HYPERMINERALOCORTICOIDISM DUE TO ADRENAL CARCINOMA: PLASMA CORTICOSTEROIDS AND THEIR RESPONSE TO ACTH AND ANGIOTENSIN II
C. G. ISLES, I. C. MACDOUGALL, A. F. LEVER AND R. FRASER
Medical Research Council Blood Pressure Unit, Western Infirmary, Glasgow, G11 6NT, Scotland
(Received 28 May 1986; returned for revision 22 July 1986; finally revised 1 September 1986; accepted 19 September 1986)
SUMMARY
A 47-year-old female presented with hypertension, hypokalaemia, low plasma renin, high plasma aldosterone and was found to have a left adrenal tumour 4 cm in diameter by computerized tomography. Detailed biochemical studies showed high plasma levels of 11-deoxycorticosterone and corticosterone in addition to aldosterone and 18-hydroxycorticosterone. Basal 11-deoxycorticos- terone levels were particularly high. Corticosterone, 18-hydroxycorticosterone and aldosterone concentrations were abnormally sensitive to infusions of ACTH and angiotensin II. Plasma cortisol and assays for sex hormones were normal although there was evidence that cortisol derived from the neoplasm. At operation a well-differentiated adrenocortical carcinoma weighing 50 g (56 × 30 × 36 mm) was removed. There was no evidence of metastases following surgery. Adrenal function returned to normal. Review of the literature suggests that adrenocortical carcinoma should be suspected in patients who otherwise have typical features of Conn’s syndrome, but whose tumours are more than 3 cm in diameter. Measurement of steroids such as 11-deoxycorticosterone in addition to aldosterone is recommended since abnormally high values may also help to distinguish between hyperaldosteronism due to adenoma and carci- noma. Previously reported cases of isolated aldosterone production by a carcinoma cannot be substantiated.
The combination of hypertension, hypokalaemia, high normal or high plasma sodium concentration and a metabolic alkalosis is the hallmark of hypermineralocorticoidism. These features occur in primary hyperaldosteronism due to an adenoma (Conn’s syndrome) or to idiopathic bilateral adrenal hyperplasia (Ferriss et al., 1978), in cases of steroid 17x-hydroxylase or 118-hydroxylase deficiency where excessive 11-deoxycorticos- terone secretion is probably mainly responsible (Fraser, 1983) and iatrogenically due to
Correspondence: Dr. R. Fraser, MRC Blood Pressure Unit, Western Infirmary, Glasgow G11 6NT, Scotland.
administration of sodium-retaining compounds such as glycerrizhinic acid derivatives or synthetic corticosteroids (Mantero, 1981). Although adrenocortical carcinoma is an uncommon cause of hypermineralocorticoidism (Melby, 1984) its early recognition and distinction from benign adrenal lesions is clearly important. An estimate of tumour size is useful here since most adrenocortical carcinomas are greater than 3 cm diameter or 30 g in weight (Neville & O’Hare, 1982). The secretion of steroids other than aldosterone and 18- hydroxycorticosterone is another useful differentiating feature (Neville & O’Hare, 1982) but there have been some adrenocortical carcinomas in which it was claimed only aldosterone was secreted in excess (Santander et al., 1965; Salassa et al., 1975; Shah et al., 1975; Revach et al., 1977; Slee et al., 1983; Greathouse et al., 1984; Levine et al., 1984). This paper describes detailed biochemical studies of a patient with features of hypermineralocorticoidism due to an adrenocortical carcinoma producing aldosterone, 18-hydroxycorticosterone, 11-deoxycorticosterone and corticosterone. It also examines the evidence for excess production solely of aldosterone in other reported cases.
CASE REPORT
A 47-year-old female subject was referred to the MRC Blood Pressure Unit for investigation of poorly controlled hypertension (up to 240/115 mmHg) of several years duration and was found to be hypokalaemic (2.8 mmol/l) while taking pindolol, clopamide and nifedipine retard. One month after withdrawing clopamide, hypokalaemia persisted (2·8-3-6 mmol/l) and plasma sodium (142 mmol/l) was at the upper end of the normal range. Plasma renin concentration was very low (<1 µU/1, normal 9-50) and that of aldosterone raised (800 pmol/l, normal <500), suggesting a diagnosis of primary hyperaldosteronism. Since it was not possible to withdraw antihypertensive therapy before further investigation, treatment was changed to prazosin (10 mg/d) which, unlike ß-blockers, does not alter renin secretion. Subsequently, the features of primary hyperaldosteronism were confirmed. Plasma potassium was 2.8 mmol/l, plasma sodium 144 mmol/l and plasma bicarbonate 37 mmol/1. By activation analysis (Williams et al., 1984), total body sodium was 114% (3082 mmol) of expected and potassium 93% (2271 mmol) of expected. Blood pressure was 194/106 mmHg lying and 176/94 mmHg standing. Plasma aldosterone concentrations of 607, 718 and 497 pmol/l were associated with concurrent renin and angiotensin II levels of 6, 3 and 3 uU/ml (normal 9-50) and 2, 1 and 1 pmol/l (normal 3-12) respectively but plasma catecholamine concentrations were normal (noradrenaline 1.6 nmol/l, normal <5.0; adrenaline <0.1 nmol/l, normal <0.5; dopa- mine 0.2 nmol/l, normal <1).
Evidence for a lesion in the left adrenal gland was as follows. Adrenal venography suggested a tumour (estimated at 2.5 cm) on the left side and plasma aldosterone concentration in the left adrenal vein was higher (2125 and 2926 pmol/l) than from the right adrenal vein (660 and 660 pmol/l). Concurrent measurements of cortisol confirmed that the catheters were correctly placed. Seventy percent of a dose of 75Se-cholesterol was detected in the left adrenal gland by scintigraphy and scanning by computerized tomography predicted a tumour of 4 cm at the same site. In view of the large tumour size and also of high peripheral plasma concentrations of both 11-deoxycorticosterone (4364 and 5117 pmol/l, normal 120-480) and corticosterone (38-6 and 37.2 nmol/1, normal 2.3- 23), features which are atypical of benign aldosterone-secreting tumours, the possibility of adrenocortical carcinoma was raised and surgical intervention expedited. Initially,
amiloride (40 mg/d) failed to control blood pressure (210/104 mmHg) although plasma potassium concentration rose (4.9 mmol/l) and that of sodium fell (137 mmol/1). However, pre-operatively, blood pressure was lowered to 140/94 mmHg using a combination of amiloride (60 mg/d), atenolol (100 mg/d) and prazosin (4 mg/d).
A tumour of the left adrenal gland, 56 x 30 x 36 mm and weighing 50 g, was removed at surgery. The right adrenal gland was normal. When cut, the tumour was yellow. Histology revealed the presence of both zona fasciculata and zona glomerulosa type cells, the latter predominating. Cells in surrounding fat tissue (Fig. 1) and in a small blood vessel (Fig. 2) suggested that it was malignant (Dr I.L. Brown, Department of Pathology, Western Infirmary, Glasgow). The cells were arranged in short cords and alveoli. Cellular and nuclear pleomorphism were not prominent and most nuclei were rounded and hyperchromatic. Foci of myeloid metaplasia and myxomatous change were apparent and
surrounding periadrenal tissue contained numerous foci of neoplastic cells. The gland attached to the tumour showed glomerulosa hyperplasia and micronodules (Prof. A.M. Neville, Ludwig Institute for Cancer Research, London).
Postoperatively, biochemical abnormalities resolved without treatment but blood pressure did not become normal (154/96 to 198/102 mmHg) and it was therefore necessary to restart antihypertensive therapy. When last seen one year following surgery, she was well with blood pressure of 168/90 mmHg and plasma potassium of 4.6 mmol/l while taking atenolol (100 mg/d).
METHODS
Plasma cortisol was measured by a direct immunoassay and other corticosteroids by radioimmunoassay after preliminary partial purification by paper chromatography.
Plasma levels of renin and angiotensin II were measured by previously reported immunoassays (Düsterdieck & McElwee, 1971; Millar et al., 1980) and catecholamines by radioenzymatic assay (Ball et al., 1981). The angiotensin II infusion procedure was as previously reported (Oelkers et al., 1974); ACTH (Synacthen, Ciba, Horsham, West Sussex, UK) was infused in the same way. During the period of basal hormone assays and studies of circadian changes the patient received a diet containing 123 mmol sodium and 62 mmol potassium together with prazosin (10 mg/d). Infusion of ACTH and angiotensin II were performed later while taking a normal ward diet after blood pressure control had been obtained with amiloride (30 mg/d), atenolol (100 mg/d) and prazosin (4 mg/d).
RESULTS
Basal hormone levels and diurnal changes
In Table 1, plasma hormone levels in the patient are compared with those found in normal subjects under comparable conditions and also with those in groups of patients with primary hyperaldosteronism due to adenomata (Conn’s syndrome) and idiopathic hyperaldosteronism due to bilateral adrenocortical hyperplasia. The patient’s plasma renin concentration was suppressed and her plasma aldosterone and 18-hydroxycorticos- terone concentrations raised compared with normal, resembling the other hyperaldoster- onism groups in these respects. However, unlike these groups, plasma corticosterone and 11-deoxycorticosterone concentrations were abnormally high. Cortisol and 11-deoxycor- tisol levels were normal as were those of oestradiol (1402 pmol/l), testosterone (<0.5 nmol/l), dehydroepiandrosterone sulphate (DHAS) (<1.0 umol/l), and androstenedione (5.8 nmol/1). Plasma renin concentrations rose and abnormal steroid levels fell to within normal limits following removal of the tumour.
Diurnal changes in plasma steroid concentrations
Measurement of plasma steroid concentrations were made at intervals during a 24-h period during which the patient remained recumbent (Table 2). Plasma 11-deoxycorticos- terone, corticosterone and cortisol levels tended to be highest in the morning and lowest at night but the amplitude of the changes was relatively small and the night values, particularly those of 11-deoxycorticosterone, remained high. Plasma aldosterone concen- tration showed no discernible rhythm. Plasma ACTH concentration was not measured.
Effect of dexamethasone
Dependence of steroid levels on endogenous ACTH secretion was also tested using a standard dexamethasone suppression test, firstly at a low dose for 7 d and then for a further 2 d at a high dose (Table 3). Aldosterone concentration fell to about 50% of the starting level on low dose dexamethasone but had increased 2 d later on the higher dose. Corticosterone and 11-deoxycorticosterone concentrations were also reduced but at no time did they fall within the normal range. Interestingly, plasma cortisol concentration, although initially not abnormally high, failed to fall to the very low levels expected of normal subjects in this test (Table 4), suggesting that at least some cortisol originated from an autonomous lesion.
| Variable | Normal subjects | Idiopathic hyperaldosteronism | Primary hyperaldosteronism | Adrenocortical carcinoma | ||||
|---|---|---|---|---|---|---|---|---|
| Pre-op | 8 d post-op | 9 d post-op | 14 d post-op | 21 d post-op | ||||
| Active renin (uU/ml) | 19.98±20.10 | 7.25 ±11.00 | 6.95±3.53 | 4* | 39 | 64 | 30 | 33 |
| Aldosterone (pmol/l) | 217.21±145-73 | 634-80±310-22 | 1011.54±513-91 | 607* | 110 | 55 | 110 | 55 |
| Corticosterone (nmol/l) | 10-25±7.71 | 12-31 ±6-64 | 6.92±5.42 | 39 | 17 | 7 | 10 | 4 |
| 18-Hydroxycorticosterone (pmol/1) | 279.55±122.30 | 835-38±594-59 | 1255.80±703.52 | 2512 | 792 | 218 | 191 | 355 |
| 11-Deoxycorticosterone (pmol/l) | 238.99±167.96 | 528-86+386-18 | 394.31±254-95 | 4365 | 331 | 90 | 211 | 120 |
| 11-Deoxycortisol (pmol/l) | 1133.65±723.53 | 2770-99 +2551.72 | 2933.71+1591.99 | 1521 | 459 | 172 | 459 | 86 |
| Cortisol (nmol/l) | 331.93± 174-35 | 244.75±119.13 | 218.90±84.15 | 303 | 550 | 303 | 303 | 193 |
| Blood pressure (mmHg) | 115-2±12.6/ | 176.9±22-0/ | 186-4 ±22-4/ | 194/106 | 164/92 | 158/90 | 154/96 | 198/102 |
| 70-8±9.6 | 108.0±11.8 | 113.9±12.2 | ||||||
Values are mean ±SD.
* Mean of three values.
| Time (h) | Aldosterone (pmol/l) | Corticosterone (nmol/l) | 11-Deoxycorticosterone (pmol/l) | Cortisol (nmol/l) |
|---|---|---|---|---|
| 0800 | 718 | 33 | 6020 | 358 |
| 1200 | 469 | 21 | 4365 | 330 |
| 1645 | 469 | 23 | 4214 | 248 |
| 2200 | 828 | 21 | 2860 | 275 |
| 0010 | 221 | 18 | 2559 | 220 |
| 0300 | 883 | 24 | 3311 | 220 |
| 0800 | 718 | 51 | 4515 | 385 |
Effect of ACTH infusion
After suppression of endogenous ACTH secretion with dexamethasone (2 mg 9 h before and 2 mg 1 h before), basal plasma samples were taken and three consecutive rates of ACTH (Synacthen, Ciba, Horsham, West Sussex, UK) were infused, each for 1 h. In Table 4 and Fig. 3 the responses are compared with those of normal subjects treated in the same way. The lack of suppression of some steroid levels by dexamethasone in our patient has already been noted. The plasma cortisol levels achieved were approximately normal although starting from a much higher basal level. The levels of all other steroids measured, including those of aldosterone and 18-hydroxycortocosterone, rose much higher than in normal subjects. At the highest rate of infusion, respective approximate ratios with mean normal levels for cortisol and 11-deoxycortisol were 1 and 7. For corticosterone and 11-deoxycorticosterone they were 2.5 and 17. The relatively more vigorous responses of the 11-deoxycorticosteroids may suggest some deficiency of 11B- hydroxylase acitivity. After surgery, steroid responses returned to normal (Fig. 3).
Effect of angiotensin II infusion
In normal subjects, angiotensin II infusion stimulates the plasma concentrations of aldosterone and 18-hydroxycorticosterone (Table 5, Fig. 4) but does not affect those of other corticosteroids.In our patient, because she was hypertensive, the highest infusion rate was 4 ng/kg compared with 8 ng/kg, min in the normal subjects. However, some increase in plasma aldosterone and 18-hydroxycorticosterone concentrations occurred at
| Dose (mg qds) | Duration (d) | Aldosterone (pmol/l) | Corticosterone (nmol/l) | 11-Deoxycorticosterone (pmol/l) | Cortisol (nmol/l) |
|---|---|---|---|---|---|
| 0 | 718 | 51 | 4515 | 385 | |
| 0.5 | 2 | 359 | 1595 | 138 | |
| 0.5 | 7 | 414 | 27 | 2559 | 248 |
| 2.0 | 2 | 1104 | 24 | 3221 | 275 |
qds, Four times a day.
| Infusion rate (ug/h) | 0 | 0 | 0.25 | 0-8 | 2.5 |
| Cortisol (nmol/l) | 193 | 248 | 440 | 633 | 715 |
| (21.0±8.79) | (165.3± 77.9) | (354.2± 190-6) | (550-0±251.7) | ||
| 11-Deoxycortisol (pmol/1) | 1234 | 2267 | 8266 | 22042 | |
| (660.1±410.0) | (1280-0± 782.1) | (2758.1±1670-6) (3294.8±1169.4) | |||
| Corticosterone (nmol/l) | 16 | 15 | 68 (11:2± 10-6) | 115 | 128 |
| (4.6±4.6) | (25.5±13.7) | (52.2±28.1) | |||
| 11-Deoxycorticosterone | 5117 | 4515 | 11649 | 18722 | 29829 |
| (pmol/l) | (63.2±15.9) | (608-0±270·8) | (1116-7± 549.5) | (1754.8±955.6) | |
| 18-Hydroxycorticosterone | 2239 | 3003 | 8463 | 13787 | 10101 |
| (pmol/l) | (259·3±57·8) | (789-8±173.3) | |||
| Aldosterone (pmol/l) | 635 (118.7±32.1) | 966 | 2153 (201.5±241-0) | 2953 (207-0±248.3) | 3119 (386-4±211.8) |
Figures in parentheses for normal subjects-mean +SD, n=7. All subjects were pretreated with dexamethasone.
all rates of infusion, with marked increase at rates of 2 and 4 ng/kg/min (Table 5). At these rates of infusion, there was also some increase in plasma cortisol concentration and rises of two-fold or more in the levels of the remaining compounds. After surgery, only plasma aldosterone and 18-hydroxycorticosterone levels responded (Fig. 4).
DISCUSSION
Suppressed plasma renin concentration, low total body and plasma potassium, with high normal or high sodium levels, high plasma bicarbonate concentration and hypertension are sufficient to establish a diagnosis of primary hypermineralocorticoidism. The basal levels of the three corticosteroids with mineralocorticoid activity, aldosterone, 11- deoxycorticosterone and corticosterone, were raised and their relative contribution to these abnormalities is difficult to assess. Similar levels of aldosterone (Ferriss et al., 1978) and 11-deoxycorticosterone (Powell-Jackson et al., 1974; Kelly et al., 1982) occurring independently are capable of causing the hypertension and biochemical abnormalities of hypermineralocorticoidism while in the few cases attributed to corticosterone (Fraser et al., 1968; Mills et al., 1980) levels were much higher than those reported here. Correction of the biochemical abnormalities by removal of the affected gland is further evidence: failure of blood pressure to respond either to amiloride or to surgery may have been due to the severity and long-term nature of the hypertension, a situation well-documented in cases of primary hyperaldosteronism (Ferriss et al., 1978). Hypersecretion of 11- deoxycorticosterone and corticosterone, not characteristic of hyperaldosteronism due to an adenoma, and the relatively large size of the tumour suggested the lesion was not benign (Neville & O’Hare, 1982), a suspicion confirmed by tumour histology.
Comparison with other forms of primary hyperaldosteronism
Interruption of treatment before infusion was not possible and thus the biochemical status of the patient may not have been strictly comparable with subjects in previous
Corticosterone (nmol/l)
18-Hydroxy-
corticosterone (pmol/l)
120
10 000
80
5000
40
0 -------- 0
0
30 000
H-Deoxycortisol (nmol/l)
II-Deoxycorticosterone (pmol/l)
20
16
20 000
12
8
10 000
4
0
0
700
3000
Cortisol (nmol/l)
500
Aldosterone (pmol/l)
2000
300
1000
100
0
0
0.25
0.8
2.5
0
0.25
0.8
2.5
ACTH infusion rate ( µg/h)
studies. However, basal plasma renin concentration remained suppressed despite treatment. Both the basal plasma steroid pattern and the changes caused by infusion of trophic agents were different, not only from normal but also from those seen in primary and idiopathic hyperaldosteronism. In these two latter conditions, only aldosterone and 18-hydroxycorticosterone secretion are raised. In primary hyperaldosteronism, plasma aldosterone concentration is more dependent upon ACTH secretion, as evidenced by circadian rhythm, effect of dexamethasone and response to infused ACTH (Wenting et al., 1978) while angiotensin II infusion evokes little response and may even be mildly inhibitory (Fraser et al., 1980) and also fails to alter plasma cortisol. In the patient, dexamethasone resulted in a partial and temporary reduction in steroid levels, suggesting partial autonomy, and ACTH elicited an abnormally large response in all steroids except cortisol. In contrast, angiotensin II infusion raised plasma aldosterone levels; a similar effect is seen in cases of idiopathic hyperaldosteronism (Fraser et al., 1981). There were also easily demonstrable increases in other corticosteroid levels. Although comparable data are not available for all steroids, in the other forms of hyperaldosteronism plasma cortisol does not respond to angiotensin II (Fraser et al., 1981). Intense stimulation of adrenal function by ACTH in the patient revealed changes in 11-deoxycortisol: cortisol and 11-deoxycorticosterone: corticosterone ratios which indicate that 118-hydroxylation may be a limiting reaction in the adrenal tumour.
| Infusion rate (ng/kg/min) | 0 | 0 | 0-5 | 1.0 | 2.0 | 4.0 | 8.0 |
| Aldosterone (pmol/l) | 800 | 690 | 966 | 911 | 1822 | 2153 | |
| (196-0±28.5) | (447-7± 192.0) | (643-9 ±244.6) | (963.5± 392.9) | ||||
| 18-Hydroxycorticosterone (pmol/l) | 2512 (266-4±71.5) | 2621 | 3003 | 4232 | 6416 (479-4±190-0) | 6689 (697-0±208.7) | (966.1±247.7) |
| Corticosterone (nmol/l) | 25 | 23 | 22 | 23 | 40 | 61 | |
| (14-0±6.2) | (10.5±6-5) | (12.8±6-1) | (12.8±8.6) | ||||
| 11-Deoxycorticosterone (pmol/l) | 3462 | 2860 | 3462 | 4365 | 7224 (351.0±206.3) | 8880 (330·8 +229-4) | (295-3±213-4) |
| (341.0±115-5) | |||||||
| Cortisol (nmol/l) | 220 | 220 | 220 | 248 | 330 (144.7±85.1) | 440 (160.6±61.8) | (177.9±65.5) |
| (169-4±115.5) | |||||||
| 11-Deoxycortisol (pmol/l) | 1521 (1156-9±461.7) | 2181 | 2554 | 3444 | 6888 (1043.5±201.2) | 3559 (998-5+479.9) | (1184.4± 595.3) |
Figures in parentheses for normal subjects-mean +SD, n=7.
18-Hydroxycorticosterone (pmol/l)
11-Deoxycorticosterone (pmol/l)
8000
11-Deoxycortisol (pmol/l)
6000
6000
6000
4000
4000
4000
2000
2000
2000
0
0
O
2100
Aldosterone (pmol/l)
Corticosterone (nmol/l)
60
Cortisol (nmol/l)
500
1200
40
-
20
3
250
300
€
0
1
O
0
0.5
2
4
8
0
0
0.5
2
4
8
0
0
0-5
2
4
8
Angiotensin II infusion rate (ng/kg/h)
Differential diagnosis: does ‘pure’ hyperaldosteronism due to adrenal carcinoma exist?
Although the levels of aldosterone and renin and the disturbance of electrolyte metabolism are indistinguishable from those of primary hyperaldosteronism due to benign adrenal lesions, the pattern of steroid secretion and its response to ACTH and to angiotensin II is clearly different. Hypersecretion of mineralocorticoids other than aldosterone is characteristic (Neville & O’Hare, 1982). A number of authors have claimed isolated production of aldosterone by malignant adrenal carcinomas (Santander et al., 1965; Salassa et al., 1975; Shah et al., 1975; Revach et al., 1977; Slee et al., 1983; Greathouse et al., 1984; Levine et al., 1984), but in none of these cases was plasma 11- deoxycorticosterone or corticosterone measured, nor were assays of their specific urinary metabolites, tetrahydro-11-deoxycorticosterone or tetrahydrocorticosterone, under- taken. By contrast, excess glucocorticoid and sex hormone production has usually been excluded (Neville & O’Hare, 1982).
The responses to trophic agents of patients described by Arteaga et al. (1984) showed similarities to and differences from our case. Plasma aldosterone and 18-hydroxycorticos- terone concentrations were increased to a comparable extent but those of 11- deoxycorticosterone, although supranormal, were less affected. Interestingly, the authors found a wider range of 11-deoxycorticosterone concentrations in patients with benign tumours than that shown in Table 1. Levels of corticosterone and cortisol in their three patients were normal. Response to dexamethasone was not reported but an i.v. bolus of ACTH failed to alter plasma aldosterone in the two patients tested and plasma 11- deoxycorticosterone in one. These results emphasize the heterogeneity of hypermineralo- corticoidism due to adrenocortical carcinoma.
In conclusion, patients who otherwise have typical clinical features of primary hyperaldosteronism with tumours larger than 3 cm in diameter by computerized tomography scan should be suspected of having adrenocortical carcinoma. Elevation of mineralocorticoids other than aldosterone is another characteristic feature, there being no good evidence in the literature for pure hyperaldosteronism as a result of this uncommon tumour. Since relatively simple assays for 11-deoxycorticosterone and corticosterone are now available, a more exhaustive initial analysis of tumour products may be a valuable adjunct to early diagnosis.
ACKNOWLEDGEMENTS
The technical assistance of Miss Mary Ingram and Mrs Christine Holloway is gratefully acknowledged. The manuscript was prepared by Miss Jean Braid.
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