SCINTIGRAPHY WITH 131]-19-IODOCHOLESTEROL IN ADRENAL DISEASE
An Evaluation
Hans Jørgensen, Nils Norman and Johan A. Sundsfjord
From the Medical Department B and the Hormone and Isotope Laboratory, Aker Hospital, Oslo, Norway
Abstract. Adrenal scintigraphy after i.v. injection of 1311- 19-iodocholesterol has been performed in 4 patients with primary aldosteronism, 5 with Cushing’s syndrome and 1 patient with phaeochromocytoma. In primary aldo- steronism a unilateral adrenocortical adenoma was demonstrated in 2 patients, while the method failed in 1 patient to visualize a tumour that was localized by meas- urements of aldosterone concentrations in the adrenal veins and by adrenal venography; in 1 patient none of the methods demonstrated a tumour. In Cushing’s syndrome, adrenal scintigraphy indicated bilateral adrenocortical hyperplasia in 1 patient and visualized the tumour in 2 patients with adrenocortical adenoma. In all patients with Cushing’s syndrome due to unilateral adrenocortical tumour, the accumulation of radioactivity in the contralat- eral adrenal was suppressed. However, a delayed and slight accumulation of the isotope in the suppressed gland contralateral to an adrenocortical carcinoma was mis- interpreted and led to exploration on the wrong side since the tumour did not concentrate radioactivity at all. The method failed in I patient to localize the adrenocortical tissue responsible for the relapse of Cushing’s syndrome after bilateral adrenalectomy for hyperplasia. In the pa- tient with phaeochromocytoma, no radioactivity was found on the tumour side due to compression of the adrenal cortex by the tumour. It is concluded that adrenal scintigraphy is a safe and valuable method for localization of adrenal tumours and their differentiation from adre- nocortical hyperplasia. Some diagnostic pitfalls do, however, exist, as demonstrated in this series of patients.
The final diagnosis of Cushing’s syndrome and of primary aldosteronism is based on hormone assays. In Cushing’s syndrome it may also be possible from suppression tests to differentiate between adrenocortical tumour and hyperplasia, whereas this cannot be done in primary aldosteronism (18). It has been shown that bilateral adrenocortical hyperplasia is present in 15-30% of cases with
primary aldosteronism (6, 9, 10, 11) and that these patients rarely benefit from surgical treatment (6, 11).
The scintigraphic procedure of Conn et al. (9, 13) with visualization of the adrenal glands after 1311- 19-iodocholesterol administration, would in pa- tients with Cushing’s syndrome mainly be of im- portance for tumour localization, while in patients with primary aldosteronism the additional informa- tion with regard to the presence of a tumour or bilateral hyperplasia would be significant.
In a preliminary report (21) we presented en- couraging results in two patients with primary aldosteronism in whom a unilateral adenoma was visualized by adrenal scintigraphy, thus making elective surgery possible. Further experience with the method has made it clear that the results are not always so unequivocal as in our first two cases. Our total series of 10 cases may be of interest in this connection, pointing to some pitfalls that can com- plicate the interpretation of adrenal scintigraphy.
METHODS
Plasma cortisol was measured fluorometrically (14), plasma aldosterone (20) and plasma renin activity (19) by radioimmunological methods. The determination of aldosterone secretion rate was performed as described by Aakvaag (1). Urinary 17-hydroxycorticosteroids were de- termined by the Norymberski procedure (3) with the modifications described by Metcalf (16). Adrenal scinti- graphy was performed as described previously (21). Pic- tures were taken with a gamma camera during a 4-10 days period following i.v. administration of 1311-19-iodocholes- terol. The localization of the adrenals in relation to the kidneys was established by gamma camera pictures of the latter during 131I-iodohippuran renography.
| Case no. | Sex | Age (y.) | ASR (µg/24 h) Supine | PA (pg/ml) Supine | PRA (ng ang.I/ml/h) | ||
|---|---|---|---|---|---|---|---|
| Supine | Upright | ||||||
| Preoperatively | |||||||
| 1 | 8 | 56 | Sodium depletion | 345 | 186 | 0.3 | 0.9 |
| Sodium loading | 503 | 205 | |||||
| Postoperatively | 15 | 1.6 | |||||
| Preoperatively | |||||||
| 2 | ? | 51 | Sodium depletion | 352 | 86 | 0.2 | 0.2 |
| Sodium loading | 725 | 108 | |||||
| Postoperatively | 54 | 0.8 | |||||
| Preoperatively | |||||||
| 3 | ? | 23 | Sodium depletion | 186 | 208 | 0.1 | 0.1 |
| Sodium loading | 76 | 133 | |||||
| Postoperatively | 47 | 1.1 | |||||
| 4 | 8 | 16 | Sodium depletion | 271 | 500 | 0.1 | 0.1 |
| Sodium loading | 254 | 171 | |||||
| Normal values (upright, | unrestricted diet) | 75-150 | 25-150 | <1.2 | |||
RESULTS
Primary aldosteronism (4 cases, Table I) All patients had arterial hypertension, hypo- kalaemia and low and suppressed plasma renin activity, as well as an increased plasma aldosterone concentration and a high aldosterone secretion rate that were not or only incompletely suppressed by sodium chloride (12 g in divided doses on each of 3 days). The criteria for the diagnosis are given in Table I. Cases 1 and 2 have been reported earlier (21).
Case 1
Female, 56 years of age. Adrenal vein catheterization was not performed as adrenal scintigraphy showed accumula- tion of radioactivity almost exclusively in the left adrenal, which contained an adenoma, 22 mm in diameter.
Case 2
Female, 51 years of age. A tumour in the right adrenal, 14 mm in diameter, was demonstrated by adrenal scinti- graphy, allowing elective surgical treatment. Previous catheterization of the right adrenal vein had not been successful.
Case 3
Female, 23 years of age. This woman had developed arter- ial hypertension and hypokalaemia during the year before the examination. Both plasma concentration and aldosterone secretion rate were reduced by sodium load- ing, but not suppressed to the extent seen normally. Fol- lowing the injection of 1311-cholesterol, a symmetrical ac- cumulation of radioactivity appeared in both adrenal re-
gions (Fig. 1). Adrenal phlebography, however, disclosed an adenoma in the right adrenal, and the plasma concen- tration of aldosterone was 10 times higher in the right than in the left adrenal vein. The right adrenal, containing an adenoma 20 mm in diameter, was subsequently removed. Two months postoperatively the serum kalium concentra- tion and BP were normal. The adrenal phlebography and
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the adrenalectomy were performed at Telemark Central Hospital, Skien, under supervision of the head of the Medical Department, B. Knutsen.
Case 4
Male, 17 years of age. Arterial hypertension and spon- taneous hypokalemia were first diagnosed two years before the present study. At adrenal scintigraphy, radio- activity was symmetrically localized to both adrenals. Scintigraphy repeated after dexamethasone 2 mg/day in divided doses given 2 days before and 2 days after the injection of 131I-cholesterol, showed the same pattern of uptake (Fig. 2). No tumour was demonstrated in the left adrenal by adrenal venography; catheterization of the right adrenal vein was unsuccessful. Treatment with spironolactone has recently been started.
Cushing’s syndrome (5 cases, Table II)
All patients presented clinical signs of Cushing’s syndrome. The results of the hormone assays are given in Table II.
Case 5
Female, 32 years of age. The hormone assays showed the pattern of bilateral adrenocortical hyperplasia. At adrenal scintigraphy the radioactivity accumulated symmetrically in both adrenals. Bilateral adrenalectomy was performed. The weights of the hyperplastic glands were 6.5 and 7.5 g, respectively.
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Case 6
Female, 39 years of age. The biochemical data, although inconclusive, were found to be compatible with the pres- ence of an adrenocortical tumour. After injection of 131I-cholesterol, a considerable accumulation of radio- activity to the right adrenal was found. No radioactivity was detected in the left adrenal, reflecting the sup- pressed function of this gland. The right adrenal was removed, containing an adrenocortical adenoma (weight 25 g). The patient had to be treated with cortisone for several months after the operation.
Case 7
Female, 27 years of age. The biochemical evaluation was inconclusive in the preoperative differentiation between adrenocortical tumour and hyperplasia. Adrenal scinti- graphy disclosed accumulation of radioactivity in the left adrenal gland exclusively, the right one being suppres- sed (Fig. 3). The left gland with an adenoma (weight 8 g) was removed. Cortisone had to be given for half a year postoperatively.
| Case no. | Age (y.) | Sex | Adrenocortical pathology | Plasma cortisol (ug/100 ml) | Urinary 17-OHCS (mg/24 h) | Basal urinary THS (mg/24 h) | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Basal at | 8 a.m. after dexamethasoneª | Basal | After | dexamethasoneª | |||||||
| 8 a.m. | 8 p.m. | I | II | I | II | ||||||
| 5 | 32 | 우 | Bilateral hyperplasia | 25.0 | 18.4 | 15.7 | 9.8 | 40.7 | 19.2 | 7.1 | 0.11 |
| 6 | 39 | 9 | Unilateral adenoma | 28.1 | 23.8 | 20.4 | 9.3 | 24.3 | - | 16.2 | 0.13 |
| 7 | 27 | ? | Unilateral adenoma | 29.7 | 27.5 | 27.0 | 7.4 | 25.1 | 28.5 | 31.6 | 0.13 |
| 8 | 35 | ở | Unilateral carcinoma | 71.0 | 66.5 | 41.1 | 39.0 | 116.0 | 128.3 | 124.0 | 0.69 |
| 9 | 51 | ? | Hyperplasia (ectopic) | 18.5 | 20.3 | 18.2 | 8.7 | 20.5 | 13.2 | 3.7 | 0.37 |
· I=2 mg/d. for 2 days, II=8 mg/d. for 2 days.
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Case 8
Male, 35 years of age. Clinical and biochemical evaluation indicated an adrenocortical tumour, and a high urinary excretion of tetrahydro-11-deoxycortisol suggested ma- lignancy. At adrenal scintigraphy, no radioactivity was visible in the adrenals until 10 days after injection of the isotope, when a small accumulation was seen in the left adrenal (Fig. 4) but no radioactivity on the right side. The left gland was explored, but disappointingly an atrophic gland was found. Subsequent exploration on the right side disclosed a metastasing adrenocortical carcinoma (weight 230 g). Remarkably this tumour, with a high hormone secretion, did not concentrate enough radioactive cholesterol to give a positive scintigram. Normally the relationship between free and esterified cholesterol in hu- man adrenals is 1:20 (7) but analysis of the removed tumour showed most of the cholesterol to be present in the free form. The adrenal cholesterol was analysed by S. Skrede, Department of Clinical Biochemistry, Riks- hospitalet, Oslo.
Case 9
Female, 51 years of age, with adrenocortical hyperplasia. Total, bilateral adrenalectomy had been performed 4 years before but Cushing’s syndrome relapsed after a re- mission of one year’s duration. Adrenal scintigraphy showed no radioactivity in the suprarenal regions. Exami- nation over the abdomen, however, disclosed a condensed radioactivity in the genital region. After removal of a tumour infiltrate, histological and scintigraphical examina- tion showed the radioactivity to be localized to a corpus luteum cyst in the left ovary. No adrenocortical tissue was demonstrated, and the excessive corticosteroid secretion is still present, probably from an ectopic site.
Phaeochromocytoma
Case 10
Female, 37 years of age. The diagnosis of phaeochromo- cytoma was established clinically and biochemically, and a tumour in the left adrenal was demonstrated by aortography. Adrenal scintigraphy showed normal ac- cumulation of radioactivity in the right gland (Fig. 5), while the left adrenal was not visualized. The left adrenal was removed, containing a phaeochromocytoma with a diameter of 70 mm. The adrenal cortex was found stretched to a thin rim lining the tumour.
DISCUSSION
Radiological methods often fail to visualize the small adrenal tumours, typical findings in primary aldosteronism. In the hands of an experienced radiologist, retrograde adrenal phlebography may demonstrate tumours that otherwise escape detec- tion (8, 15, 17) but unfortunately the method is accompanied by complications in about 5% of the cases (4). Hypertensive crisis as well as adrenocortical insufficiency have been described (4, 12). Depending on the method’s diagnostic accu- racy, adrenal scintigraphy could be an important advance, since it is performed without risks or dis- comfort to the patient.
The positive results reported by Conn et al. (9), and by ourselves (21) applying the method on pa-
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tients with primary aldosteronism have, however, been somewhat difficult to reconcile with what is known of the adrenocortical function under normal and pathological conditions. Before discussing the present cases it may therefore be of interest to review some basic facts.
Firstly, as evidenced by cortisol determinations in blood and urine, the cortisol production in the adrenal cortical tissue is usually not suppressed by an aldosterone-producing tumour unless the tumour is also producing cortisol. Secondly, since the nor- mal cortisol secretion rate (15-20 mg/24 h) is 20-30 times above the highest aldosterone secretion rate we have measured in a patient with primary al- dosteronism, it is surprising that the increased up- take of radioactivity in an aldosterone-producing tumour will give rise to a detectable difference in radioactivity between the two adrenals. The ob- served concentration in the small adenomas of sufficient radioactive cholesterol to be of diagnostic importance is rather difficult to explain.
Irrespective of these considerations, empirically, the method of adrenal scintigraphy is obviously able, at least in some patients, to disclose the in- creased accumulation of radioactivity in such a tumour, as was the case in patients 1 and 2. It is,
however, evident from the findings in patient 3, in whom the tumour was demonstrated by adrenal venography only, that a symmetrical concentration of radioactivity in both adrenals does not rule out the presence of a unilateral tumour.
Conn et al. (9) have reported on a patient with primary aldosteronism and symmetrical accumula- tion of radioactive cholesterol to both adrenals, in whom a unilateral adenoma was visualized by adrenal scintigraphy repeated after suppression of the cortisol production with dexamethasone. The inability of dexamethasone to suppress the accumu- lation of radioactivity in the adrenals in case 4 could mean that the primary aldosteronism in this patient was due to bilateral adrenocortical hyperplasia. The duration and timing of dexamethasone administra- tion in relation to the injection of radioactive cholesterol could, however, be a factor of im- portance. As adrenal radioactivity usually becomes visible from the third day after injection of 1311- -cholesterol and is maximal on the 6th or 7th day, dexamethasone should probably be given 2 days before and at least 5-6 days after injection of the isotope to assure adequate suppression of the cortisol production. It is our opinion that until further experience is gained with scintigraphy after dexamethasone suppression, catheterization with determination of plasma concentrations of al- dosterone and cortisol from both adrenal veins combined with adrenal venography should be performed preoperatively in all patients with pri- mary aldosteronism in whom adrenal scintigraphy is unable to localize a unilateral tumour, even when performed during administration of dexametha- sone. Possibly the diagnostic accuaracy of adre- nal scintigraphy could also be improved by adopting more objective methods for quantitation of the adrenal radioactivity.
Presumably the localization of an adrenal tumour as well as its differentiation from bilateral ad- renocortical hyperplasia would be more accurate in patients with Cushing’s syndrome. In bilateral hyperplasia a symmetrical concentration of radio- activity in both adrenals was to be expected. In the tumour cases the radioactivity is supposed to accumulate predominantly in the tumour, the func- tion of the contralateral adrenal being suppressed. It is difficult to see how these assumptions could be wrong when the glucocorticoid excess is due to bilateral adrenocortical hyperplasia. The adrenal scintigraphy in case 5, the only patient in this cate-
gory we have examined, is in agreement with this, as are the results reported by Lieberman et al. (13).
In the two patients with Cushing’s syndrome caused by an adrenocortical adenoma, the heavy concentration of radioactivity to one adrenal left no doubt of the tumour side. In addition to the diagnos- tic value, the lack of accumulation of radioactivity in the contralateral adrenal, implying a suppressed function, also predicted that postoperative substitu- tion therapy with corticosteroids would be neces- sary.
So far our presuppositions hold true. In the pa- tient with adrenocortical carcinoma, however, there was no scintigraphically detectable radioactiv- ity in the large, hormone-secreting tumour. A slight and delayed accumulation of 131I-cholesterol in the contralateral, atrophic gland was misinterpreted, leading to exploration on the wrong side. The reason why radioactive cholesterol was not con- centrated in the tumour probably was a high cholesterol turnover, with increased synthesis and secretion of corticosteroid hormones and their pre- cursors. The high cholesterol turnover was indi- cated not only by increased concentration of hormones in blood and urine, but also by the finding that most of the cholesterol in the tumour was pres- ent as free, non-esterified cholesterol. These obser- vations-no accumulation of radioactivity in the adrenocortical tumour and suppression of the con- tralateral gland in two patients with adrenocortical carcinoma and one with adrenocortical adeno- ma-have also been made by others (2, 13) and are probably typical findings in tumours with a high endocrine activity. Such a scintigraphical pattern represents a diagnostic pitfall and radiological methods will have to be adopted for correct side localization of the tumour.
That the method is also applicable for the locali- zation of phaeochromocytomas is demonstrated by case 10. The lack of radioactivity on the tumour side was due to compression of the adrenocortical cortex by the phaeochromocytoma. Identical find- ings in two patients with phaeochromocytoma have been reported by Anderson and Beierwaltes (2).
The visualization of adrenal remnants or ectopic adrenocortical tissue represents another problem not resolved by radiographical methods. Theoreti- cally scintigraphy should be an ideal method, and successful localization of adrenal remnants after “total” adrenalectomy for adrenocortical hyper- plasia has been demonstrated (2, 13). Unfortunate-
ly, in our patient with relapse of Cushing’s syn- drome after bilateral adrenalectomy (no. 9), we did not have the same success. The uptake of radioac- tive cholesterol in an ovarian corpus luteum cyst was mistaken for radioactivity in ectopic adreno- cortical tissue. Since the ovarian hormones are syn- thetized from cholesterol, a concentration of cir- culating cholesterol to the ovaries is not surprising. The important question, which still remains to be settled, is whether accumulation of 1311-cholesterol in the gonads regularly takes place and if it could be teratogenous in fertile patients. The radiation doses to ovaries and testes given by Beierwaltes et al. (5) may seem unimportant, but further studies are needed as the calculations are based on observa- tions in only one patient. The inability to detect any radioactivity in the genital regions in two men and five women in whom we later performed adrenal scintigraphy, could indicate that the risk is negli- gible. We prefer, however, to administer 131]- cholesterol early in the follicular phase in men- struating women, and to perform the examination only in patients in whom the actual diagnosis is established clinically and by hormone assays.
In conclusion, we consider adrenal scintigraphy with 1311-19-cholesterol to be a valuable method which, in most cases of Cushing’s syndrome, will localize an adrenocortical tumour and distinguish tumour from bilateral adrenocortical hyperplasia. In primary aldosteronism the diagnostic accuracy of the method is less, but may possibly be improved when performed under dexamethasone suppression and with more exact measurement of the radioactiv- ity in each adrenal. When no side difference is found, determinations of hormone concentrations in both adrenal veins combined with adrenal phlebography should be performed.
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