. Fasting plasma immunoreactive glucagon (IRG) activity was 800 pg per ml, five-fold elevated, confirming the diagnosis of glucagonoma. Visceral angiography showed a small pancreatic tumor and many liver metastases. Further medical evaluation uncovered no other noteworthy findings. The only medical history worth noting was a moderately severe depression three years before. Her mother and sister were reported to have glucose intolerance, and a maternal aunt to have overt diabetes. Extensive laboratory studies showed the following abnormal findings: hemoglobin, 10.2 grams per dl; hematocrit, 31 percent; leukocyte count, 3,700 with relative lymphocytosis; plasma parathyroid hormone, 84 /lEq per ml; while calcium was 9.3 mg per dl, with the normal range up to 82 ,dEq per ml (Nichols Institute, Portland, Oregon); fasting plasma insulin, 17 to 30 /,U per ml. Plasma amino acids concentrations were mostly depressed, especially those of ornithine, threonine, asparagine/glutamine, valine and alanine, which were below half of normal values. Results of liver function tests were within normal limits. When the diagnosis was established dietary restrictions were removed and the rash concurrently improved. After informed consent, pretreatment physiologic studies were done, followed by excision of all primary tumor tissue and chemotherapy of metastases with intravenous administration of tubercidin (1.5 mg per kg of body weight), and 5-fluorouracil (1 gram per day for eight days) by hepatic arterial infusion. After an initial exacerbation the skin rash disappeared and most of the lost weight and muscle mass was regained; the patient's sense of well-being returned. Fasting plasma IRG fell by half, to 300 to 400 pg per ml, and insulin to 5 to 20 1tU per ml. Chemotherapy has continued: Intravenously given tubercidin, 1.5 mg per kg of body weight every one to two months, and orally or intravenously given 5-fluorouracil, 750 to 1,000 mg a week, supplemented with 1 gram per day given intravenously for two to eight days coinciding with tubercidin doses. Placement of a femoral

CASE REPORTS

arteriovenous (umbilical vein biograft) shunt has facilitated chemotherapy. The remission has lasted 31 months to date.

rabbit antiglucagon serum, and rabbit antisomatostatin serum (a gift of Dr. B. L. Baker, University of Michigan).

Methods

Results

Immunoreactive glucagon was assayed using the Unger 30K antibody, usually after removal of large molecular weight species (over 3,500 daltons) in plasma by acetone precipitation.4'5 Plasma IRG activity was fractionated on a column of Bio-gel P-10 calibrated with proinsulin, insulin, glucagon and tritiated water. Insulin was assayed by the method of Zaharko and Beck,6 and glucose by glucose oxidase. Dynamic studies of plasma glucose, insulin and glucagon responses to various stimuli were carried out after an overnight fast, each on a separate day. Standard commercial preparations of oral (Koladex) and intravenous (Cutter) glucose, regular insulin (Squibb), tolbutamide (Upjohn), epinephrine (Parke-Davis) and diazoxide (Schering) were used. Casein hydrolysate (Mead-Johnson) and vegetable oil (Wesson) were used for oral loading studies. Tissue was fixed in neutral formalin and Bouin's solution for light microscopy, and in glutaraldehyde for electron microscopy. Tumor sections were stained with hematoxylin and eosin, aldehyde fucsin, and the silver impregnation methods of Grimelius7 and Hellerstrom and Hellman.8 Immunofluorescence studies of primary tumor and adjacent normal pancreas were done by the indirect technique,9 using anti-insulin serum, 30K

Studies of Circulating IRG IRG activity in unmodified fasting plasma at the time of diagnosis was 800 pg per ml. Activity in acetone extracts was 600 pg per ml, suggesting that only about 25 percent of the total was accounted for by high molecular weight material excluded by the extraction procedure. Fractionation of unmodified plasma by column chromatography verified this inference, showing 70 percent of IRG in species of molecular weight approximating that of normal glucagon (3,500 daltons). Most of the remaining IRG eluted in an area corresponding to molecular weight of 8,000 to 12,000 daltons. IRG assay in all subsequent studies was done on acetone extracts.

Physiologic Studies Results of several standard physiologic studies done before treatment are shown in Table 1. Little or no suppression of plasma IRG occurred following oral administration of glucose, intravenous administration of glucose or immediately after injection of insulin. No clear response in IRG followed insulin-induced hypoglycemia. In contrast, a quick rise in IRG immediately followed intravenous administration of tolbutamide, the elevation persisting an hour. Tolbutamide injec-

TABLE 1.-Responses of plasma glucose (mg per dl), plasma immunoreactive glucagon (pg per ml) and plasma immunoreactive insulin (AU per ml) to various stimuli before surgical therapy or chemotherapy. Oral glucose 100 grams Glucose ...... IRG .....

Baseline 91 ................ ................. 504 Baseline

Intravenous glucose 25 grams 77 ................. Glucose ..... ................. 620 IRG ..... IRI ..................... 22

30 min.

60 min.

218 513

191 473

2 min. 810 224 10 mn.

Baseline Intravenous insulin 0.2 unit per kg 41 58 ................ Glucose .... 680 IRG .................... 550 2 mii. Baseline Intravenous tolbutamide 1.0 grams Glucose .... 72 ................ IRG .................... 590 1,070 IRI .................... 26 105 Intravenous epinephrine 6 ,ug per min. continuously Baseline Glucose .... 71 ................ IRG .................... 510 IRI .................... 25

15 min. 75

1,490 12

90 min.

120 min.

180 min.

155 382

121 416

86 456

10 mi.

20 mi.

40 min.

60 min.

760 184 20 min.

276 660 152

246 500 252

204 550 267

163 410 171

30 min.

40 min.

50 min.

60 min.

34 540

14 480

22 770

39 660

82 550

10 min.

20 min.

40 min.

60 min.

75 860 122

73 730 118

59 720 83

46 800 50

5 min.

5

min.

850

115 30 min.

40 min.

125 830 53

137 1,260 25

IRG = immunoreactive glucagon IRI =immunoreactive insulin

THE WESTERN JOURNAL OF MEDICINE

69

CASE REPORTS

fore, studies of plasma IRG response to a standard mixed lunch after no pretreatment, pretreatment for one day with 100 mg of diazoxide given orally every eight hours, and pretreatment with diphenylhydantoin ( 100 mg given orally three times a day for several weeks) were carried out. No clear suppression of postprandial IRG occurred with either drug. Tumor Pathology The primary tumor was a 2.5 cm cystic nodule. With hematoxylin and eosin staining both primary and metastatic tissues showed morphology typical of islet cell carcinomas. Both failed to show selective staining for A or D cells when examined with the methods of Grimelius7 and of Hellerstrom and Hellman.8 Immunofluorescence studies showed glucagon immunoreactivity in many but not all tumor cells, but failed to show either insulin or somatostatin. Studies of adjacent normal pancreas validated the methods used, showing the usual immunofluorescence pattern of these hormones. Tumor content of IRG measured in acid ethanol extracts was 3.2 ,ug per gram wet weight in primary, and 0.3 ,ug per gram in metastatic tissue.

tion is reported to lower plasma IRG under normal conditions.10 IRG also increased during continuous epinephrine infusion., The response of plasma IRG to ordinary mixed meals over 24 hours also was studied preoperatively (Figure 1). A prominent rise in IRG followed each meal, subsiding to the basal level before the next meal. Insulin responses were very brisk. Because of these results, three further studies were done postoperatively to identify what component of meals was responsible (Figure 1). Baseline IRG concentration was lower in the posttreatment studies, when tumor hormone derived only from metastatic tissue. A 500 ml water load failed to provoke any response of glucose, insulin or IRG. Gastric distension consequently seemed not to account for the IRG response. In contrast, meals of casein or vegetable oil were followed by large increases of IRG. In each case plasma glucose rose as well. The hyperglycemia after fat ingestion suggested biological activity of the elevated IRG. The prominent rise of plasma IRG after meals was considered possibly harmful, and possibly susceptible to drug blockade. There500cc H20

cCasein Hydrolysote 100 gms -200 in 500cc H20

45cc Vegetoble Oil +455cc H20

400 1-..

400

300

300

A--.* -

iz-

N

:Zs

.41

I --

-

e-

--* -4

-

200

200

100

100 .

0'

1500r 11-.

qt

cz2

61s-s

k..,

N. t-lh 'k t-ti

@

1000

/

I--,0

0

11500 .

1000

N 500

500 diL

-&-&

° ':::::::: --::::-- :t: :: :: :: : : : t ::::: ::: :::: ::::-::::: 0800 1600 2400 0 ..... 30 60 120 1200 2000 0800

0

1800

30 60

120

180 0

30 60

120

180

'

Hours Minutes Figure 1.-Responses of plasma glucose, immunoreactive. insulin (IRI) and immunoreactive glucagon (IRG) to mixed meals, water, vegetable oil and casein, all given orally. The latter three studies were done after treatment. IRG was assayed after acetone extraction, and the stippled area denotes the normal range of up to 120 pg per ml. 70

JULY 1978

*

129

*

1

CASE REPORTS

Cells of the primary tumor were not homogeneous to electron microscopy. In some areas cells with granules typical of A cells were seen, while in others, cells contained dense homogeneous 100 to 200 nm granules lacking a halo. In other areas few secretion granules of any type were seen. The cells containing the small granules resembled the second cell type in the glucagonoma described by Leichter and colleagues."

Discussion Most reported patients with glucagon-secreting tumors causing systemic effects have been over 50 years old, though a few reports describe younger patients with some features of the syndrome.'2-'4 This case verifies that the full syndrome does occur even in the second decade of life. Since this woman was otherwise healthy her course clearly traces the early natural history of the disorder. The rash came first, followed by a recurrence of previous emotional problems. Weight loss, weakness, anemia and glucose intolerance were recognized a year after the rash developed. Like other patients with the syndrome, she had persistent hyperglucagonemia, hypoaminoacidemia and mild hyperinsulinemia. Plasma IRG suppressed subnormally with oral and intravenous administration of glucose. An immediate and sustained increase of IRG followed intravenously given tolbutamide. Insulin hypoglycemia did not elicit the usual increase of plasma IRG. Similar findings of faulty regulation of IRG secretion have been documented in other cases."' 15-'8 Several features of this case other than the patient's youth are remarkable. One is the high proportion (70 percent) of circulating IRG activity present in a fraction corresponding to normal molecular weight glucagon. The rise in plasma glucose coinciding with the rise in IRG after fat ingestion suggests this material has high biologic potency. The rather sluggish decline in glucose after tolbutamide also suggests this, since the insulin response was normal. These findings contrast with other experience,'8-20 which suggests that the plasma of glucagonoma patients typically contains a relative excess of IRG of molecular weight of 8,000 to 12,000 or even higher, probably of decreased biologic potency. The dominance of 3,500 dalton IRG in this patient may relate to the rapid onset and severity of the clinical syndrome. Another important finding in this patient is the prominent IRG response to mixed meals, orally

given protein and orally given fat. An increase in plasma IRG after protein meals occurs in normal persons,2' and has also been reported in a patient with glucagonoma syndrome.'8 Mixed meals and fat normally elicit only modest increases in plasma IRG.22'23 A substantial rise of IRG after mixed meals has been described in other patients with glucagonoma,"1-'5 but this appears to be the first demonstration that fat can also be a tumor IRG secretagogue. Possibly a gut factor mediates this response.24 The effect of meals on plasma IRG may have clinical importance for this patient. We have recommended a diet with 60 to 70 percent of calories as carbohydrate and 15 to 20 percent each as fat and protein, to minimize the postprandial IRG surge. She reports that this diet is more palatable, with less early satiety. The tumor histology also merits comment. Heterogeneity of cell types in islet cell tumors is recognized, and in this patient was evident both by electron microscopy and glucagon immunofluorescence. This finding strengthens the suspicion that these tumors often produce more than one humoral factor.25 Also noteworthy is the absence of insulin and somatostatin from the tumor. It is suspected that both normally suppress and modulate glucagon secretion,26'27 and that this process requires close contact between the several secretory cells in the normal islet. Perhaps the abnormal rises in plasma IRG after various stimuli in this patient reflect lack of both suppressive hormones in the tumor. Finally, the apparent persistence of biological actions of IRG in this patient argues against glucagon's effects being entirely evanescent. Some evidence suggests that the hyperglycemic effect of physiologic hyperglucagonemia is transient.28 Despite this, our patient had mild but progressive glucose intolerance, fasting hyperinsulinemia and a rise in glucose after a rise in IRG provoked by oral fat. In other cases similar carbohydrate intolerance associated with glucagonomas has been seen.29 While indirect, this evidence suggests that the hyperglycemic effect of persistent hyperglucagonemia in the range found in this patient may be of long duration.

Summary A case of the glucagonoma syndrome in a 19year-old woman is described. During a year, severe dermopathy, depression, weight loss, anemia and mild glucose intolerance developed, leadTHE WESTERN JOURNAL OF MEDICINE

71

CASE REPORTS

ing to recognition of a metastatic islet cell tumor. Fasting plasma immunoreactive glucagon (IRG) was 0oo pg per ml, and 70 percent of this consisted of normal (3,500) molecular weight IRG. Faulty regulation of plasma IRG included pronounced increases after mixed meals and orally given fat. Tumor cell morphology was heterogeneous, and while glucagon immunofluorescence was shown, insulin and somatostatin immunofluorescence were lacking. A clinical remission was induced and sustained by surgical therapy and chemotherapy. The case documents the occurrence of this syndrome in the second decade of life, a favorable response to palliative therapy, and a relationship between meal composition and plasma IRG that may have clinical importance for this patient.

26. Samols E, Harrison J: Intraislet negative insulin-glucagon feedback. Metabolism 25 (Suppl 1): 1443-1447, Nov 1976 27. Orci L, Unger RH: Functional subdivision of islets of Langerhans and possible role of D cells. Lancet 2:1243-1244, Dec 20, 1975 28. Sherwin R, Wahren J, Felig P: Evanescent effects of hypoand hyperglucagonemia in blood glucose homeostasis. Metabolism 25 (Suppl I):1381-1383, Nov 1976 29. Lightman SL, Bloom SR: Cure of insulin-dependent diabetes mellitus by removal of a glucagonoma. Br Med J 1:367-368, Mar 2, 1974

Referto: Graber ML, Cogan MG, Connor DG: Idiopathic acute interstitial nephritis. West J Med 129:72-76, Jul 1978

Idiopathic Acute Interstitial Nephritis

REFERENCES

1. McGavran MH, Unger RH, Recant L, et al: A Glucagon secreting alpha-cell carcinoma of the pancreas. N Eng J Med 274: 1408-1413, Jun 23, 1966 2. Mallinson CN, Bloom SR, Warin AP, et al: A glucagonoma syndrome. Lancet 2:1-5, Jul 6, 1974 3. Case records of the Massachusetts General Hospital (Case 20-1975). N Engl J Med 292:1117-1123, May 22, 1975 4. Walter RM, Dudl RJ, Palmer JP, et al: The effect of adrenergic blockade on the glucagon responses to starvation and hypoglycemia in man. J Clin Invest 54:1214-1220, Nov 1974 5. Ensinck JW, Shepard C, Dudl RJ, et al: Use of benzamidine as a proteolytic inhibitor in the radioimmunoassay of glucagon in plasma. J Clin Endocrinol Metab 35:463-467, Sep 1972 6. Zaharko DS, Beck LV: Studies of a simplified plasma insulin immunoassay using cellulose powder. Diabetes 17:444-457, Jul 1968 7. Grimelius L.: A silver nitrate stain for A2 cells in human pancreatic islets. Acta Soc Med Ups 73:243-270, 1968 8. Hellerstrom C, Hellman B: Some aspects of silver impregnation of the islets of Langerhans in the rat. Acta Endocr 35: 518-532, Dec 1960 9. Sternberger LA: Immunocytochemistry. Englewood Cliffs, NJ, Prentice Hall, Inc, 1974 10. Samols E, Tyler JM, Mialhe P: Suppression of pancreatic glucagon release by the hypoglycemic sulfonylureas. Lancet 1: 124-176, Jan 25, 1969 11. Leichter SB, Pagliara AS, Grieder MH, et al: Uncontrolled diabetes mellitus and hyperglucagonemia associated with an islet cell carcinoma. Am J Med 58:285-293, Feb 1975 12. Bianchi C. Maehor M, Zar E: Dermatosis paraneoplastica in carcinoma "di tipo endocrino" del pancreas. Riv Anat Patol Oncol 33:319-324, 1968 13. Yoshinaga T, Okuno G, Shinji Y, et al: Pancreatic A-cell tumor associated with severe diabetes mellitus. Diabetes 15: 709-713, Oct 1966 14. Croughs RMJ, Hulsmans HAM, Israel DE, et al: Glucagonoma as part of the polyglandular syndrome. Am J Med 52: 690-698, May 1972 15. Boden G, Owen 0, Rezvani I, et al: An islet cell carcinoma containing glucagon and insulin. Diabetes 26:128-137, Feb 1977 16. Tiengo A, Fedele D, Marchiori E, et al: Suppression and stimulation mechanisms controlling glucagon secretion in a case of islet-cell tumor producing glucagon, insulin, and gastrin. Diabetes 25:408-412, May 1976 17. Walter RM, Dudl RJ, Ensinck JW: Immunoreactive glucagon in islet cell tumors. Diabetes 21 (Suppl 1):333-334, 1972 18. Danforth DN, Triche T, Doppman JL, et al: Elevated plasma proglucagon-like component with a glucagon-secreting tumor. N Engl J Med 295:242-245, Jul 29, 1976 19. Recant L, Perrino PV, Bhathena SJ, et al.: Plasma immunoreactive glucagon fractions in four cases of glucagonoma: Increased "large glucagon" immunoreactivity. Diabetologia 12:319326, Aug 1976 20. Weir GL, Horton ES, Aoki TT, et al: Secretion by glucagonomas of a possible glucagon precursor. J Clin Invest 59: 325-330, Feb 1977 21. Muller WA, Faloona GR, Auilar-Parada E, et al: Abnormal alpha cell function in diabetes. N Engl J Med 283:109-115, Jul 16, 1970 22. Gerich JE: Control of pancreatic IRG secretion in vivo. Metabolism 25 (Suppl 1) :1437-1441, Nov 1976 23. Bottger I, Dobbs R, Faloona GR, et al: The effects of triglyceride absorption upon glucagon, insulin, and gut glucagonlike immuno-reactivity. J Clin Invest 52:2532-2541, Oct 1973 24. Bloom SR, Iverson J: Gut hormones and the alpha cell. Metabolism 25 (Suppl 1):1457-1458, Nov 1976 25. Polak JM, Adrian TE, Bryant MG, et al: Pancreatic polypeptide in insulinomas, gastrinomas, vipomas, and glucagonomas. Lancet 1:328-330, Feb 14, 1976

72

JULY 1978 * 129 * 1

MARK L. GRABER, MD Boston MARTIN G. COGAN, MD DAVID G. CONNOR, MD San Francisco ACUTE INTERSTITIAL NEPHRITIS (AIN) must be considered in any patient presenting with acute renal failure; the pathologic inflammation may resolve and the prognosis is generally favorable. Previous reports emphasize that AIN with acute renal failure is most frequently seen as a manifestation of drug hypersensitivity, or rarely in association with overt infection. We report the case of a patient with reversible acute renal failure and biopsy-confirmed MN in whom none of the known pharmacologic or infectious associations of AIN were identifiable. Fluorescent antiglobulin studies showed intense interstitial staining for IgM, with staining of both tubular and glomerular basement membranes for IgG, IgM and complement. We believe that the AIN in this case may represent virus induced immunologic

injury. Report of a Case A 36-year-old woman, a schoolteacher, had a three-week illness characterized by fatigue, low grade fever, nasal congestion, cough and mild diarrhea. Findings on physical examination were From the Department of Medicine, Mt. Zion Hospital and Medical Center, San Francisco. Dr. Graber is now with University Hospital, Boston. Submitted, revised, September 19, 1977. Reprint requests to: Mark Graber, MD, Department of Medicine, University Hospital, 75 E. Newton St., Boston, MA 02118.

Glucagonoma syndrome in a 19-year-old woman.

CASE REPORTS Refer to: Riddle MC, Golper TA, Fletcher WS, et al: Glucagonoma syndrome in a 19-year-old woman. West J Med 129:68-72, Jul 1978 Glucagon...
854KB Sizes 0 Downloads 0 Views