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Failure of hypophysectomy in generalized lipodystrophy
990
Brief clinical and laboratory observations
Failure of hypopbysectomy in generalized lipodystrophy C. Charlton Mabry, M.D., and D o r o t h y R. Hollingsworth, M.D.,
Lexington, Ky.
G E N ~ R A L I Z ~ D lipodystrophy in a young girl progressed so t h a t h e r a p p e a r a n c e caused social isolation, t t y p o p h y s e c t o m y seemed to offer h o p e in arresting the progression of the disorder. T h r e e cases have been reported as helped by p i t u i t a r y irradiation, 1-8 a n d our own investigations i n d i c a t e d t h a t the pituitary plays a central role in the pathophysiology of the disorder. 4 T h e long-term results in our p a t i e n t i n d i c a t e t h a t o t h e r similar patients should not be subjected to hypophysectomy.
CASE REPORT This Caucasian child appeared normal at birth and during infancy. During the third year of life she experienced prolonged fever with generalized lymphadenopathy followed by an insidious onset of the various manifestations of generalized lipodystrophy. These included a total loss of subcutaneous and other body fat, skeletal and muscular overgrowth, massive hepatomegaly due to fat infiltration, genital enlargement, intense hyperpigmentation with acanthosis nigricans over much of her body, insulin-resistant hyperglycemia, hyperlipemia, and hyperinsulinism (Fig. 1, A). At age 13 years an attempt at hypophysectomy was made by the transsphenoid approach, but the procedure was terminated because of excessive bleeding from her overly dense cranial bones. Three months later the pituitary was approached transfrontally. MacroscopicalIy, the sella turcica
From the Departments of Pediatrics and Pathology, University of Kentucky. Presented in part at the forty-first annual meeting of the Society for Pediatric Research, Atlantic City, N. ]., April 28 to May 1, 1971. Reprint address: Department of Pediatrics, University o] Kentucky Medical Center, Lexington, Ky. 40506. -
The Journal of Pediatrics November 1972
and gland appeared normal. The pituitary was removed by suction and curettage. Microscopically, the adenohypophysis did not appear normal. The percentage of basophils was twice to three times the expected 11 per cent, and their granularity was excessive. Electron microscopy showed other abnormalities; these included parenchymal ceil cytoplasmic lipid droplets, tortuous membranous extensions of parenchymal cell walls, and occasional interstitial lymphocytes. 5 FolIowing hypophysectomy, the patient required replacement therapy consisting of vasopressin, cortisone, and thyroid extract. Within two weeks the patient's condition began changing. The abdomen became less protuberant, due to reduction in liver size. Formerly the liver edge was below the umbilicus, but after several weeks it was above the umbilicus. The patient's skin showed the greatest change. Before hypophysectomy, large areas were very thick and black with acanthosis nigricans. These areas began to peel and, in general, her skin became lighter in color (Fig. 1, B). The regression in the skin abnormalities was especially dramatic in the perineum, and the clitoris diminished in size (from 4 cm. to 2 cm. in length). However, no subcutaneous fat returned. Prior to surgery, the patient's serum was always lipemic with the neutral fat portion in great excess. Soon after surgery, her serum rarely was lipemic. The moderately abnormal liver functions did not improve, but the hyperglycemia and insulin resistance seemed less intense. A dose of insulin (0.5 units per kilogram) that formerly had caused little effect induced sufficient hypoglycemia (blood sugar of 118 mg. per deciliter decreased to 60 mg. per deciliter at 30 minutes) to warrant interruption of the test by the administration of glucose. Nine months postoperatively, no evidence of hypophyseal function was discernible, as assessed by withdrawal of replacement hormone therapy and measurement of circulating pituitary and target gland hormones or their urinary derivatives. Twelve months postoperatively it was evident that her clinical condition had worsened. The improvements observed in the early months following hypophysectomy had waned, and in most ways her condition appeared to be comparable to that prior to hypophysectomy. Intense hyperpigmentation and acanthosis nlgricans had returned, the liver edge was palpable below the umbilicus, the clitoris was its former length and size, no subcutaneous fat had appeared, and
Volume 81 Number 5
Brief clinical and laboratory observations
991
Fig. 1. A, Patient at age 13 years prior to hypophysectomy. B, Patient at 3 months after hypophysectomy. Note the peeling away of large segments of acanthosis nigricans and the general lightening of skin color. Later, the hyperpigmentation with intense acanthosis nigricans returned. abnormalities in the plasma chemical values were as intense as before hypophysect0my. Fifteen months postoperatively she lapsed into coma. Liver functions had deteriorated, as shown by greatly elevated hepatic serum enzymes and blood ammonia. No evidence of an acute cerebral accident or disturbance could be discerned by skull x-rays, cerebral angiography, or cerebral spinal fluid examination. She was sustained on a respirator for several days. As the liver function spontaneously improved, she returned to a conscious state. At this time she experienced severe abdominal discomfort; the spleen had rapidly enlarged, extending to the iliac crest. The ensuing hypersplenism resulted in persistent anemia and thrombocytopenia. A low-protein diet was pre-
scribed to prevent ammonia intoxication; now she requires no special dietary precautions. She is unusually sensitive to chlorpromazine, which causes deep somnolence; this probably is a reflection of her liver dysfunction. Now, 19 months after hypophysectomy, the disorder is as intense as ever and she is more pigmented than ever before. Fortunately, the hypersplenism has subsided, and the disordered liver functions seem stable. CONCLUSIONS T h e progress of the patient's disease seemed to have been reversed for severa!i' months following hypophysectomy. However, these early good effects have waned, a n d the
99 2
Brie[ clinical and laboratory observations
abnormalities are as intense as before surgery. It seems that the underlying pathophysiologic process adjusted to the patient's hypophysectomy. Thus we cannot advocate hypophysectomy as proper treatment of generaIized lipodystrophy. T h e abnormalities of the pituitary, as demonstrated by light and electron microscopy, are not understood at this time, but they indicate that the pituitary is affected.
REFERENCES i. Berardinelli, W.: An undiagnosed endocrinometabolic syndrome: Report of 2 cases, J. Clin. Endoerlnol. Metab. 14: 193, 1954.
Cytocentrifugation in the management of central nervous system leukemia
The Journal o/ Pediatrics November 1972
2. Witzgall, H.: Hyperlipaemische llpoatrophie, Aerztl. Woehenschr. 12: 1093, 1957. 3. Reed, W. B., Ragsdale, W., Jr., Curtis, A. C., and Richards, H. J.: Aeanthosis nigricans in association with various genodermatoses; with emphasis on lipodystrophlc diabetes and Prader-WiIli syndrome, Acta Derm. VenereoI. (Stockh.) 48: 465, 1968. 4. Mabry, C. C.,. and Hollingsworth, D. R.: Generalized lipodystrophy (lipoatrophic diabetes); evidence for abnormal pituitary function, Pediatr. Res. 5: 397, 1971. (Abst.) 5. Bergland, R. M., and Torack, R. M.: An ultrastructural study of follicular cells in the human anterior pituitary, Am. J. Pathol. 57: 273, 1969.
is a technique that concentrates and adheres cells in ccrebrospinal fluid to glass slides without distortion. T h e purpose of this paper is to present preliminary data and to point to areas of diagnostic dilemma where Cytocentrifugation m a y be most useful.
METHODS Diane M. Komp, M.D., with the technical assistance of Betty J. Cox, M.T. (A.S.C.P.), Charlottesville, Va.
A s s u R V I V A L for children with acute leukemia becomes longer, central nervous system involvement has become a more common problem? Concentration of cerebrospinal fluid by ordinary centrifugation does not, in m a n y cases, allow for clear distinction between blasts and other mononuclear cells. Cytocentrifugation (Cyto-Centrifuge, Shandon Scientific Co., Inc., Se~iekley, Pa.)
From the Department of Pediatrics, University o[ Virginia School o[ Medicine. Supported in part by Public Health Service Grant No. 2-RIO-CA08223-0682. Reprint address: Department o[ Pediatrics, University o] Virginia School o[ Medicine, Charlottesville, Va. 22901.
Cerebrospinal fluid is processed within one hour of collection. A 1.5 ml. aliquot of cerebrospinal fluid is placed in the sample chasnber. For very cloudy samples, smaller amounts of diluted specimens are used. T h e cells are centrifuged along a ~ e inch tube directly onto a glass slide, while the supernatant fluid is withdrawn radially at right angles to the direction of the centrifugal force by a fluid absorbing stripy T h e fluid is spun at 1,500 r.p.m, for 10 minutes. T h e slide is stained with Wright's stain with the timing gauged by the expected cellularity.
CASE REPORTS Case 1. Patient R. S., a patient with acute tymphoblastie leukemia, has had seven episodes of central nervous system leukemia during five years. The most recent episode occurred 12 months ago. After initial clearing of cerebrospinal fluid and clinical findings with intrathecal treatments of methotrexate, hydrocortisone, and cytosine arabinoside, central nervous system remission was maintained with intrathecal
Brief clinical and laboratory observations
Failure of hypopbysectomy in generalized lipodystrophy C. Charlton Mabry, M.D., and D o r o t h y R. Hollingsworth, M.D.,
Lexington, Ky.
G E N ~ R A L I Z ~ D lipodystrophy in a young girl progressed so t h a t h e r a p p e a r a n c e caused social isolation, t t y p o p h y s e c t o m y seemed to offer h o p e in arresting the progression of the disorder. T h r e e cases have been reported as helped by p i t u i t a r y irradiation, 1-8 a n d our own investigations i n d i c a t e d t h a t the pituitary plays a central role in the pathophysiology of the disorder. 4 T h e long-term results in our p a t i e n t i n d i c a t e t h a t o t h e r similar patients should not be subjected to hypophysectomy.
CASE REPORT This Caucasian child appeared normal at birth and during infancy. During the third year of life she experienced prolonged fever with generalized lymphadenopathy followed by an insidious onset of the various manifestations of generalized lipodystrophy. These included a total loss of subcutaneous and other body fat, skeletal and muscular overgrowth, massive hepatomegaly due to fat infiltration, genital enlargement, intense hyperpigmentation with acanthosis nigricans over much of her body, insulin-resistant hyperglycemia, hyperlipemia, and hyperinsulinism (Fig. 1, A). At age 13 years an attempt at hypophysectomy was made by the transsphenoid approach, but the procedure was terminated because of excessive bleeding from her overly dense cranial bones. Three months later the pituitary was approached transfrontally. MacroscopicalIy, the sella turcica
From the Departments of Pediatrics and Pathology, University of Kentucky. Presented in part at the forty-first annual meeting of the Society for Pediatric Research, Atlantic City, N. ]., April 28 to May 1, 1971. Reprint address: Department of Pediatrics, University o] Kentucky Medical Center, Lexington, Ky. 40506. -
The Journal of Pediatrics November 1972
and gland appeared normal. The pituitary was removed by suction and curettage. Microscopically, the adenohypophysis did not appear normal. The percentage of basophils was twice to three times the expected 11 per cent, and their granularity was excessive. Electron microscopy showed other abnormalities; these included parenchymal ceil cytoplasmic lipid droplets, tortuous membranous extensions of parenchymal cell walls, and occasional interstitial lymphocytes. 5 FolIowing hypophysectomy, the patient required replacement therapy consisting of vasopressin, cortisone, and thyroid extract. Within two weeks the patient's condition began changing. The abdomen became less protuberant, due to reduction in liver size. Formerly the liver edge was below the umbilicus, but after several weeks it was above the umbilicus. The patient's skin showed the greatest change. Before hypophysectomy, large areas were very thick and black with acanthosis nigricans. These areas began to peel and, in general, her skin became lighter in color (Fig. 1, B). The regression in the skin abnormalities was especially dramatic in the perineum, and the clitoris diminished in size (from 4 cm. to 2 cm. in length). However, no subcutaneous fat returned. Prior to surgery, the patient's serum was always lipemic with the neutral fat portion in great excess. Soon after surgery, her serum rarely was lipemic. The moderately abnormal liver functions did not improve, but the hyperglycemia and insulin resistance seemed less intense. A dose of insulin (0.5 units per kilogram) that formerly had caused little effect induced sufficient hypoglycemia (blood sugar of 118 mg. per deciliter decreased to 60 mg. per deciliter at 30 minutes) to warrant interruption of the test by the administration of glucose. Nine months postoperatively, no evidence of hypophyseal function was discernible, as assessed by withdrawal of replacement hormone therapy and measurement of circulating pituitary and target gland hormones or their urinary derivatives. Twelve months postoperatively it was evident that her clinical condition had worsened. The improvements observed in the early months following hypophysectomy had waned, and in most ways her condition appeared to be comparable to that prior to hypophysectomy. Intense hyperpigmentation and acanthosis nlgricans had returned, the liver edge was palpable below the umbilicus, the clitoris was its former length and size, no subcutaneous fat had appeared, and
Volume 81 Number 5
Brief clinical and laboratory observations
991
Fig. 1. A, Patient at age 13 years prior to hypophysectomy. B, Patient at 3 months after hypophysectomy. Note the peeling away of large segments of acanthosis nigricans and the general lightening of skin color. Later, the hyperpigmentation with intense acanthosis nigricans returned. abnormalities in the plasma chemical values were as intense as before hypophysect0my. Fifteen months postoperatively she lapsed into coma. Liver functions had deteriorated, as shown by greatly elevated hepatic serum enzymes and blood ammonia. No evidence of an acute cerebral accident or disturbance could be discerned by skull x-rays, cerebral angiography, or cerebral spinal fluid examination. She was sustained on a respirator for several days. As the liver function spontaneously improved, she returned to a conscious state. At this time she experienced severe abdominal discomfort; the spleen had rapidly enlarged, extending to the iliac crest. The ensuing hypersplenism resulted in persistent anemia and thrombocytopenia. A low-protein diet was pre-
scribed to prevent ammonia intoxication; now she requires no special dietary precautions. She is unusually sensitive to chlorpromazine, which causes deep somnolence; this probably is a reflection of her liver dysfunction. Now, 19 months after hypophysectomy, the disorder is as intense as ever and she is more pigmented than ever before. Fortunately, the hypersplenism has subsided, and the disordered liver functions seem stable. CONCLUSIONS T h e progress of the patient's disease seemed to have been reversed for severa!i' months following hypophysectomy. However, these early good effects have waned, a n d the
99 2
Brie[ clinical and laboratory observations
abnormalities are as intense as before surgery. It seems that the underlying pathophysiologic process adjusted to the patient's hypophysectomy. Thus we cannot advocate hypophysectomy as proper treatment of generaIized lipodystrophy. T h e abnormalities of the pituitary, as demonstrated by light and electron microscopy, are not understood at this time, but they indicate that the pituitary is affected.
REFERENCES i. Berardinelli, W.: An undiagnosed endocrinometabolic syndrome: Report of 2 cases, J. Clin. Endoerlnol. Metab. 14: 193, 1954.
Cytocentrifugation in the management of central nervous system leukemia
The Journal o/ Pediatrics November 1972
2. Witzgall, H.: Hyperlipaemische llpoatrophie, Aerztl. Woehenschr. 12: 1093, 1957. 3. Reed, W. B., Ragsdale, W., Jr., Curtis, A. C., and Richards, H. J.: Aeanthosis nigricans in association with various genodermatoses; with emphasis on lipodystrophlc diabetes and Prader-WiIli syndrome, Acta Derm. VenereoI. (Stockh.) 48: 465, 1968. 4. Mabry, C. C.,. and Hollingsworth, D. R.: Generalized lipodystrophy (lipoatrophic diabetes); evidence for abnormal pituitary function, Pediatr. Res. 5: 397, 1971. (Abst.) 5. Bergland, R. M., and Torack, R. M.: An ultrastructural study of follicular cells in the human anterior pituitary, Am. J. Pathol. 57: 273, 1969.
is a technique that concentrates and adheres cells in ccrebrospinal fluid to glass slides without distortion. T h e purpose of this paper is to present preliminary data and to point to areas of diagnostic dilemma where Cytocentrifugation m a y be most useful.
METHODS Diane M. Komp, M.D., with the technical assistance of Betty J. Cox, M.T. (A.S.C.P.), Charlottesville, Va.
A s s u R V I V A L for children with acute leukemia becomes longer, central nervous system involvement has become a more common problem? Concentration of cerebrospinal fluid by ordinary centrifugation does not, in m a n y cases, allow for clear distinction between blasts and other mononuclear cells. Cytocentrifugation (Cyto-Centrifuge, Shandon Scientific Co., Inc., Se~iekley, Pa.)
From the Department of Pediatrics, University o[ Virginia School o[ Medicine. Supported in part by Public Health Service Grant No. 2-RIO-CA08223-0682. Reprint address: Department o[ Pediatrics, University o] Virginia School o[ Medicine, Charlottesville, Va. 22901.
Cerebrospinal fluid is processed within one hour of collection. A 1.5 ml. aliquot of cerebrospinal fluid is placed in the sample chasnber. For very cloudy samples, smaller amounts of diluted specimens are used. T h e cells are centrifuged along a ~ e inch tube directly onto a glass slide, while the supernatant fluid is withdrawn radially at right angles to the direction of the centrifugal force by a fluid absorbing stripy T h e fluid is spun at 1,500 r.p.m, for 10 minutes. T h e slide is stained with Wright's stain with the timing gauged by the expected cellularity.
CASE REPORTS Case 1. Patient R. S., a patient with acute tymphoblastie leukemia, has had seven episodes of central nervous system leukemia during five years. The most recent episode occurred 12 months ago. After initial clearing of cerebrospinal fluid and clinical findings with intrathecal treatments of methotrexate, hydrocortisone, and cytosine arabinoside, central nervous system remission was maintained with intrathecal