High Plasma Renin Activities in Primary Aldosteronism with Malignant Hypertension A Case Report Taisuke IWAOKA, M.D., Teruhisa UMEDA, M.D., Tatsuo SATO, M.D., Shoichi KATSURAGI, M.D.,* and Tadao TAKEUCHI, M.D.* SUMMARY Primary aldosteronism usually shows mild hypertension and is characterized by suppression of plasma renin activity (PRA) and elevation of plasma aldosterone concentration (PAC). Almost all previously reported cases of malignant hypertension associated with primary aldosteronism showed low PRA.3)-6) However, only I case which showed high PRA was reported by Baglin et al in 1973.2) The patient reported below is the second case of primary aldosteronism with high PRA. A 34-year-old man was admitted to our clinic because of severe hypertension, renal insufficiency, and papilledema. Both PRA and PAC were abnormally high, 4.6ng/ml/hr and 23.0ng/100ml, respectively. Serum cortisol levels and urinary catecholamine excretion were within normal ranges. Serum K was normal ranging from 3.6 to 4.9mEq/L. In spite of strong anti-hypertensive drugs, peritoneal, and hemodialysis, the patient died of pulmonaly infection about 3 months later. Postmortem examination revealed a right adrenocortical tumor of 8mm in diameter. Histologically, the tumor consisted of large clear cells; that was adenomatous hyperplasia characteristic in primary aldosteronism. Neither juxtaglomerular tumor nor renal artery stenosis was found. We thought that PRA in primary aldosteronism could rise with progress of renal involvement as secondary changes due to long-standing and untreated hypertension. Normal serum K could be explained by the fact that retention of potassium due to severely disturbed renal function exceeded its loss through aldosterone action. It must be kept in mind that normokalemia and elevated PRA can be encountered under these circumstances. Additional Indexing Words: Plasma aldosterone concentration Renal insufficiency Adrenocortical tumor Aldosterone contents of the tumor From the Third Department of Internal Medicine and the Second Department of Pathology,* Medical School, Kumamoto University. Address for reprint: Taisuke Iwaoka, M.D., Third Department of Internal Medicine, Medical School, Kumamoto University, Honjyo 1-1-1, Kumamoto 860, Japan. Received for publication October 8, 1979. 423
424 IWAOKA, UMEDA, SATO, KATSURAGI AND TAKEUCHI Jap. Heart J. May, 1980 IN general, hypertension due to primary aldosteronism is mild and not rapidly progressive.1) In 1963, however, Kaplan reported the first case of primary aldosteronism which developed to malignant hypertension.2) Subsequently several such cases have been reported.3)-6) Even in those cases, plasma renin activity (PRA) always remained suppressed. It is well known that suppressed PRA is one of the most important criteria in making diagnosis of the disease. Therefore if the disease progresses to malignant hypertension accompanied with renal insufficiency yielding high PRA, correct diagnosis would be extremely difficult. Our patient presented here was thought to be the case, who showed severe hypertension with an encephalopathy, renal failure, and high plasma aldosterone concentration (PAC) with high PRA. Unfortunately, in spite of various treatments for malignant hypertension, the patient died. It was surprising that we found a typical aldosteronoma on the right adrenal cortex at autopsy. Therefore, it is our purpose to emphasize that the presence of such unusual case of primary aldosteronism must be considered in practice. CASE REPORT A 34-year-old man was admitted to the university hospital on April 26, 1978, for the treatment and more precise survey of his severe hypertension. Four years ago, he was noticed to have hypertension (systolic pressure 180mmHg) for the first time, but he did not receive any treatments because of no obvious symptoms. In March of 1978, he became to have continuous throbbing headache and frequent epistaxis, so he visited a doctor. At that time, blood pressure was 250/150mmHg, BUN 39.8mg/100ml, and serum creatinine 2.9mg/100ml, respectively. Serum Na was 138mEq/L, K 3.8mEq/L, Cl 91mEq/L, and fasting blood sugar was 95 mg/100ml. PRA at the resting supine position in the morning was 19.2ng/ml/hr (normal 0.25-1.4ng/ml/hr). In spite of various antihypertensive agents administered orally in the combination of trichlormethiazide 4mg, alphamethyldopa 750 mg, propranolol 30mg, and guanfacine 0.5mg/day, his blood pressure did not fall sufficiently, and then he was referred to our hospital. On admission, he complained of severe headache, anorexia, nausea, general fatigue, dizziness, and obscure sight. He was pale and thin, 168cm in hight and 45Kg in weight, with anemic conjunctiva. Blood pressure was 204/125mmHg. Optic fundi showed exudates, hemorrhages, retinal, and papilledema (KW-IV). Serum Na was 137mEq/L, K 4.1mEq/L, and Cl 96mEq/L. BUN was 65mg/ 100ml and serum creatinine was 6.2mg/100ml. PSP excretion for the first 15 min was below 5% and creatinine clearance was 11.4ml/min. PRA and PAC at the resting supine position were 4.6ng/ml/hr (normal 0.25-1.4ng/ml/hr) and 23.0 ng/100ml (normal 2.5-14.0ng/100ml), respectively. Serum cortisol concentration and urinary catecholamine output were normal. Antihypertensive therapy with furosemide, hydralazine, pindolol, clonidine, alphamethyldopa, and bethanidine was not effective on his blood pressure and it remained as high as 200/140
Vol. 21 PRIMARY ALDOSTERONISM WITH HIGH PLASMA RENIN 425 No. 3 Fig. 1. The clinical course of the patient after admission to our clinic. mmhg during first 4 weeks. At 28th hospital day, he had the first attack of cardiac failure with dyspnea, cough, and bloody sputa. To rescure the patient from the hypertensive emergency, repetitive injections of diazoxide, sodium nitroprusside, and angiotensin II analogue were attempted and the peritoneal dialysis was begun. Both peritoneal and hemodialysis seemed to be more effective to lower his blood pressure in combination with drug therapy (Fig. 1). However, BUN and serum creatinine remained 32-58mg/100ml and 2.2-3.9mg/100ml, respectively. The peritoneal dialysis over 5 weeks brought severe fungus infection in the peritoneal cavity. Finally, he died from pulmonary infection. Approximately 5 hours later, postmortem examination was carried out. The heart was hypertrophied prominently with the weight of 450Gm and the left ventricular wall was 19mm in thickness. Both kidneys did not contract and the weight was 130Gm each. The surface was granular. There was no apparent stenosis in the main renal arteries and segmental branches. Microscopically, glomeruli were considerably preserved and renal arterioles showed sclerosis with onion-like wall. Juxtaglomerular cells showed neither hyperplasia nor adenoma. Although the left adrenal gland was normal, the right one had small solitary tumor of 8mm in diameter (Fig. 2). The consistency of the tumor was elastic soft and the cut surface was so called canary yellow. Histologically, the clear large cells containing abundant lipids were dominant (Fig. 3). The tumor was not clearly encapsulated and the transitional zone showed hyperplasia. Pathological diagnosis was adenomatous hyperplasia as observed in primary aldosteronism. The contents of aldosterone both in the tumor and the adjacent normal adrenal cortex were measured by the method of Louis et al12) with following modifications. About 50mg of the tissue was treated by sonication with 2 ml of saline followed by the extraction with 5ml dichlormethane. Three ml of extract was evaporated to dryness and the residue was dissolved in 1ml aldosterone-free serum. One hundred Đl aliquot of the serum
426 IWAOKA, UMEDA, SATO, KATSURAGI AND TAKEUCHI Jap. Heart J. M ay, 1980 Fig. 2. The cut surface of the right adrenocortical adenoma of 8mm in diameter. Fig. 3. Photomicrograph of the right adrenal adenoma showing large cells with clear cytoplasm (hematoxylin and eoxin stain). was used for the radioimmunoassay of aldosterone.14) Aldosterone contents of the tumor and normal adrenal cortex were 38.2 and 37.5ng/g wet weight, respectively. DISCUSSION It is well known that primary aldosteronism is characterized by the following 3 conditions: 1) hyposecretion of renin which fails to increase appropriately during volume and salt restriction, 2) hypersecretion of aldosterone, and 3) normal excretion of urinary 17-OHCS and 17-KS. Excess aldosterone secreted from an adrenal adenoma causes characteristic symptoms,
Vol. 21 PRIMARY ALDOSTERONISM WITH HIGH PLASMA RENIN 427 No. 3 i.e., low renin type hypertension and hypokalemia manifesting headache, muscle weakness, polydipsia, polyuria, and metabolic alkalosis. The hypertension in primary aldosteronism is usually mild and seldom to develop to malignant hypertension.1) However, Kaplan reported a patient in 1963 who had shown clinically malignant hypertension and later have demonstrated to have an aldosteronoma on the left adrenal cortex.2) Thereafter several such cases of primary aldosteronism complicated with malignant hypertension were reported.3)-6) All these cases showed suppressed PRA and high PAC. Therefore, it might not be so difficult to suspect primary aldosteronism as an underlying disease of the malignant hypertension. In 1973, Baglin et al reported a case of primary aldosteronism who had initially shown mild hypertension with low PRA, but showed elevated PRA after development of malignant hypertension with severely disturbed renal function.7) Similarly, a case of 17 ƒ -hydroxylase deficiency with normal PRA which also seemed to be elevated after development of malignant hypertension was reported in 1977.17) Usually, this type of hypertension shows low PRA resulting from excess of some mineralocorticoids like deoxycorticosterone and corticosterone. In these 2 cases, it is considered the renin release from the juxtaglomerular cells was accelerated with rapidly deteriorating renal function despite of the suppression by excess mineralocorticoids. This hypothesis seemed to be well documented in our case. Conn et al have pointed out if malignant hypertension developed in a patient with previously asymptomatic primary aldosteronism, diagnosis of the latter condition is virtually impossible by laboratory findings only, otherwise an aldosteronoma is discovered at laparotomy or autopsy.1) As stated above, our case already showed malignant hypertension at admission. Serum potassium was normal or slightly elevated throughout his hospitalized period probably due to disturbed excretion of the potassium from the kidney. Since PRA and PAC were always high, we suspected renovascular or renoparenchymal hypertension or renin producing tumor. However, we had no chance for further examination to differentiate them because of his severe condition. Primary aldosteronism was not taken into consideration as an underlying disease of the malignant hypertension. Although it is well documented that an adrenal nodule is often discovered in hypertensive patients at autopsy as in our case, it is not always easy to judge it as having been the cause of hypertension.8)-11),15),16) In order to clarify the relationship between an adrenal adenoma and the hypertension, an attempt was made to prove high content of aldosterone in the tumor tissue. However, the content was not elevated and almost equivalent to that of the adjacent normal cortex. To this discrepancy, following explanations may be offered;
428 IWAOKA, UMEDA, SATO, KATSURAGI AND TAKEUCHI Jap. Heart J. M ay, 1980 1) Tissue aldosterone might be broken down or leaked during postmortem 5 hours until autopsy. 2) It is questionable that the adenoma had been sufficiently functioning just before death because of his emaciation. Fukuchi et al pointed out that in some cases of aldosteronoma there were no significant differences of aldosterone contents between tumor and non-tumor portions even in freshly obtained surgical specimens.13) Our patient seemed to be the case. In conclusion, we emphasize that primary aldosteronism could be one of the underlying diseases of malignant hypertension and could show high PRA resulted from the deteriorating renal function. REFERENCES 1. Conn JW, Knopf RDF, Nesbit RM: Clinical characteristics of primary aldosteronism from an analysis of 145 cases. Am J Surg 107: 159, 1964 2. Kaplan NM: Primary aldosteronism with malignant hypertension. New Engl J Med 269: 1282, 1963 3. DelGreco F, Dolkart R, Scom J, Method H: Association of accelerated (malignant) hypertension in a patient with primary aldosteronism. J Clin Endocrinol 26: 808, 1966 4. McAllister RG, Van Wan CW, Dayani K, Anderson WJ, Temple E, Michelakis AM, Coppage WS, Jr, Oates JA: Malignant hypertension: effect of therapy on renin and aldosterone. Circulat Res 28-29 (Suppl): 160, 1971 5. Baxter RH, Wang I: Malignant hypertension in a patient with Conn's syndrome. Scot M J 19: 161, 1974 6. Aloia JF, Beutow G: Malignant hypertension with aldosteronoma producing adenoma. Am J Med 268: 241, 1974 7. Baglin A, Weiss Y, Safter M, Milliez P: Hyperaldosteronisme Primaire avec Hypertension Maligne. Le Nouvelle Presse Medicale, 2 n 5, 1973 8. Flynn P: Adrenal cortical tumor with fulminating hypertension. J Irish Med Ass 39: 77, 1956 9. Laidiaw JC, Yendt ER, Gornall AG: Hypertension caused by renal artery occlusion simulating primary aldosteronism. Metabolism 9: 612, 1960 10. Eales L, Linder GC: Potassium-losing pyelonephritis and malignant hypertension: a case report with balance studies. Metabolism 8: 445, 1959 11. Hoet JJ, Molineaux L: Conn's syndrome: the effect of amphenone. Acta Endocrinol (Kobenhavn) 33: 375, 1960 12. Louis LH, Conn JW: Primary aldosteronism: content of adrenocortical steroids in adrenal tissue. Recent Prog Horm Res 17: 415, 1961 13. Fukuchi S, Nakajima K, Sasano N, Nakamura K: Microdetermination of corticosteroids in adrenocortical zones in various adrenal diseases. Folia Endocrinol Jap 53: 898, 1978 14. Haruyama K, Nakajima K, Fukuchi S, Saito M, Iinuma K: A simple method measuring plasma aldosterone by radioimmunoassay without extraction. Fol Endocrinol Jap 53: 810, 1977 15. Symington T: Functional Pathology of the Human Adrenal Gland. E S Livingstone, Edinburgh and London, p132, 1969 16. Sommers SC: Adrenal Gland. Pathology, 6th Ed, ed by Anderson WAD, CV Mosby, Saint Louis, 1971, Chapt 36 17. Kitajima Y, Konishi K, Saito I, Oka M, Saruta T, Matsuki S: A case of 17-hydroxylase deficiency associated with malignant hypertension. Fol Endocrinol Jap 386: 53, 1977