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ACTA CLINICA BELGICA -----------
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Hypermineralocorticoidism : The Sole Clinical Manifestation Of An Adrenal Cortical Carcinoma
R. Six, R. Leclercq & F. Noeninckx
To cite this article: R. Six, R. Leclercq & F. Noeninckx (1972) Hypermineralocorticoidism : The Sole Clinical Manifestation Of An Adrenal Cortical Carcinoma, Acta Clinica Belgica, 27:1-2, 426-434, DOI: 10.1080/17843286.1972.11716810
To link to this article: https://doi.org/10.1080/17843286.1972.11716810
Published online: 19 May 2016.
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HYPERMINERALOCORTICOIDISM : THE SOLE CLINICAL MANIFESTATION OF AN ADRENAL CORTICAL CARCINOMA
R. SIX (*), R. LECLERCQ ( ** ) & F. NOENINCKX ( *** ).
INTRODUCTION
Adrenal cortical carcinoma is an uncommon disease. It seems to affect women more frequently than men. This distinction could at least partially be due to the greater accuracy of diagnosis of endocrine disease in women (10, 12).
Especially in male patients, adrenal cortical carcinoma may develop without producing any endocrine symptoms. In these cases the clinical picture consists only of weight loss, lumbar pain, an abdominal mass and metastases.
Most cases however do develop an endocrine syndrome. This syn- drome has nearly always a mixed character : signs of hypercortisolism coexist with true virilization in the female patient (10. 13). Hypertension and hypokalemic alkalosis can develop here as part of the Cushing’s syn- drome, as well as in the cases due to an adenoma or bilateral hyperplasia of the adrenal cortex (6).
In rather exceptional cases, hypertension and hypokalemic alkalosis represent the sole symptoms of adrenal cortical carcinoma, imposing a dif- ferential diagnosis with primary hyperadosteronism due to a Conn adenoma.
CASE REPORT
A 54 year old female patient was admitted to the Middelheimziekenhuis on December 8, 1970. She was in good health until the summer of 1970, when she complained of rapidly increasing asthenia. She noticed the appearance of polydipsia and polyuria. She was short of breath and developed edema of the lower limbs. Medical advice was sought and a treatment with diuretics was started after arterial hypertension had been discovered. Several days prior to admission, asthenia had become extreme. The patient was unable to get up without help after she had acci- dentally fallen in her kitchen.
On admission the patient looked extremely weak. She was slightly short of breath. Pulse rate was 60 min. Blood pressure was 185/100 mm Hg. The liver was
(*) Dienst Inwendige Ziekten (Prof. P.P. Lambert), Universitair Ziekenhuis Brugmann, Brussel.
( ** ) Service de Chimie clinique, Hôpital universitaire St-Pierre, Bruxelles.
( *** ) Dienst Inwendige Ziekten, Middelheimziekenhuis. Antwerpen.
moderately enlarged (3 cm on the mid-clavicular line). No mass was found on abdo- minal examination. There was important edema of the lower limbs. The tendon reflexes were difficult to evoke. Pelvic examination was unremarkable.
No signs of hypercortisolism or virilization were demonstrable.
X-ray examination of the chest showed left ventricular hypertrophy without lung congestion. ECG showed flattened T waves in all leads. Retinal blood vessels were narrowed.
Laboratory examinations gave the following results : erythocyte sedimentation rate 17 mm/1 hour; Hb 12,9 g/100 ml; red blood cells 4.300.000/ mm2; leucocytes 9.300/mm2 (lymphocytes 8 %); urea 54 mg/100 ml; fasting glucose 82 mg/100 ml; sodium 144 mEq/L; potassium 1,7 mEq/L; bicarbonate 37,7 mEq/L; arterial blood pH 7.60; p CO2 34 mm Hg; creatinine clearance 48 ml/min.
Diuresis averaged 2000 ml.
All diuretic therapy was immediately withdrawn upon evidence of lowered serum potassium.
Up to 8 g potassium chloride were administered daily. Nevertheless serum potas- sium remained very low while abundant urinary excretion of potassium was noted. Alkalosis also persisted.
The determination of sweat electrolytes showed a lowered sodium/potassium ratio (0,6).
Plasma cortisol, measured by radiocompetition, was increased : 49,4 µg/100 ml (normal : 9-21). The I.V. administration of synthetic ACTH at « physiological , (200 ng) or « pharmacological (250 µg) doses no longer increased the cortisolemia after 10, 15, 20, 30 and 45 minutes.
Cortisol secretion rate was also very high : 98,9 mg/24 hours (normal : 10-25). Partition of 17 ketogenic corticoids into 11 desoxysteroids and 11 oxysteroids showed a clearly increased 11 desoxy/11 oxy ratio : 0,45 (normal : 0,03-0.32), proof of an abnormal excretion of cortisol precursor metabolites.
The urinary excretion of both 17 ketosteroids and 17 hydroxycorticoids was also high. Gas chromatographic fractionation of 17 ketosteroids (table 1) showed
| Patient | Normal | |
|---|---|---|
| 17 HYDROXYCORTICOIDS | 25,5 | 2,3 - 9,2 |
| 17 KETOSTEROIDS | 34,0 | 6,5 - 17,6 |
| PURE COMPOUNDS (gas chromatography) | ||
| dehydroepiandrosterone | 0,3 | 0,1 - 0,3 |
| androsterone | 2,9 | 0,3 - 5,8 |
| epiandrosterone | 0 | 0 - 0,5 |
| etiocholanolone | 2,4 | 0,6 - 5,9 |
| 11 ketoandrosterone | 2,7 | 0,1 - 0,7 |
| 11 ketoetiocholanolone | 0,9 | 0,2 - 1,9 |
| 11 hydroxyandrosterone | 5,9 | 0,5 - 2,0 |
| 11 hydroxyetiocholanolone | 3,0 | 0,2 - 1,3 |
| FREGNANEDIOL | 12,7 | 0,2 - 4,8 |
| PREGNANETRIOL | 2,3 | 0,1 - 2.1 |
an increased excretion of several steroids oxygenated in C 11. Urinary dehydroepi- androsterone was normal. Pregnanediol excretion was high. Urinary pregnanetriol
was only slightly increased but the chromatographic determination of the pregna- nolones (method of Dingemanse) showed a very high excretion : 9,1 mg/24 hours.
On a diet containing a normal amount of sodium, tetrahydroaldosterone excre- tion was increased : 829 ug/24 hours (normal : 46-95 µg). On a low sodium diet (10 mEq/24 hours), this excretion did not markedly change : 670 µg/24 hours.
The biological determination of plasma renin in the resting state gave a normal result : 8 U/L (normal : 4-22). After 4 hours of walking, renin showed a paradoxical decrease to 2 U.
Glucose tolerance was shown to be decreased by an oral glucose loading test. Insulin response to this glucose loading was abnormally low.
The patient was kept on bed rest. The edema of the lower limbs disappeared progressively and the patient felt less tired. Polydipsia and polyuria persisted. A thrombophlebitis of the left leg delayed the clinical evaluation.
An I.V. pyelography showed normal pyelo-caliceal cavities despite a clearly insufficient concentration of contrast medium. The right kidney was lowered by the presence of an important mass situated above its upper pole. The aortographic exami- nation showed a lowered right renal artery and confirmed the existence of this round mass which was surrounded by a dense arterial plexus.
Plasma HCO3 mEq/l
30
25
Plasma K mEq/l
4
2
Urinary volume l/ day
2
1
0
Urinary K + excretion
mEq/day
100
KČI mEq/day
0
100
0
13
21
29 Jan.
5 Feb.
Therapy
400 mg
SPIRONOLACTONE
The liver scan showed an important deformation of this organ.
At the end of January the mass became perceptible upon abdominal palpation. Patient complained of pain in the right lumbar region.
Administration of up to 400 mg of spironolactone a day. in addition to the important dosage of potassium chloride (5 to 8 g a day) resulted only in a very slow correction of hypokalemic alkalosis (fig. 1).
On March 3 a laparotomy by a large thoraco-abdominal incision revealed the existence of a hypervascularised mass extending behind the liver and tightly adhering to its fascia visceralis and to the inferior vena cava. There were no metastases. Biopsy of the mass resulted in an important hemorrhage. This biopsy confirmed the diagnosis of adrenocortical carcinoma.
Treatment with o p ’ DDD (2.2 bis (2 chlorophenyl-4 chlorophenyl) - 1.1 dichlo- roethane) was started on March 26 and continued until May 5. A total dose of 230 g was administered. Dosage was limited by gastric and intestinal intolerance. A slight somnolence was also noted. During this treatment the volume of the tumor. evaluated only by abdominal palpation, decreased noticeably. A reduction of the urinary excretion of both 17 ketosteroids and 17 hydroxycorticoids was noted (fig. 2). Tetrahydroaldosterone excretion was also reduced to a normal level (37 and 25 ug/ 24 hours) at the end of the treatment. We were however obliged to continue the administration of potassium chloride. Hypertension also persisted.
Steroid excretion mg/day
☐ 17 Keto
100
☒ 17 Hydroxy
75
50
25
0
25 Mar.
2 Jul.
230 g op’ DDD
On June 8 the patient presented an abrupt attack of pulmonary edema. From that moment on she developed progressively worsening heart failure. Despite prudent administration of digitalis and diuretics she died on July 28.
Post mortem examination confirmed the diagnosis of adrenal cortical carcinoma. The tumoral mass, weighing 650 g. presented large necrotic zones: no metastases were found.
In primary hyperaldosteronism due to a Conn adenoma the hypersecre- tion of aldosterone is responsible for the development of arterial hyperten- sion and hypokalemic alkalosis. In certain cases, corticosterone (3. 4) and 11 desoxycorticosterone (+ 6) are also produced in excess. Cortisol secre- tion is always found to be normal.
The hypermineralocorticoidism in cases of congenital hyperplasia of the adrenal cortex due to deficiency of 11 ß hydroxylase originates from hypersecretion of 11 desoxycorticosterone. The resulting extracellular fluid expansion depresses aldosterone production.
Hypersecretion of both corticosterone and 11 desoxycorticosterone leads to the development of hypertension and hypokalemic alkalosis in cases of congenital hyperplasia of the adrenal cortex due to 17 a hydroxylase deficiency. In exceptional cases aldosterone production is also abnormally high. On the contrary, as a rule, the renin - angiotensin - aldosterone system is depressed.
In these two types of congenital adrenal hyperplasia cortisol secretion is diminished. An increased urinary excretion of pregnanolones and of pregnanetriol proves the existence of an enzymatic block.
Cushing’s syndrome originating from adenoma or bilateral hyperplasia of the adrenal cortex is due to cortisol hypersecretion. In most cases the production of androgens is only slightly in excess. Symptoms of hirsutism are sometimes observed; they are not to be mistaken for the true virilization that exists in other diseases of the adrenal cortex.
According to the studies of Christy et Laragh (6) cortisol hypersecre- tion is directly responsible for hypokalemic alkalosis in these cases. Hyper- cortisolism can also lead to the development of hypertension by its sodium retaining effect, by increasing angiotensin production and possibly also by sensitizing the arterioles to the vasoconstrictive action of noradrenaline (5).
Neither the cases reported by Christy et Laragh (6) nor those studied by Biglieri et al. in 1963 (3) showed any hypersecretion of aldosterone. In 1968 Biglieri et al. (4) found hypersecretion of corticosterone and of 11 desoxycorticosterone in 1 of his 3 cases of Cushing’s syndrome due to bilateral hyperplasia of the adrenal cortex; in the 2 cases due to an ade- noma, mineralocorticoid secretion was found to be normal.
The secretory pattern of adrenal cortical carcinoma is characterized by a certain degree of anarchy.
Even in the case of « non functioning » tumors, where no endocrine symptoms exist, the production of corticoids can be abnormally high (13).
Androgen secretion, principally of dehydroepiandrosterone, is often important. In these conditions true virilization coexists with Cushing’s syndrome.
The tendency to develop hypokalemic alkalosis is more important in these cases than in the other etiological types of adrenal cortical hyper- function (5). In contradiction to previous reports (3. 6), where, even in cases with hypokalemic alkalosis, aldosterone and corticosterone secretion was generally found to be normal, Biglieri et al. (4) found an increased production of corticosterone in 2 cases of adrenal cortical carcinoma. In 2 of their 3 cases 11 desoxycorticosterone secretion was also abnormally high. The production of aldosterone was very important in 1 case, dimi- nished in an other and normal in 2 cases. In 2 cases of feminizing carci- noma of the adrenal cortex, 11 desoxycorticosterone secretion was increased. corticosterone production was normal and aldosterone secretion was diminished.
In 1964 West et al. (21) reported a case of feminizing adrenal cortical carcinoma where arterial hypertension seemed to be related to a deficiency of 11 ß hydroxylase, with resulting hypersecretion of 11 desoxycortico- sterone.
In certain cases, as reported by Crane and Harris (7) an enzymatic block with hypersecretion of 11 desoxycorticosterone, comparable to that observed in the case of congenital adrenal hyperplasia, could at least par- tially account for the development of the hypokalemic alkalosis.
In 1969 Alterman et al. (1) reported a case of adrenal cortical carci- noma where arterial hypertension and hypokalemic alkalosis were the only clinical manifestations of the disease. They reviewed 10 other cases in the literature where the clinical manifestations were entirely attributed to hyper- mineralocorticoidism. With only one exception, all these patients had an increased excretion of 17 hydroxycorticoids, of 17 ketosteroids or of both of them. Nevertheless they showed no clinical signs of hypercortisolism or of virilization.
Six of these patients had an increased production of aldosterone. An increased excretion of other corticoids made it possible to distinguish these cases from primary hyperaldosteronism.
Our own case seems to be strictly comparable to the patients reported by Alterman et al. From the clinical point of view the most characteristic features were : pronounced hypokalemia with muscular weakness, impor- tant urinary loss of potassium and arterial hypertension. There were no signs of hypercortisolism or of virilization.
The cortisolemia, the secretory rate of cortisol and the increased urin- ary excretion of 17 hydroxycorticoids nevertheless clearly showed a very important production of glucocorticoids. The increased excretion of 17 ketosteroids was due to an enhanced secretion of the catabolites of proges- terone; the production of androgens seemed to be normal.
The important urinary excretion of tetrahydroaldosterone was proof of a hypersecretion of aldosterone. The important excretion of pregnano- lones and of catabolites of cortisol precursors could result from an enzyma- tic block leading to corticosterone and 11 desoxycorticosterone hyperpro- duction.
The increased secretion of cortisol and aldosterone, the supposed hyperproduction of corticosterone and 11 desoxycorticosterone may all have contributed to the development of the clinical picture.
The rapid evolution and a relative lack of sensitivity of the end organs may have been responsible for the absence of clinical signs of hypercorti- solism.
Discussion of therapy
Surgical removal of the tumor appeared to be impossible. Adrenocor- tical carcinoma is reputed to have low sensibility to radiotherapy. We preferred to treat our patient with the chemotherapeutic agent o p ’ DDD.
In 1948 Nelson and Woodard (14) showed that the insecticide DDD had a cytolytic action on the adrenal cortex of the dog. Cueto et al. (8. 9) in 1958 attributed this action to the presence of a contaminating isomere o p ’ DDD. Bergenstal et al. (2) in 1960 used this isomere for the first time in man for the treatment of metastatic adrenocortical carcinoma. From this moment on o p ’ DDD was used regularly at high dosage in this indication (11. 15). The side effects were somnolence and gastro-intestinal intolerance. Southren et al. (17, 18) reported the results of low dosage treat- ment of cases of Cushing’s syndrome due to bilateral hyperplasia of the adrenal cortex.
In a recent report Temple et al. (19) insist that during long term low dosage treatment of bilateral adrenal hyperplasia, aldosterone secretion remains unaffected. This fact must be related to the studies in the dog of Villar and Tullner (20) who found early lesions in the zona reticulosa and fasciculata. After 6 days of treatment, the zona glomerulosa remained unchanged.
The important reduction of tetrahydroaldosterone excretion after o p ’ DDD therapy in our case proves the existence of an influence of high dosage administration on the production of aldosterone.
Roginsky and Schick (16) reported on the other hand a case of adrenal cortical insufficiency resulting from the treatment of a carcinoma of the adrenal cortex with o p ’ DDD and 5 fluoro-uracil.
ACKNOWLEDGMENT
The authors wish to express their appreciation to Prof. A. Verniory for review- ing the manuscript.
SUMMARY
An adrenocortical carcinoma in a 54 year old female patient is reported. Arte- rial hypertension, muscular weakness, hypokalemic alkalosis and urinary potassium loss were the prominent features. Although plasma corticol was increased, there were no clinical signs of hypercortisolism. Surgical removal of the tumor appeared to be impossible; o p ’ DDD therapy achieved to normalize temporarily the urinary excre- tion not only of 17 hydroxycorticoids and of 17 ketosteroids but also of tetrahydro- aldosterone.
The pathogenesis of the mineralocorticoid syndrome and the influence of o p ’ DDD on the adrenocortical aldosterone production are discussed.
RESUME
Les auteurs rapportent un carcinome cortico-surrénal chez une femme âgée de 54 ans. L’hypertension artérielle, la faiblesse musculaire, l’alcalose hypokaliémique et la perte urinaire de potassium constituent les éléments essentiels du tableau clinique. Bien que le cortisol plasmatique soit élevé il n’existe aucun signe clinique d’hyper- cortisolisme. L’exérèse chirurgicale de la tumeur s’est avérée impossible. L’excrétion urinaire non seulement des 17 hydroxycorticoïdes et des 17 cétostéroïdes mais aussi celle de la tétrahydroaldostérone a été ramenée temporairement à la normale par un traitement à l’ o p ’ DDD.
Les auteurs discutent la pathogénie du syndrome minéralocorticoïde et l’influence exercée par le traitement à l’ o p ’ DDD sur la sécrétion corticosurrénale d’aldosterone.
SAMENVATTING
Een geval van carcinoma van de bijnierschors bij een vrouw van 54 jaar wordt voorgesteld. Hypertensie, spierzwakte, hypokaliemische alkalose en urinair kaliumverlies maakten het ziektebeeld uit. Alhoewel de cortisolemie verhoogd was bestond er geen enkel klinisch teken van hypercortisolisme. De tumor kon niet weggenomen worden. Een behandeling met o p ’ DDD liet toe tijdelijk de urinaire excretie te normaliseren niet alleen van de 17 hydroxycorticoiden en van de 17 ketosteroiden maar ook deze van tetrahydroaldosterone.
De auteurs bespreken de pathogenese van het mineralocorticoid syndroom en de invloed van de behandeling met o p ’ DDD op de aldosteronesekretie van de bijnier.
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