Hypoglycemia by Adrenocortical Carcinoma with Cushing’s Syndrome
KIYOHIKO YOSHIKAWA and HARUKI WAKASA*
Clinic of Internal Medicine, Iwaki Kyoritsu General Hospital,
Iwaki 973 and *the Second Department of Pathology, Tohoku University School of Medicine, Sendai 980
YOSHIKAWA, K. and WAKASA, H. Hypoglycemia by Adrenocortical Carcinoma with Cushing’s Syndrome. Tohoku J. exp. Med., 1980, 132 (1), 49-60 - A case of adrenocortical carcinoma, a 18-year-old female with Cushing’s syndrome and later hypoglycemia, was reported. Cushing’s syndrome was corroborated by clinical signs of moon face, obesity, hirsutism and amenorrhea as well as by elevated urinary steroid levels. A huge tumor in the right adrenal region weighing 171 g was removed and histologically diagnosed as adrenocortical carcinoma. Shortly after the surgery, urinary levels of steroid excretion became within normal ranges. However, hypoglycemia with elevated levels of urinary steroid appeared in 6 months postoperatively. She died of massive hemorrhage from gastric ulcer. Autopsy revealed a huge tumor in the right hypochondrial region pressing the liver and right kidney. Tumor cells of autopsy material showed much more ana- plastic feature than those of surgical one. Several possible mechanisms for hypoglycemia were discussed. hypoglycemia; adrenocortical carcinoma; Cushing’s syndrome
Adrenocortical carcinoma is infrequent cause of hypoglycemia and estimated at 10% among extrapancreatic tumors associated with hypoglycemia (Ensincks and Williams 1974).
Thanhauser (1949) first reported two cases of hypoglycemia caused by an adrenocortical glucocorticoid-producing carcinoma. Since then a few case reports on an adrenocortical carcinoma with hypoglycemia have appeared in the literature, but the descriptions of endocrinological examinations were not satisfactory.
Glucocorticoids, represented mainly by cortisol, have diverse effects on fuel metabolism, which, in general, are opposite to those of insulin and tend to elevate plasma sugar concentrations. Thus chronically excessive glucocorticoid levels in Cushing’s syndrome increase the fasting plasma glucose concentrations associated with an impaired glucose tolerance. Therefore, the association of hypoglycemia with Cushing’s syndrome caused by adrenocortical carcinoma would deserve a documentation.
Eymontt et al. (1965) reported such a case of Cushing’s syndrome with hypoglycemia.
The pathogenesis of this peculiar combination of symptoms will be discussed below.
CASE
A senior high school girl, aged 18.
Family history: Nothing worthy of special mention.
Chief complaint: Abdominal distension.
Case history: The patient developed amenorrhea, irritation and loss of interest in the daily school work around November, 1971. In those days, she found herself hairy and obese with cutaneous streaks in lower limbs. A physician or a gynecologist detected no physical abnormalities and she was treated as a neurosis by a psychiatrist.
In April, 1972, she fell unconscious during a school excursion and on the next day marked edema was noticed in the lower limbs. She was admitted to a certain hospital and suspected to be Cushing’s syndrome. A right adrenal tumor was revealed and extirpated on 20 June, 1972.
The removed tumor weighed 171 g, fist-sized, and appeared to be malignant, though there was no evidence of metastasis. The left adrenal was not explored.
Histologically, the tumor consisted of carcinoma cells mostly with clear cytoplasm and vesicular nuclei, solid and alveolar in arrangements (Fig. 1, left). In some portion, carcinoma cells had dark cytoplasm, and were arranged solid (Fig. 1, right). Cellular pleo- morphism was unremarkable, but spindle or polygonal shaped cells were seen. Blood vessels were abundant associated with perivascular radial arrangement of carcinoma cells (Fig. 2).
Her postoperative course was favorable, the menstruation restarted in August 1972, and obesity and hirsutism became less evident. The patient was discharged and followed up.
In November, 1972, abdominal distension recurred, lower limbs were swollen and a large tumor was palpable in the right hypochondrium. She was referred to our clinic on 24 November, 1972.
Findings on admission: The patient was clearly conscious and had a flushed moon face, an obese body, and overall edema. She was 154 cm in height, and 56 kg in weight. Blood pressure was 140/80 mmHg and temperature was 36.8℃. Pulse rate was 84/min.
Fig. 2. Tumor tissue is abundant in vascular channel revealing sinusoidal pattern. H.E. × 280. ☒
TABLE 1. Laboratory findings
Urinalysis prot. (-) glu. (-) urob. (±) r.b.c. (+) w.b.c. (-) ep. (3~4/1) cyl. (-)
Hematological examination
RBC 400× 104/mm3 Ht 32% Hb 11.2 g/100 ml WBC 12600/mm3
Eo. 0 Stab. 13 Seg. 70 Mo. 1 Lym. 16%
Bleeding time 2’30” Coagulation time 8’30”
ESR 1h 42 2h 74 mm
Serum protein T.P. 5.7 g/100 ml Alb. 49.1 Glob. 50.9 (@1 5.0, a2 10.9, ₿ 15.6,
y 19.3) % Serum electrolyte
Na 139 CI 99 K 3.9 Ca 4.2 mEq/liter
Serum lipid total lipid 770 mg/100 ml total cholesterol 284 mg/100 ml
LDH 2190 u Au antigen (-) @-feto. (-)
FBS 66.1 mg/100 ml
Liver function icterus index 3 TAKADA 100 TTT 1.4 ZTT 7.0 GOT 149 GPT 124 Al-P 9.9
BUN 16 mg/100 ml Cr 0.5 mg/100 ml
Urine 17-OHCS 68.9 17-KS 98.0 mg/day VMA (-)
Marked cutaneous striae were noted on the abdomen and thigh. No abnormality was found in the chest. Cardiac sound was normal. There was a linear scar of the previous laparotomy across the upper abdomen. Caput Medusae was found on the abdomen. Abdomen was distended with ascites. In the right hypochondrium a hepatoma-like tumor was tasted six-finger width below the costal margin.
Laboratory examinations (Table 1): Leucocytosis was noted in the peripheral blood. Hemogram revealed hypernormocytosis and lymphopenia. Blood sedimentation rate was
as high as 45 mm/hr, and serum total protein was 5.8 g/100 ml. Serum electrolytes were normal. Serum LDH was as high as 2190 U. Fasting blood sugar was as low as 66.1 mg/100 ml. Serum GOT and GPT were high, but ALP was within normal range. Renal function was normal.
x-Ray examinations revealed no abnormality in the mediastinum or the lung, but an unusual rise of diaphragm and the stomach pressed leftward. The pituitary fossa showed no abnormality. There was microhematuria, and intravenous pyelography revealed laterally pushed right kidney and presence of a tumor (Figs. 3 and 4).
Urine sample collected on December 30, 1972 showed 25.4 mg of 17-OHCS, 163.0 mg of 17-KS, and 78.7 mg of 17 KGS per day. Dehydroepiandrosterone was particularly high. Urinary aldosterone excretion was within normal range at the first determination and slightly increased at the second one. Urinary adrenaline and noradrena- line remained in the normal range. The daily urinary 17-OHCS and 17-KS excretions were continuously high. It seemed that she might have recurrent adrenal carcinoma producing steroid hormones. The other endocrinological data are put in Tables 2 and 3.
As the edema and oliguria were noticed, furosemide was injected as a symptomatic treatment (Fig. 5). The therapy improved edema of the lower limbs as well as oliguria (to 1300-2000 ml/day), but caused hypokalemia and metabolic alkalosis. Large doses of KCI plus anti-aldosterone preparation were given to improve these symptoms. Epigastric pain became marked and the abdominal tumor grew larger gradually. She could take only half of meals, and the anorexia worsened progressively. Finally the diet had to be changed to a liquid food containing 1,800 kcal.
In the midnight of December 13, 1972, the patient complained of general lassitude, epigastric pain, nausea and vomiting and clouding of consciousness. The blood sugar level was found as low as 35 mg/100 ml. Glucose was instilled and the patient regained her consciousness. Thereafter, she was attacked by the hypoglycemia every night, and on each occasion she was given glucose instillation plus oral carbohydrate. Blood sugar level at each occasion was as low as around 30 mg/100 ml.
3
2
4
10 % glucose 500 ml + 2 % furosemide 2 ml x 4
10 % NaCl 20 ml + IM KCI 10 ml x 6
Spironolacton 75 mg + KCI 8.0 g
Serum Na (mEq/liter )
150
(mEq/liter 0-0)
110
140
100
9
130
Serum cl
90
0
120
80
NWAU
(mEq/liter &-6)
70
Serum K
٥
A
60
50
50
HCO3
( MEq/liter o-o)
(mmHg & 6)
40
PCO2
40
7.6
1
90
F BS ( mg/100 ml ** )
30
30
7.5
80
20
20
7.4 ㅎ
70
·
60
volume (ml)
2000
50
Urine
1000
40
0
30
21
25
1
5
10
15
20
25
30
5
8
Nov
Dec 1972
Jan 1973
| 1972, 12, 30 | 1973, 1, 6 | Normal value ? | |
|---|---|---|---|
| 17-OHCS total urine 17-OHCS (fraction) | 25.4 | 29.2 | 3.04~6.16 mg/24hr |
| Cortisone | 0.44 | 1.82 | 0.06~0.6 # |
| Cortisol | 1.20 | 0.79 | 0.05~0.57 # |
| 11 deoxycortisol | 0.95 | 2.03 | 0.05~0.43 # |
| Tetrahydrocortisone | 8.65 | 9.45 | 0.47~1.41 # |
| Tetrahydrocortisol | 5.75 | 0.43 | 0.78~2.34 # |
| Tetrahydro-11-deoxycortisol | 0.44 | 11.8 | 0.03~0.53 # |
| 17-KGS | 78.7 | 217.0 | 3~15 # |
| 17-KS total urine, 17-KS (fraction) | 163.0 | 113.0 | 3.0~11.9 !! |
| 11-oxy-17-KS | 29.4 | 38.4 | 0.3~ 5.9 # |
| 11-deoxy-17-KS | 62.5 | 77.0 | 1.5~9.6 !! |
| Androsterone | 11.07 | 9.70 | 0.2~2.0 " |
| Dehydroepiandrosterone | 59.7 | 29.2 | 0~1.5 " |
| Etiocholanolone | 2.0 | 2.8 | 0.2~ 3.0 # |
| 11-hydroxyandrosterone | 2.93 | 1.17 | 0~1.0 # |
| 11-hydoxyetiocholanolone | 1.67 | 1.4 | 0~1.0 # |
| 11-ketoetiocholanolone | 1.53 | 0.65 | 0~1.0 # |
| Aldosterone | 7.2 | 17.2 | 2~15 mcg/24hr |
| 1972, 12, 11 1972, 12, 18 | |||
| Adrenaline | 12.6 | 19.8 | 0~30 µg/24hr |
| Noradrenaline | 30.8 | 32.0 | 30~80 # |
The 50 g oral glucose tolerance test (Fig. 6) revealed a flat curve; 47 mg/100 ml at pre-dosing, 111 mg/100 ml at 1 hr, and 102 mg/100 ml at 2 hr. Blood IRI level showed almost no response; 4IRI/4BS at 30 min was only 0.14. Blood Il-OHCS level showed a decrease at 90 min, returning to the pre-dosing level at 3 hr, while blood NEFA level remained low.
11-OHCS ( pg/100 ml 0-0)
100
Blood glucose ( mg /100 ml
40
0.8
O
30
0.6
50
20
RI (_U /ml
NEFA (mEq/ liter
0.4
10
0.2
0
2
3
0
0.0
0
1
Time after loading (hr)
| 1972, 12, 30 | 1973, 1, 6 | Normal value | |
|---|---|---|---|
| THE/THF | 1.50 | 21.97 | 0.60 |
| Et/AN | 0.18 | 0.28 | 3.0 |
| Et+AN/17-KS | 0.03 | 0.03 | 0.33 |
| 17-KS/17-OHCS | 6.41 | 3.86 | 1.93 |
| AN/Et | 0.68 | 3.46 | 0.66 |
| THE/THS | 19.65 | 0.80 | 2.66 |
The patient’s general conditions became worse with the gradual increase of the abdominal tumor associated with pain in the right hypochondrium. She ejected tarry stool in January, 1973 and died on the 45th hospital day.
POSTMORTAL EXAMINATIONS
Gross and histologic findings
The body was well-nourished and obese. The face was round, but not enough to be called moon-face. Cutaneous striae were marked on the lower back and thigh. There was a male pattern of pubic hair distribution but no clitoral hypertrophy.
In the abdominal cavity, numerous nodular tumors, measuring 1 to 5 cm in the largest diameter, were scattered on the greater omentum. More than one dozen of tumor nodules, measuring 5 cm in the largest diameter, were noted in the mesenteric lymph nodes, especially around the terminal ileum. These tumors were smooth on the surface and solitary in each other without any conglomeration.
The main tumor was huge, weighing 3,450 g, and occupied the right side of the peritoneal cavity below the liver through retroperitoneum and pressing the liver and the right kidney (Fig. 7). The cut surface was generally yellowish-white in color and elastic in consistency but various in appearance with foci of hemorrhagic necrosis in the central part. It showed an expansive growth with a well demarca- tion from adjacent tissues. Histologically, carcinoma cells were extremely
pleomorphic and/or anaplastic with abundant basophilic cytoplasm. The nuclei were hyperchromatic and giant cells with 2-3 nuclei were occasionally found. Alveolar arrangement of carcinoma cells was remarkable (Figs. 8 and 9).
Metastatic lesions in the liver were a few in number and covered with thin capsule (Fig. 10). In these lesions, carcinoma cells were rather small and arranged in groups irregularly intermingled with connective tissues. Carcinoma cells in trabecular or alveolar arrangement had clear cytoplasm. The stroma had abundant vascular channels with perivascular fibrosis.
The liver was slightly icteric in color histologically with bile thrombi in bile capillaries. Slight atrophy was found in centrolobular areas. Glycogen could hardly be found in liver cells. The left adrenal was considerably atrophic. No gross abnormalities were found in the brain and pituitary. In the anterior pituitary, Crooke’s changes were noted in some of basophilic cells (Fig. 11). In the ovaries, pseudoxanthoma cells aggregated around the degenerated corpus luteum showing an irregular outline.
The spleen was swollen, weighing 190 g, and was a little softer. Extramedullary hematopoiesis was marked with well developed three series of hematopoietic cells. Fibrosis was noted in the medullary cord. The right kidney weighed 200 g, and showed moderate dilatation of pelvis, while the left kidney, weighing 210 g, showed ischemic appearance on the cut surface. Histologically a moderate dilatation and epithelial cell damage of distal tubuli and interstitial edema were observed in association with the presence of uromucoid substance in tubuli.
The stomach had a deep ulcer, thumb-tip in size, with poorly developed granulation tissue in the antrum on lesser curvature. The ulcer involved the serosa and the ulcer bottom covered with fibrin and necrotic tissue was formed by adipose tissue of the greater omentum. The heart, lungs, or pancreas was not particular on naked eye. The pancreas was generally atrophic in the appearance of lobular
structure. Langerhans’ islets were small in size and increased in number (Fig. 12). Swelling of centro-acinar cells was also detected.
Insulin content in the tumor tissue
Insulin or insulin-like activities were not detected in the tumor tissue by acid alcohol extraction, while 3.1 U/g was recovered from the tail of the pancreas.
Glycogen content in the tumor and liver tissue
The glycogen content of the tumor, determined in sections from 3 different parts of the tumor, were 38.7 mg/100 g wet tissue, 11.2 mg/100 g and 47.9 mg/ 100 g, respectively, by means of Roe and Dailey method. These ranges were far
lower than that of the normal liver and roughly the same as those in the organs not distinguished for the storage of glycogen; e.g., the animal submaxillary gland had 50-100 mg/100 g wet tissue in male rats, about 50 mg/100 g wet tissue in male mice and 100-200 mg/100 g wet tissue in female mice. Significant storage of glycogen was thus not detected.
The activity of G-6-Pase was determined with a sample obtained by homo- genizing the liver tissue with 9 volumes of 0.25 M sucrose. Its specific activity was 0.004 pmoles/min/mg protein (Swanson’s method), as low as 1/30 of that in the control mouse liver, 0.119 pmoles/min/mg protein.
Histochemical evidence of glycogen was hardly detected in the liver cells. The tumor was huge, weighing 3,450 g and made up of numerous nodules in sizes of little finger tip to a duck egg clustering like mushrooms. From the above findings, it seemed likely that hypoglycemia resulted from massive consumption of glucose by the giant tumor.
DISCUSSION
It is known that glucocorticoids have an influence on the matabolism of carbohydrate favoring the glucose formation by mechanisms which are still uncertain. Still more, glucocorticoids activate glycogen synthetase by glucose-6- phosphate and pyruvate carboxylase by acetyl CoA with saturation of gluconeogenic enzymes by precursors and indirect inhibition of glycolysis by free fatty acid, resulting in increased glycogenesis. Clinically an abnormal glucose tolerance is frequently observed in patients with hypersecretion of glucocorticoids, Cushing’s syndrome and glucocorticoid treatment.
In the present case hypoglycemia was observed at her last stage in spite of increased glucocorticoid secretion.
The pathogenesis of hypoglycemia associated with massive tumors has not been elucidated. Recent studies on glucose kinetics in some of these patients have suggested a multifactorial etiology, e.g., (1) increased glucose utilization, (2) decreased glucose production, (3) defective glycogen synthesis and release, (4) synthesis and store of insulin or its precursors (Ensincks and Williams 1974).
In recent years, elevated levels of insulin-like activity (ILA) have often been reported in plasma and tumor extracts in cases of hypoglycemia caused by
extrapancreatic tumors. Hyodo et al. (1977) recorded increased ILA by radiore- ceptor assay and bioassay in an adrenocortical carcinoma. This case had no evidence for hyperadrenocorticism.
In the present case, ILA was not detected by radioimmunoassay in the tumor extracts.
The datum that glycogen content in the tumor tissue was far lower than that in the normal liver suggests a marked increase of glucose consumption in tumor tissue. It has often been said that hypoglycemia is caused by excess glucose utilization by the neoplasm itself. These results support the theory that the glucose turnover rates are elevated with excessive diversion of blood glucose to the neoplastic tissue in patients with gigantic tumors.
In order to explain the hypoglycemia which occurred in patients with adreno- cortical carcinoma manifesting Cushing’s syndrome, Eymontt et al. (1965) remarked androgenic steroids of usual product by adrenocortical carcinoma. They spe- culated that the greatly increased secretion of anabolic steroids channels amino acids into protein synthesis and makes them unavailable for gluconeogenesis. This would be supported by the fact that in the reported cases of hypoglycemia caused by adrenocortical carcinoma with hyperadrenocorticism, adrenogenital syndrome is superior to Cushing’s syndrome. In the study on 18 cases of functioning adrenocortical carcinoma, Huvos et al. (1970) emphasized elevated urinary 17- ketosteroids and 17-hydroxycorticoid excretion with or without clinical symptoms of virilism or other signs of sex-steroid overproduction. According to Scholz et al. (1967), when 17-ketosteroids were measured in the 14 reported cases of adreno- cortical carcinoma with spontaneous hypoglycemia including their own one, markedly elevated values were found in all but one of the patients. In patients with adrenocortical carcinoma, hypoglycemia is observed when anabolic steroids predominate. In the present case, urinary levels of 17-OHCS, 17-KGS and 17-KS were increased and the 17-KS fraction revealed markedly high values at dehydro- epiandrosterone, androsterone and ethiocholanolone.
Acknowledgment
We are indebted to Prof. Sasano and Dr. Ojima for their specialized advice for prepara- tion of this article.
References
1) Ensincks, J. & Williams, R.H. (1974) Disorders causing hypoglycemia. In: Textbook of Endocrinology. 5th Ed., edited by R.H. Williams, Saunders, Philadelphia, pp. 627-659.
2) Eymontt, M.J., Gwinup, G., Kruger, F.A., Maynard, D.E. & Hamwi, G.J. (1965) Cushing’s syndrome with hypoglycemia caused by adreno-cortical carcinoma. J. clin. Endocr., 25, 46-52.
3) Huovs, A.G., Hajdu, S.I., Brasfield, R.D. & Foote, F.W., Jr., (1970) Adrenal cortical carcinoma: Clinicopathologic study of 34 cases. Cancer, 25, 354-361.
4) Hyodo, T., Megyesi, K., Kahn, C.R., McLean, J.P. & Friesen, H.G. (1977) Adreno- cortical carcinoma and hypoglycemia. Evidence for production of nonsuppressible insulin-like activity by the tumor. J. clin. Endocr. Metab., 44, 1175-1184.
5) Scholz, D.A., Horton, E.S., Lebovitz, H.E. & Ferris, D.O. (1967) Spontaneous hypoglycemia associated with an adrenocortical carcinoma. J. clin. Endocr., 27, 991-996.
6) Thanhauser, S.J. (1949) Hypoglycemia in the early phase of adrenocortical carcinoma. J. clin. Endocr., 9, 791.