Spontaneous Hypoglycemia Associated with an Adrenocortical Carcinoma
DONALD A. SCHOLZ, EDWARD S. HORTON, HAROLD E. LEBOVITZ, AND DEWARD O. FERRIS
Mayo Clinic and Mayo Foundation, Rochester, Minnesota: Section of Medicine (Dr. Scholz) and of Surgery (Dr. Ferris); Department of Medicine and Division of Endocrinology, Duke University Medical Center, Durham, North Carolina (Drs. Horton and Lebovitz)
ABSTRACT. A 16-yr-old girl with spontaneous hypoglycemia was found to have a large, left adrenocortical carcinoma. There were no other clinical manifestations to indicate the presence of a functioning adrenal tumor. Studies of plasma insulin failed to demonstrate an elevation of either immunoreactive insulin or insulinlike activity when the patient was hypoglycemic. The level of growth hormone in the plasma dur- ing fasting was normal despite severe hypo- glycemia and rose only slightly as the concentra-
tion of blood glucose decreased rapidly after a load of orally administered glucose. After re- moval of the tumor, there was amelioration of the patient’s hypoglycemia for 7 months, after which the recurrence of symptoms was associated with the finding of pulmonary metastases. Cur- rent concepts regarding the genesis of spontane- ous hypoglycemia in patients with nonislet-cell tumors are reviewed. (J Clin Endocr 27: 991, 1967)
S INCE the initial report of hypogly- cemia associated with an adrenocorti- cal carcinoma by Anderson in 1930 (1), 13 additional cases have been described in the literature (2-12). Although the mecha- nism by which these tumors produce hypo- glycemia is not known, studies of insulin- like activity in plasma or in tumor extracts have been carried out in only three cases (10-12). In all three the plasma insulin- like activity during fasting was found to be normal, as measured by either rat dia- phragm or adipose tissue assays. The insulinlike activity of an extract of tumor tissue was measured in two of the cases and was found to be normal in one (11) and “significant” in the other (12).
Received November 28, 1966; accepted March 13, 1967.
This investigation was supported in part by grants from the American Cancer Society (P 166 F) and the NIH, USPHS (T1 AM 5074).
Dr. Horton is recipient of the National Institutes of Health Fellowship Award (1 F3 AM-32, 326-01); Dr. Lebovitz is recipient of the Research Career Development Award (K3 AM 17, 954) from the NIH, USPHS.
In view of the rarity of this syndrome the following case is presented. Studies of plasma insulin, insulinlike activity and growth hormone were performed in an effort to further elucidate the mechanism of the hypoglycemia.
Report of Case
In August 1965, a 16-yr-old white girl was seen at Duke Hospital for treatment of obesity which had been progressive during the previous 2-3 yr. The patient had been in good health un- til 2 yr prior to admission when she first noted frequent episodes of drowsiness during the day- time and occasional difficulty waking in the morning. The latter was sometimes associated with mental confusion and transient diplopia, both of which cleared rapidly after food was in- gested. The patient’s mother also noted that the girl was often extremely irritable and uncooper- ative before eating breakfast, but was pleasant at other times.
Shortly after the onset of these symptoms, the patient was admitted to a hospital in her home community for evaluation. Results of studies, including blood sugar determinations, were allegedly normal. The patient then at- tempted various weight-reduction programs without success. She was unable to tolerate
dietary restriction without exacerbation of her symptoms and usually ate continuously throughout the day. During the 6 months prior to her evaluation in August 1965, she had gained 15 lb.
The review of the patient’s endocrine system revealed nothing remarkable except for an in- creased menstrual frequency during the past 2 yr; menarche had occurred when the patient was 11 yr old. There was no history of voice change, clitoral enlargement, or recent increase in body hair growth, although the patient had noted a moderate growth of dark hair on the arms, legs and sideburn areas since puberty. There was no history of easy bruising, hyper- tension, or abdominal striae. The family history revealed that 2 maternal aunts had diabetes mellitus.
When first examined at Duke Hospital in August 1965, the patient weighed 156 lb. There were no unusual findings on physical examina- tion other than moderate, generalized obesity. The value for blood sugar (Technicon auto- analyzer) (13) was 84 mg/100 ml during fasting and 84 mg 2 hr after a 100-g oral glucose load. Serum sodium value was 149 mEq/liter, potas- sium 4.5 mEq/liter, chloride 106 mEq/liter, carbon dioxide 32 mmoles/liter and blood urea nitrogen 6 mg/100 ml.
To reduce her weight, the patient was given a Kempner rice diet. Shortly after commencing the diet, the patient became drowsy and irri- table, and on the mornings of the fifth and sev- enth days her family had difficulty arousing her from sleep. On both occasions, she was given orange juice, after which she became more re- sponsive and cooperative. The diet was con- tinued in a modified form, with some relief of symptoms. However, on the morning of the fourteenth day the patient again could not be easily aroused from sleep and was admitted to the hospital. Examination revealed her to be disoriented, with slurred speech, excessive per- spiration and horizontal nystagmus. The pa- tient’s blood sugar was less than 50 mg/100 ml, and her symptoms cleared promptly after glu- cose administration.
Blood pressure was 120 mm Hg systolic and 80 mm diastolic, pulse rate was 76 beats/min, and the respiration rate was 16/min. There was moderate generalized obesity, with normal skin texture, pigmentation, and female hair distri- bution. No stigmata of Cushing’s syndrome were present. The thyroid was not enlarged. Examinations of the heart, lungs and abdomen revealed no abnormality except for a grade II /VI systolic ejection murmur along the left sternal border. Pelvic examination revealed no abnormality and no evidence of clitoral hyper-
trophy. Subsequent laboratory studies revealed a hemoglobin value of 12.3 g/100 ml, leukocyte count of 6400 cells/mm3, with a normal differ- ential, and normal urine. Serum sodium was 139 mEq/liter, potassium 4.0 mEq/liter, chloride 102 mEq/liter, carbon dioxide content 33 mmoles/liter, calcium 9.5 mg/100 ml, phos- phorus 3.5 mg/100 ml, urea nitrogen 5.0 mg /100 ml, uric acid 3.1 mg/100 ml, albumin 3.6 g/100 ml and globulin 2.6 g/100 ml. Roentgeno- grams of the skull, chest and abdomen showed only a blurring of the psoas shadows. No intra- abdominal masses were seen. Results of an electroencephalogram were normal.
Values for urinary 17-hydroxysteroids were 4.4 mg in 24 hr (normal 2-12) and for 17- ketosteroids 30.6 mg in 24 hr (normal 5-15).
During the first 2 hospital days, the patient was maintained on frequent carbohydrate feed- ings and remained asymptomatic. On the third day, blood glucose, plasma insulin and plasma growth hormone were measured after an 8-hr fast and for 7} hr after a 100-g load of orally administered glucose (Table 1). The study was terminated with glucose administration when the patient became disoriented and com- bative.
During this test, the plasma insulin concen- tration during fasting was less than 2 uU/ml. Insulin levels rose only moderately after oral glucose loading and decreased to levels that were not measurable (less than 2 uU/ml) when the patient became hypoglycemic. Since plasma insulin levels were not measurable whenever the patient was hypoglycemic, a noninsulinogenic cause of the hypoglycemia was evident. A tentative diagnosis of a non- pancreatic tumor with hypoglycemia was made. An elevated level for urinary 17-ketosteroids was suggestive of the presence of an adreno- cortical carcinoma.
At the request of the patient’s family, no further studies were performed and she was transferred to the Mayo Clinic, where results of examination on admission were unchanged ex- cept for palpation of a mass deep in the left upper quadrant of the abdomen. An excretory urogram revealed a large mass in the left upper quadrant, pressing the left kidney downward and distorting its upper pole. Nephrotomo- grams confirmed these findings.
The initial fasting blood glucose was 61 mg /100 ml (normal 65-90). The 24-hr urinary ex- cretion of 17-ketogenic steroids was 12.2 mg and 17-ketosteroids 7.3 mg. The value for plasma cortisol (14) was 16.6 ug/100 ml at 8 AM and 5.7 ug/100 ml at 4 PM. Within 12 hr after the fast was started, the value for blood sugar decreased to 46 mg/100 ml and the pa-
tient became belligerent, argumentative and uncooperative. At that time, the pulse rate was regular and no sweating was evident. Glucose was administered intravenously, and the pa- tient’s status was dramatically improved.
Studies of tryptophan metabolites in blood and urine specimens obtained when the patient was hypoglycemic revealed values within the normal range. Further proposed studies in- cluding blood-glucose response to epinephrine and glucagon, leucine and tolbutamide toler- ance tests, as well as stimulation and sup- pressive tests of adrenocortical function, were not allowed by the patient or her family.
Surgical exploration on Sept. 3, 1965, re- vealed a large, vascular, left adrenocortical carcinoma. The tumor was intimately attached to the mesenteric vessels and aorta, making surgical removal difficult. No obvious metas- tases were detected. The pathologist reported a “semicapsulated, necrotic, solid, grade II, adrenal cortical carcinoma.” The tumor mea- sured 20 by 15 by 15 cm and the combined weight of the tumor and left kidney was 1800 g. Unfortunately, an extract of tumor tissue was not obtained for measurement of insulin- like activity, nor was liver tissue obtained for glycogen content and enzymatic studies. On the day prior to dismissal, the value for the 24- hr urinary excretion of 17-ketogenic steroids was 7.9 mg and for 17-ketosteroids 2.8 mg. Follow-up examination late in December 1965 revealed no clinical evidence of metastatic spread of the tumor. The patient denied any recurrent symptoms of hypoglycemia, and the blood sugar after overnight fasting (14 hr) was 75 mg/100 ml. Routine blood studies, includ- ing determinations of alkaline phosphatase and the sedimentation rate, were normal. Early in May 1966, however, the patient was re- studied at a hospital in her home community because of the recurrence of some of her symp- toms. At that time, a chest roentgenogram re- vealed pulmonary metastases, and she was given chemotherapy (Mithramycin) under the supervision of her physician. The patent died in Oct. 1965. Post-mortem examination revealed extensive metastases involving the retroperi- toneal and mediastinal lymph nodes as well as the lungs and liver.
Special Studies
Prior to surgery, only limited studies of blood glucose and plasma insulin, insulinlike activity and growth hormone were performed. The data from studies of blood glucose, plasma in- sulin and growth hormone are outlined in Table 1. Heparinized blood was obtained after an 8-
| Time,* min | Blood glucose, mg/100 ml | Plasma insulin, „U/ml | Plasma growth hormone, mug/ml |
|---|---|---|---|
| 0 | 21 | <2 | 1.9 |
| 30 | 122 | 68 | <1.0 |
| 60 | 141 | 87 | <1.0 |
| 90 | 118 | 45 | <1.0 |
| 120 | 107 | 34 | <1.0 |
| 180 | 27 | <2 | 4.2 |
| 240 | 27 | <2 | 2.4 |
| 300 | 30 | <2 | <1.0 |
| 435 | 24 | <2 | 1.5 |
| Overnight | 36 | <2 | 1.4 |
| fast (8 hr) |
* After 100-g load of orally administered glucose.
hr fast and at frequent intervals after a 100-g load of orally administered glucose.
Blood glucose was measured by a glucose oxidase method (13). Fasting levels were 21 and 36 mg/100 ml. After the oral administra- tion of glucose, a peak blood concentration of 141 mg/100 ml was reached at 1 hr; this was followed by a rapid decrease to 27 mg at 3 hr. The concentration of blood glucose remained low until the test was terminated shortly after 7 hr because of severe hypoglycemic symptoms.
Plasma insulin was measured by a radioim- munoassay method with the use of purified pork insulin labeled with iodine-125 as tracer and a double antibody precipitation technique for separation of bound and free insulin (15). With this system, concentrations of plasma in- sulin as low as 2 U/ml can be measured ac- curately.
At all times when the concentration of blood glucose was below normal, the concentration of plasma insulin was less than 2 uU/ml. After the oral glucose load, there was an appropriate rise in plasma insulin that coincided with the rise in blood glucose. Thus, the hypoglycemia could not be attributed to an abnormally ele- vated concentration of circulating insulin or to an increased secretion of insulin after glucose stimulation.
Since this assay measures only immunolog- ically reactive insulin, the possibility that another material with insulinlike activity was producing the hypoglycemia was not ruled out. A modification of the method of Renold and co-workers (16) utilizing the oxidation of the 14C in glucose-1-14C to 14CO2 by rat adipose tis- sue was used to measure plasma insulinlike activity. Three plasma samples drawn when the blood glucose was 24-36 mg/100 ml had a
mean insulinlike activity that was equivalent to 79 uU/ml (range 47-110) of pork insulin standard. This is well below the mean normal fasting value of 345 uU/ml (17). Therefore, there was no evidence for either increased cir- culating insulin or an insulinlike material at a time when the patient was severely hypogly- cemic.
Plasma growth hormone was measured by a radioimmunoassay similar to that used for insulin (18). Purified human growth hormone (Wilhelmi) was used for preparation of the tracer and standards, and the assay system was constructed to measure concentrations of plasma growth hormone as low as 1.0 mug/ml. On 2 occasions when the patient was fasting and frankly hypoglycemic, the concentration of plasma growth hormone was 1.9 and 1.4 mug /ml. After the oral glucose load, the concentra- tion of growth hormone was suppressed below 1 mug/ml during the first 2 hr, as expected. However, at 3 and 4 hr, when the blood sugar level decreased precipitously to hypoglycemic levels, there was only a slight increase in con- centration of plasma growth hormone to a maximum of 4.2 mug/ml.
The reason for the failure of hypoglycemia to stimulate release of growth hormone in this pa- tient is not clear, although we have observed the same phenomenon in patients with islet- cell adenomas. It is possible that frequent, pro- longed hypoglycemia results in an alteration of the normal response of growth hormone to a rapidly falling concentration of blood glucose.
The above studies confirm the findings of Williams and co-workers (10), Eymontt and associates (11) and Wikman and McCracken (12) that there is no evidence for an elevation of circulating insulin or insulinlike material to explain the profound hypoglycemia occasionally seen in patients with adrenocortical tumors.
Discussion
Many hypotheses have been suggested to explain the genesis of the hypoglycemia that occasionally occurs in patients with nonpancreatic tumors. Unfortunately, no consistent pathophysiologic derangement has proved applicable to all reported cases. The attractive thesis that insulin or an insulinlike substance is produced by these tumors lacks convincing confirmation since an increase in insulinlike activity has been found in serum or tumor extracts in only a few instances (19). When our patient was hypoglycemic, no significant increase in
plasma insulin or insulinlike activity could be measured.
In previously reported cases, there has been no valid evidence of abnormal sensi- tivity of the pancreas to glucose or other substances that stimulate secretion of insulin. Administration of tolbutamide does not produce hypoglycemia in patients with nonpancreatic neoplasms, in contrast to the prolonged hypoglycemic response usually seen in patients with islet-cell tumors. Possible sensitivity to leucine has been noted in only one patient with a fibrosarcoma (20), but the decrease in blood sugar level was not overly decisive, as documented. Leucine sensitivity was not present in the patient with adrenocorti- cal carcinoma studied by Eymontt and co-workers (11). The response of plasma insulin during an oral glucose tolerance test was entirely normal in the case pre- sented herein. Although tolbutamide and leucine tests were not performed, the mechanism for the production of hypogly- cemia in this case does not appear to be an excessive stimulation of insulin secretion.
At surgical exploration, the liver ap- peared normal, thus excluding extensive hepatic metastases as the basis of the hypo- glycemia. Unfortunately, the arterial-ve- nous glucose difference across the tumor was not measured so that no estimation of glucose utilization by the tumor could be made. No demonstrable glucose difference was observed in the patient reported by Eymontt and co-workers (11).
Theoretically, a deficiency in cortisol production by the tumor, as seen in some patients with the adrenogenital syndrome, might lead to hypoglycemia. No decrease in plasma cortisol concentration was de- tected in our patient, nor have previous studies documented cortisol deficiency. In fact, when measured in previous cases, the 24-hour urine excretion of 17-hydroxy- corticoids has been found to be increased (Table 2).
As noted, other clinical signs suggesting the presence of a functioning adrenocorti-
July 1967
| Author | Year | Age & sex | mg/24-hr urine | Tumor | Pathologic diagnosis | ||
|---|---|---|---|---|---|---|---|
| 17-Keto- steroids | 17-Hydroxy- steroids | Size | Side | ||||
| Anderson (1) | 1930 | 33, M | 400 g | L | Carcinoma | ||
| Lawrence (2) | 1937 | 24, F | Grapefruit | L | Carcinoma | ||
| Thannhauser (3) | 1946 | 3 patients | with adrenocortical carcinoma | (2 had hypoglycemia) | |||
| Broster and | 1948 | 14, F | 1,980 | 2.98 kg, | L | Carcinoma | |
| Patterson (4) | tumor & | ||||||
| kidney | |||||||
| Staffieri and co-workers (5) | 1949 | 25, M | 23.2 | 20 by 11 by 9 cm | R | * | |
| Dohan and co-workers (6) | 1953 | 48, F | 80 | (Large amounts of tetrahydro- | 2.2 kg | L | Carcinoma |
| S in urine) | |||||||
| Schamaun and co-workers (7) | 1957 | 37, M | 33-41 | 1.7 kg | R | Adenoma | |
| Askanazy and co-workers (8) | 1958 | 26, F | 2.2 kg | L | Carcinoma | ||
| Kühnlein and | 1958 | 45, M | 166 | 2.6 kg | R | Carcinoma | |
| Meythaler (9) | |||||||
| Williams and co-workers (10) | 1961 | 24, F | 56.8 | 162 | 2.0 kg | L | Carcinoma |
| Williams and co-workers (10) | 1961 | 48, M | 130 | 400 mg (tetra- hydro-S 147) | 1.1 kg | L | Carcinoma |
| Eymontt and co-workers (11) | 1965 | 19, F | 85-236 | 35.7-48.9 | 1.4 kg | L | Carcinoma |
| Wikman and McCracken (12) | 1965 | 59, M | 2.4 kg | L | Carcinoma | ||
| Scholz and co-workers | 1967 | 16, F | 7.3-30.6 | 17-ketogenic steroids 12.2 | 1.8 kg, tumor & kidney | L | Carcinoma |
* Sarcomatous dysembryoplasia with cortico-adrenal differentiation.
cal tumor were lacking. The urinary excre- tion of 17-ketogenic steroids and 17-keto- steroids was normal when determined at the Mayo Clinic, although moderate ele- vation of 17-ketosteroids was detected in the original studies at Duke University. When 17-ketosteroids were measured, markedly elevated values were found in all but one of the patients previously reported.
Eymontt and co-workers (11) have recently proposed the thesis that the hypo- glycemia might be explained by the greatly increased secretion of anabolic steroids which channel amino acids into protein synthesis, thus making them unavailable for gluconeogenesis. This concept is pred- icated on observations that, under certain circumstances, testosterone can cause a lowering of the level of blood sugar (21). No fractionation of the urinary 17-keto- steroids was carried out in our patient; but there were no clinical findings to indicate androgen excess, and documented levels
of urinary 17-ketosteroids failed to support a marked overproduction of androgenic steroids with anabolic properties by the tumor. Further biochemical studies includ- ing steroid fractionation data will be neces- sary to support or disprove this concept.
Recently, Silverstein and co-workers (22) have postulated another possible mechanism for the hypoglycemia in certain patients with neoplasms. The exhibition of potent hypoglycemic activity in mice by several tryptophan metabolites indicated that increased concentrations of trypto- phan metabolites might be responsible for hypoglycemia in some patients. Increased levels of these metabolites in blood and urine were demonstrated in two patients with extrapancreatic neoplasms, namely, a fibrosarcoma and an adenocarcinoma of the stomach (23). Additional studies of tryptophan metabolites in five patients who had hypoglycemia associated with neoplasms (3 with islet-cell tumors, 1 with
metastatic carcinoma of the breast, and 1 with adrenocortical carcinoma and exten- sive metastatic involvement of the liver) have revealed normal values for the blood and urine tryptophan metabolites (24).
None of the proposed mechanisms ap- pears to account for the hypoglycemia in the case presented herein.
References
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