Selective Calcification of Pancreatic Islets of Langerhans An Unusual Association with Hypercalcemia and Diabetes Mellitus James D. Cotelingam, M.D.,* and H. Richard Hellstrom, M.D., Pittsburgh
SUMMARY An unusual and extensive calcification of islets of Langerhans was found at autopsy in a man, 58 years old, who developed myeloma and, subsequently, hypercalcemia and diabetes. Although the islet cell calcification appears to be related to the hypercalcemia, the pathogenesis of the calcification is not clear, as primary metastatic calcification of pancreatic islets due to hypercalcemia does not occur. In support of this, a retrospective study of pancreatic tissue from 52 hypercalcemic patients with parathyroid adenoma and 34 patients with multiple myeloma, who frequently have hypercalcemia, did not reveal islet calcification. The islet calcification is ascribed to primary islet cell degeneration and necrosis, with hypercalcemia playing an augmenting but crucial role. It is considered that the combination of islet degeneration and calcification resulted in the diabetic state. DIABETES 27:620-24, June, 1978.
In diabetes mellitus, certain pathologic lesions develop in pancreatic islets. 1 " 5 These include hydropic change due to glycogert infiltration, reduction and degranulation of B-cells, lymphocytic infiltration (von Meyenburg's insulitis), fibrosis, amyloid infiltration, B-cell hemosiderin deposits in hemochromatosis, and islet hyperplasia with eosinophilic infiltration in
From the Departments of Pathology, University of Pittsburgh, School of Medicine and the Veterans Administration Hospital, Pittsburgh, Pennsylvania. *Dr. Cotelingam was a resident in pathology; he is presently staff pathologist at the Naval Regional Medical Center in Orlando, Florida. Address for reprints: H. Richard Hellstrom, M.D., Laboratory Service, Veterans Administration Hospital, University Drive C, Pittsburgh, Pennsylvania 15240. Accepted for publication December 20, 1977. 620
neonates born to diabetic mothers. A correlation, frequently exists between the clinical form of diabetes and the severity, extent, and type of morphologic lesion. However, on occasion no lesion may be found. To our knowledge, the association of calcification in islets with hypercalcemia and diabetes has not been previously described; hence this brief report. CASE REPORT, AUTOPSY FINDINGS, AND CONTROL STUDY A 58-year-old man presented to the Oakland Veterans Hospital in November 1972 with an eight month history of low backache, anemia, and fatigue. On the basis of clinical, laboratory, and radiologic data, a diagnosis of multiple myeloma was made. Before the onset of these symptoms, the patient was in good health and on no medication. There was no family history of malignancy or diabetes. Laboratory data included a hemoglobin of 9 0 gm. per cent and hematocrit of 27 per cent. The total WBC count was 4,878/c.mm. with a normal differential, and the platelet count was 143,000/c.mm. The peripheral blood film revealed hypochromic red cells with considerable rouleaux formation. The bone marrow was markedly infiltrated by plasma cells including immature nucleolated forms. Total proteins were 14.3 gm. per cent, of which the globulin fraction comprised 11.8 gm. per cent. On serum immunoelectrophoresis, homogenous IgG-lambda protein was detected. However, immunoelectrophoresis of the urine revealed no Bence Jones protein. At this first admission the serum calcium, phosphorus, blood sugar, and alkaline phosphatase were normal and no glycosuria was present. X-ray examination revealed lytic lesions in the skull, pelvis, and vertebrae, with a fracture of the second lumbar vertebra. A therapeutic regimen with Alkeran, procarbazine, prednisone, and radiation therapy to the spine were started. Five months later, the patient was readmitted for follow-up and complained of polyuria and polydipsia. At this time the fasting blood sugar was 230 mg./lOO ml. and glycosuria was present. A subsequent glucose tolerance test revealed a blood sugar of 246 mg./lOO ml. at three hours. The serum calcium was 11.6 mg./ 100 ml. and phosphorus 2.4 mg./lOO ml. Alkaline phosphatase at DIABETES, VOL. 27, NO. 6
JAMES D. COTELINGAM, M.D., A N D H. RICHARD HELLSTROM, M.D.
this and subsequent admissions was normal. In addition to the treatment for multiple myeloma, the diabetes was controlled with Orinase (tolbutamide). Later, when the dose of prednisone was increased from 10 to 80 mg. per day, he required additional insulin. A month after this second admission he was readmitted for treatment of chronic active hepatitis and received additional treatment with azathioprine. During several subsequent admissions the diabetes remained controlled and plasma cells in the bone marrow decreased. However, the serum calcium remained intermittently elevated. His final admission was in March 1976, 40 months after the initial diagnosis of multiple myeloma. During his final admission the myeloma was resistant to therapy and total plasma protein concentration was elevated at 11.7 gm. per cent, with a globulin fraction of 6.42 gm. per cent. Serum calcium varied between 14 and 15.2 mg./lOO ml. but intermittently responded to saline diuretics. Serum phosphorus varied between 3.3 and 5.8 mg./lOO ml. The diabetes was controlled, but he remained anemic. His platelet count dropped to 72,000/c.mm. and he developed guaiac-positive stools. Repeated immunoelectrophoretic testing for Bence Jones protein was negative.-Terminally, he developed a coagulase-positive staphylococcic septicemia and spiked a fever of 100° F. He died on the 13th hospital day. At autopsy, extensive and diffuse multiple myeloma with osteoporosis was present in numerous samples of bone.
The pancreas weighed 120 gm. and showed no gross pathologic change. Microscopically, extensive and selective calcification of islets was present in numerous samples of tissue (figures 1 and 2). A count of 355 islets revealed calcification in 315 (88.7 per cent), and, in 90 per cent of these calcified islets, more than three quarters of the islet parenchyma were calcified. In noncalcified islets and in noncalcified areas of involved islets, the Bcell:non-B-cell ratio, evaluated with Gomori's aldehyde-fuchsin stain, was about 3:1. Examination of decalcified tissue revealed extensive degeneration and necrosis of calcified islets. A search for amyloid using Congo red with polarized light and Thioflavin-T preparations was negative. Inflammatory reaction, fibrosis, and hemosiderin were absent also. The size of islets was normal and the presence of calcium was confirmed by the von Kossa stain and a Faxitron x-ray preparation of wet tissue (figure 3). The exocrine and interstitial tissues were not calcified, although intraparenchymal arteries were focally involved. Metastatic calcification was seen in alveoli, bronchi from both lungs, focally in renal tubules, and in the myocardium. The kidneys revealed no amyloid deposits or changes associated with multiple myeloma. Parathyroid glands were normal, and no calcification was present in other endocrine organs. Micronodular cirrhosis was present with congestive splenomegaly. Petechial hemorrhages and focal necrosis were noted in the duodenum and jejunum. Post mortem, blood cultures grew coagulase-positive
FIG. 1. Typical low power microscopic field of pancreas with numerous calcified islets. Magnification: 3 5 0 X .
JUNE, 1978
621
HYPERCALCEMIA A N D DIABETES MELLITUS
FIG. 2. Higher magnification (160x) of a severely calcified islet.
staphylococci and enterobacter aerogenes. The immediate cause of death was septicemia in this patient with multiple myeloma diagnosed 40 months previously. As a control study of Langerhans' islets, a 20-year survey (1954-1974) of the autopsy files from Presbyterian-University Hospital was carried out. This included 34 patients with multiple myeloma and 52 hypercalcemic patients with parathyroid adenoma. No example of islet calcification was found in this material. DISCUSSION
The occurrence of islet calcification and its association with diabetes mellitus and hypercalcemia appears unique, as similar examples were not found in the literature, including experimental models.6-7 However, calcification of hyaline material in islets, now considered to be amyloid, 3 has been previously described.8" 11 In Fisher's case,8 the calcification was grossly visible and associated with islet hyperplasia, and it developed in an 18-year-old male with fatal diabetic coma. The sequence of clinical events provides some aid in 622
relating the myeloma, hypercalcemia, diabetes, and islet calcification. At the time of the first admission for myeloma, serum calcium and fasting glucose were normal. Five months later, hypercalcemia and glycosuria were detected, and a diagnosis of diabetes mellitus was made for the first time. At autopsy, 40 months later, extensive islet cell calcification with degeneration and necrosis was observed without evidence of amyloid infiltration or siderosis. This circumstantial evidence suggests that the diabetic state was related to the hypercalcemia and islet calcification and degeneration. Also, the prednisone treatment 12 probably enhanced the severity of the diabetes. In spite of the obvious relationship of hypercalcemia to calcification, the pathogenesis of the islet calcification is not clear. Although there was metastatic calcification in the lungs, kidneys, and heart, it does not seem likely that the extensive islet cell calcification can be attributed directly to the hypercalcemia. Pancreatic islets are not among the tissues affected by metastatic calcification in hypercalcemia,13 DIABETES, VOL. 27, NO. 6
JAMES D. COTELINGAM, M . D . , A N D H. RICHARD HELLSTROM, M.D.
FIG. 3.
Faxitron x-ray preparation of wet pancreatic tissue with extensive speckled calcification. Magnification: 6 x .
and, in our review of 52 autopsies of hypercalcemic subjects, islet calcification was absent. Also, myeloma, commonly complicated by hypercalcemia, does not result in islet calcification, and no calcification was evident in islets in our retrospective review of 34 autopsy cases of myeloma. We consider the key to the diabetes and the calcification to be the extensive degeneration and necrosis of islets seen in decalcified sections. Dystrpphic calcification after necrosis is common, 13 and, in this case, it is likely that the primary event was islet cell injury. The tendency for necrotic tissue to calcify was augmented, probably critically, by the hypercalcemia. It might be argued that the necrosis evident at autopsy was entirely secondary to the extensive calcification rather than was its cause. However, as islet cell calcification due solely to hypercalcemia seems unlikely, the necrosis is accepted as primary. The cause for primary islet cell degeneration is unknown. By exclusion the most reasonable explanation appears to be a hypersensitive reaction to one of the drugs used to treat the myeloma. Direct islet toxicity JUNE, 1978
is not likely, as none of the antineoplastic drugs used are known to have a diabetogenic effect or structural similarity to streptozotocin, alloxan, or other agents that selectively destroy B-cells. 14 Since treatment with azothioprine for chronic active hepatitis was given after the onset of the diabetes, its role in the pathogenesis of the calcification is not considered. The possibility that islet cell injury followed focal ischemia from precipitated myeloma proteins was considered, but there is no evidence for this, as the capillary microvasculature of islets in decalcified blocks was unremarkable. Radiation injury does not appear to be responsible for islet injury, as both endocrine and exocrine tissues are resistant to the usual therapeutic dose. Moreover, no pancreatic fibrosis or vascular sclerosis was present, which usually is the case with higher doses of radiation. 15 It is of interest that, despite the clarity and resolution of calcium deposits in the Faxitron preparation, calcification could not be visualized on routine abdominal films. We believe this extensive and selective islet cell 623
HYPERCALCEMIA AND DIABETES MELLITUS
calcification in this patient is a unique and striking phenomenon. Moreover, its association with hypercalcemia and diabetes is of considerable interest. ACKNOWLEDGMENTS Dr. Andrew Dekker and Dr. Arthur A. Like made valuable suggestions. Dr. Robert E. Lee made available the autopsy files of Presbyterian-University Hospital. Bill Hiller, Bud Jozwiak, and Saul Weiss rendered technical and photographic assistance. Mrs. Patricia Turkovich typed the manuscript. REFERENCES 'Lacy, P. E.: Pathology of the islets of Langerhans. In Pathology Annual. Vol. 1. Sommers, S. C., Ed. New York, AppletonCentury-Crofts, 1966, pp. 352-70. 2 Warren, S., LeCompte, P. M., and Legg, M. A.: Pathology of Diabetes Mellitus. Fourth edit. Chapter 3. Philadelphia, Lea & Febiger, 1966, pp. 53-88. 3 Lacy, P. E.: The islets of Langerhans. In Endocrine Pathology. Bloodworth, J. M. B., Jr., Ed. Baltimore, Williams and Wilkins, 1968, pp. 316-29. 4 Steiner, H.: Morphology of diabetes mellitus. In Clinical Endocrinology. Third edit. Chapter 13. Labhart, A., Ed. New York, Heidelberg, and Berlin, Springer-Verlag, 1974, pp. 76467. 5 Williams, R. H., and Porte, D., Jr.: The pancreas. Pathol-
624
ogy. In Textbook of Endocrinology. Fifth edit. Williams, R. H., Ed. Philadelphia, W. B. Saunders, 1974, pp. 566-67. 6 Klemm, G.: Chronische kalziphylaktische Pankreatitis. Z. Gesamte Inn. Med. Ihre Grenzgeb. 29:722-25, 1974. r Wexler, B. C : Arteriosclerosis of the pancreas and changes in the islets of Langerhans of repeatedly bred rats. Br. J. Exp. Pathol. 51:107-13, 1970. 8 Fischer, B.: Pankreas und Diabetes. Frankf. Z. Pathol. 77:218-75, 1915. 9 Mallory, F. B.: The Principles of Pathologic Histology. Part II. Philadelphia, W. B. Saunders, 1914, p. 521. 10 Gibbs, W. F., Jr., and Logan, V. W.: Diabetes mellitus. A study of 147 autopsies. Arch. Intern. Med. 43:376-83, 1929. n Escudero, P.: Tratado de la Diabetes, Buenos Aires, 1927. Quoted by Warren, S., LeCompte, P. M., and Legg, M. A. In The Pathology of Diabetes Mellitus. Fourth edit. Chapter 3. Philadelphia, Lea & Febiger, 1966, pp. 53-88. 12 West, K.: Epidemiology of diabetes. In Diabetes Mellitus: Diagnosis and Treatment. Vol. 3. Chapter 21. Fajans, S. S., and Sussman, K. E., Eds. New York, American Diabetes Association, 1971, pp. 121-26. 13 Scarpelli, D. G., and Chiga, M.: Cell injury and errors of metabolism. In Pathology. Seventh edit. Chapter 3. Anderson, W. A. D., and Kissane, J. M., Eds. St. Louis, C. V. Mosby, 1977, pp. 90-147. 14 Larner, J., and Haynes, R. C., Jr.: Insulin and oral hypoglycemic drugs; glucagon. In The Pharmacological Basis of Therapeutics. Fifth edit. Chapter 71. Goodman, L. S., and Gilman, A., Eds. New York, Macmillan, 1975, pp. 1507-33. 15 White, D. C : An Atlas of Radiation Histopathology. Chapter 8. Oak Ridge, U.S. Energy Research and Development Administration, 1975, pp. 161-70.
DIABETES, VOL. 2 7 , NO. 6
SUMMARY An unusual and extensive calcification of islets of Langerhans was found at autopsy in a man, 58 years old, who developed myeloma and, subsequently, hypercalcemia and diabetes. Although the islet cell calcification appears to be related to the hypercalcemia, the pathogenesis of the calcification is not clear, as primary metastatic calcification of pancreatic islets due to hypercalcemia does not occur. In support of this, a retrospective study of pancreatic tissue from 52 hypercalcemic patients with parathyroid adenoma and 34 patients with multiple myeloma, who frequently have hypercalcemia, did not reveal islet calcification. The islet calcification is ascribed to primary islet cell degeneration and necrosis, with hypercalcemia playing an augmenting but crucial role. It is considered that the combination of islet degeneration and calcification resulted in the diabetic state. DIABETES 27:620-24, June, 1978.
In diabetes mellitus, certain pathologic lesions develop in pancreatic islets. 1 " 5 These include hydropic change due to glycogert infiltration, reduction and degranulation of B-cells, lymphocytic infiltration (von Meyenburg's insulitis), fibrosis, amyloid infiltration, B-cell hemosiderin deposits in hemochromatosis, and islet hyperplasia with eosinophilic infiltration in
From the Departments of Pathology, University of Pittsburgh, School of Medicine and the Veterans Administration Hospital, Pittsburgh, Pennsylvania. *Dr. Cotelingam was a resident in pathology; he is presently staff pathologist at the Naval Regional Medical Center in Orlando, Florida. Address for reprints: H. Richard Hellstrom, M.D., Laboratory Service, Veterans Administration Hospital, University Drive C, Pittsburgh, Pennsylvania 15240. Accepted for publication December 20, 1977. 620
neonates born to diabetic mothers. A correlation, frequently exists between the clinical form of diabetes and the severity, extent, and type of morphologic lesion. However, on occasion no lesion may be found. To our knowledge, the association of calcification in islets with hypercalcemia and diabetes has not been previously described; hence this brief report. CASE REPORT, AUTOPSY FINDINGS, AND CONTROL STUDY A 58-year-old man presented to the Oakland Veterans Hospital in November 1972 with an eight month history of low backache, anemia, and fatigue. On the basis of clinical, laboratory, and radiologic data, a diagnosis of multiple myeloma was made. Before the onset of these symptoms, the patient was in good health and on no medication. There was no family history of malignancy or diabetes. Laboratory data included a hemoglobin of 9 0 gm. per cent and hematocrit of 27 per cent. The total WBC count was 4,878/c.mm. with a normal differential, and the platelet count was 143,000/c.mm. The peripheral blood film revealed hypochromic red cells with considerable rouleaux formation. The bone marrow was markedly infiltrated by plasma cells including immature nucleolated forms. Total proteins were 14.3 gm. per cent, of which the globulin fraction comprised 11.8 gm. per cent. On serum immunoelectrophoresis, homogenous IgG-lambda protein was detected. However, immunoelectrophoresis of the urine revealed no Bence Jones protein. At this first admission the serum calcium, phosphorus, blood sugar, and alkaline phosphatase were normal and no glycosuria was present. X-ray examination revealed lytic lesions in the skull, pelvis, and vertebrae, with a fracture of the second lumbar vertebra. A therapeutic regimen with Alkeran, procarbazine, prednisone, and radiation therapy to the spine were started. Five months later, the patient was readmitted for follow-up and complained of polyuria and polydipsia. At this time the fasting blood sugar was 230 mg./lOO ml. and glycosuria was present. A subsequent glucose tolerance test revealed a blood sugar of 246 mg./lOO ml. at three hours. The serum calcium was 11.6 mg./ 100 ml. and phosphorus 2.4 mg./lOO ml. Alkaline phosphatase at DIABETES, VOL. 27, NO. 6
JAMES D. COTELINGAM, M.D., A N D H. RICHARD HELLSTROM, M.D.
this and subsequent admissions was normal. In addition to the treatment for multiple myeloma, the diabetes was controlled with Orinase (tolbutamide). Later, when the dose of prednisone was increased from 10 to 80 mg. per day, he required additional insulin. A month after this second admission he was readmitted for treatment of chronic active hepatitis and received additional treatment with azathioprine. During several subsequent admissions the diabetes remained controlled and plasma cells in the bone marrow decreased. However, the serum calcium remained intermittently elevated. His final admission was in March 1976, 40 months after the initial diagnosis of multiple myeloma. During his final admission the myeloma was resistant to therapy and total plasma protein concentration was elevated at 11.7 gm. per cent, with a globulin fraction of 6.42 gm. per cent. Serum calcium varied between 14 and 15.2 mg./lOO ml. but intermittently responded to saline diuretics. Serum phosphorus varied between 3.3 and 5.8 mg./lOO ml. The diabetes was controlled, but he remained anemic. His platelet count dropped to 72,000/c.mm. and he developed guaiac-positive stools. Repeated immunoelectrophoretic testing for Bence Jones protein was negative.-Terminally, he developed a coagulase-positive staphylococcic septicemia and spiked a fever of 100° F. He died on the 13th hospital day. At autopsy, extensive and diffuse multiple myeloma with osteoporosis was present in numerous samples of bone.
The pancreas weighed 120 gm. and showed no gross pathologic change. Microscopically, extensive and selective calcification of islets was present in numerous samples of tissue (figures 1 and 2). A count of 355 islets revealed calcification in 315 (88.7 per cent), and, in 90 per cent of these calcified islets, more than three quarters of the islet parenchyma were calcified. In noncalcified islets and in noncalcified areas of involved islets, the Bcell:non-B-cell ratio, evaluated with Gomori's aldehyde-fuchsin stain, was about 3:1. Examination of decalcified tissue revealed extensive degeneration and necrosis of calcified islets. A search for amyloid using Congo red with polarized light and Thioflavin-T preparations was negative. Inflammatory reaction, fibrosis, and hemosiderin were absent also. The size of islets was normal and the presence of calcium was confirmed by the von Kossa stain and a Faxitron x-ray preparation of wet tissue (figure 3). The exocrine and interstitial tissues were not calcified, although intraparenchymal arteries were focally involved. Metastatic calcification was seen in alveoli, bronchi from both lungs, focally in renal tubules, and in the myocardium. The kidneys revealed no amyloid deposits or changes associated with multiple myeloma. Parathyroid glands were normal, and no calcification was present in other endocrine organs. Micronodular cirrhosis was present with congestive splenomegaly. Petechial hemorrhages and focal necrosis were noted in the duodenum and jejunum. Post mortem, blood cultures grew coagulase-positive
FIG. 1. Typical low power microscopic field of pancreas with numerous calcified islets. Magnification: 3 5 0 X .
JUNE, 1978
621
HYPERCALCEMIA A N D DIABETES MELLITUS
FIG. 2. Higher magnification (160x) of a severely calcified islet.
staphylococci and enterobacter aerogenes. The immediate cause of death was septicemia in this patient with multiple myeloma diagnosed 40 months previously. As a control study of Langerhans' islets, a 20-year survey (1954-1974) of the autopsy files from Presbyterian-University Hospital was carried out. This included 34 patients with multiple myeloma and 52 hypercalcemic patients with parathyroid adenoma. No example of islet calcification was found in this material. DISCUSSION
The occurrence of islet calcification and its association with diabetes mellitus and hypercalcemia appears unique, as similar examples were not found in the literature, including experimental models.6-7 However, calcification of hyaline material in islets, now considered to be amyloid, 3 has been previously described.8" 11 In Fisher's case,8 the calcification was grossly visible and associated with islet hyperplasia, and it developed in an 18-year-old male with fatal diabetic coma. The sequence of clinical events provides some aid in 622
relating the myeloma, hypercalcemia, diabetes, and islet calcification. At the time of the first admission for myeloma, serum calcium and fasting glucose were normal. Five months later, hypercalcemia and glycosuria were detected, and a diagnosis of diabetes mellitus was made for the first time. At autopsy, 40 months later, extensive islet cell calcification with degeneration and necrosis was observed without evidence of amyloid infiltration or siderosis. This circumstantial evidence suggests that the diabetic state was related to the hypercalcemia and islet calcification and degeneration. Also, the prednisone treatment 12 probably enhanced the severity of the diabetes. In spite of the obvious relationship of hypercalcemia to calcification, the pathogenesis of the islet calcification is not clear. Although there was metastatic calcification in the lungs, kidneys, and heart, it does not seem likely that the extensive islet cell calcification can be attributed directly to the hypercalcemia. Pancreatic islets are not among the tissues affected by metastatic calcification in hypercalcemia,13 DIABETES, VOL. 27, NO. 6
JAMES D. COTELINGAM, M . D . , A N D H. RICHARD HELLSTROM, M.D.
FIG. 3.
Faxitron x-ray preparation of wet pancreatic tissue with extensive speckled calcification. Magnification: 6 x .
and, in our review of 52 autopsies of hypercalcemic subjects, islet calcification was absent. Also, myeloma, commonly complicated by hypercalcemia, does not result in islet calcification, and no calcification was evident in islets in our retrospective review of 34 autopsy cases of myeloma. We consider the key to the diabetes and the calcification to be the extensive degeneration and necrosis of islets seen in decalcified sections. Dystrpphic calcification after necrosis is common, 13 and, in this case, it is likely that the primary event was islet cell injury. The tendency for necrotic tissue to calcify was augmented, probably critically, by the hypercalcemia. It might be argued that the necrosis evident at autopsy was entirely secondary to the extensive calcification rather than was its cause. However, as islet cell calcification due solely to hypercalcemia seems unlikely, the necrosis is accepted as primary. The cause for primary islet cell degeneration is unknown. By exclusion the most reasonable explanation appears to be a hypersensitive reaction to one of the drugs used to treat the myeloma. Direct islet toxicity JUNE, 1978
is not likely, as none of the antineoplastic drugs used are known to have a diabetogenic effect or structural similarity to streptozotocin, alloxan, or other agents that selectively destroy B-cells. 14 Since treatment with azothioprine for chronic active hepatitis was given after the onset of the diabetes, its role in the pathogenesis of the calcification is not considered. The possibility that islet cell injury followed focal ischemia from precipitated myeloma proteins was considered, but there is no evidence for this, as the capillary microvasculature of islets in decalcified blocks was unremarkable. Radiation injury does not appear to be responsible for islet injury, as both endocrine and exocrine tissues are resistant to the usual therapeutic dose. Moreover, no pancreatic fibrosis or vascular sclerosis was present, which usually is the case with higher doses of radiation. 15 It is of interest that, despite the clarity and resolution of calcium deposits in the Faxitron preparation, calcification could not be visualized on routine abdominal films. We believe this extensive and selective islet cell 623
HYPERCALCEMIA AND DIABETES MELLITUS
calcification in this patient is a unique and striking phenomenon. Moreover, its association with hypercalcemia and diabetes is of considerable interest. ACKNOWLEDGMENTS Dr. Andrew Dekker and Dr. Arthur A. Like made valuable suggestions. Dr. Robert E. Lee made available the autopsy files of Presbyterian-University Hospital. Bill Hiller, Bud Jozwiak, and Saul Weiss rendered technical and photographic assistance. Mrs. Patricia Turkovich typed the manuscript. REFERENCES 'Lacy, P. E.: Pathology of the islets of Langerhans. In Pathology Annual. Vol. 1. Sommers, S. C., Ed. New York, AppletonCentury-Crofts, 1966, pp. 352-70. 2 Warren, S., LeCompte, P. M., and Legg, M. A.: Pathology of Diabetes Mellitus. Fourth edit. Chapter 3. Philadelphia, Lea & Febiger, 1966, pp. 53-88. 3 Lacy, P. E.: The islets of Langerhans. In Endocrine Pathology. Bloodworth, J. M. B., Jr., Ed. Baltimore, Williams and Wilkins, 1968, pp. 316-29. 4 Steiner, H.: Morphology of diabetes mellitus. In Clinical Endocrinology. Third edit. Chapter 13. Labhart, A., Ed. New York, Heidelberg, and Berlin, Springer-Verlag, 1974, pp. 76467. 5 Williams, R. H., and Porte, D., Jr.: The pancreas. Pathol-
624
ogy. In Textbook of Endocrinology. Fifth edit. Williams, R. H., Ed. Philadelphia, W. B. Saunders, 1974, pp. 566-67. 6 Klemm, G.: Chronische kalziphylaktische Pankreatitis. Z. Gesamte Inn. Med. Ihre Grenzgeb. 29:722-25, 1974. r Wexler, B. C : Arteriosclerosis of the pancreas and changes in the islets of Langerhans of repeatedly bred rats. Br. J. Exp. Pathol. 51:107-13, 1970. 8 Fischer, B.: Pankreas und Diabetes. Frankf. Z. Pathol. 77:218-75, 1915. 9 Mallory, F. B.: The Principles of Pathologic Histology. Part II. Philadelphia, W. B. Saunders, 1914, p. 521. 10 Gibbs, W. F., Jr., and Logan, V. W.: Diabetes mellitus. A study of 147 autopsies. Arch. Intern. Med. 43:376-83, 1929. n Escudero, P.: Tratado de la Diabetes, Buenos Aires, 1927. Quoted by Warren, S., LeCompte, P. M., and Legg, M. A. In The Pathology of Diabetes Mellitus. Fourth edit. Chapter 3. Philadelphia, Lea & Febiger, 1966, pp. 53-88. 12 West, K.: Epidemiology of diabetes. In Diabetes Mellitus: Diagnosis and Treatment. Vol. 3. Chapter 21. Fajans, S. S., and Sussman, K. E., Eds. New York, American Diabetes Association, 1971, pp. 121-26. 13 Scarpelli, D. G., and Chiga, M.: Cell injury and errors of metabolism. In Pathology. Seventh edit. Chapter 3. Anderson, W. A. D., and Kissane, J. M., Eds. St. Louis, C. V. Mosby, 1977, pp. 90-147. 14 Larner, J., and Haynes, R. C., Jr.: Insulin and oral hypoglycemic drugs; glucagon. In The Pharmacological Basis of Therapeutics. Fifth edit. Chapter 71. Goodman, L. S., and Gilman, A., Eds. New York, Macmillan, 1975, pp. 1507-33. 15 White, D. C : An Atlas of Radiation Histopathology. Chapter 8. Oak Ridge, U.S. Energy Research and Development Administration, 1975, pp. 161-70.
DIABETES, VOL. 2 7 , NO. 6
