SYMPTOMATIC HYPOKALEMIC ALKALOSIS IN HYPERADRENOCORTICISM SECONDARY TO CARCINOMA OF THE PROSTATE
THOMAS C. HALL, MD*
A case of hyperadrenocorticism in association with prostatic cancer is described. This rare condition was complicated further by markedly increased severity of previously controlled diabetes. Hypokalemic alkalosis, secondary to these condi- tions, progressed to coma mimicking intracranial pathology. The severity and complexity of these relations indicates the importance of considering cancer as a process with multiple metabolic overtones.
S YMPTOMATIC METABOLIC DISTURBANCES MAY accompany many types of cancer.1 Hyper- adrenocorticism has been commonly de- scribed in conjunction with adenocarcinoma of the pancreas,2 lung9 and, on two previous occasions, the prostate.4, 10 Some prostatic tumors have also been reported to secrete prod- ucts which lyse fibrin.7 Since most of the evidences of adrenal hyperfunction seem un- related to direct involvement of the adrenal cortex by tumor, the production of an ACTH-like substance by the tumor itself has been postulated.5 In some instances the clini- cal manifestations of the “paraneoplastic” endocrinopathy have over shadowed the di- rect effects of the cancer itself.
Somers has reported that carcinoma of the prostate is associated with a high incidence of pathologic changes suggesting pituitary- adrenocortical hyperfunction;8 however, it has not been described as a cancer which frequently gives rise to clinical hyperadreno- cortical syndromes. The present case is of interest because of the rarity with which prostatic carcinomas produce a Cushing’s type syndrome, because of the unusual form in which the clinical manifestations of adren- ocorticism presented themselves and because of the remarkable clinical response to treat- ment of the secondary endocrine effects in the absence of specific antitumor effects.
From the Departments of Medicine, Harvard Medi- cal School, Boston, and McLean Hospital, Belmont, Mass.
Supported in part by grants CA 04739 and C 6516 of the National Institutes of Health.
* Assistant Clinical Professor of Medicine, Harvard Medical School, formerly Consulting Internist, Mc- Lean Hospital. Present address: Children’s Cancer Research Foundation, Boston, Mass.
Received for publication April 10, 1967.
CASE REPORT
A 63-year old man was transferred to the McLean Hospital because of unmanageable hypomanic behavior. Three years previously he had developed locally inoperable prostatic adenocarcinoma. Following treatment with orchiectomy and oral diethylstilbestrol daily, all evidences of neoplasm disappeared. At the time of orchiectomy mild hyperglycemia and glycosuria was noted; these were controlled by diet. Two months before the present ill- ness examination was negative except for moderate gynecomastia.
Shortly thereafter he developed polydipsia, polyuria, 4+ glycosuria and hyperglycemia. Hypomanic behavior appeared and he re- sisted attempts to control his diabetic status with Orinase and NPH insulin. A 20-pound weight loss occurred and massive peripheral edema appeared. He was admitted to a gen- eral hospital for control of diabetes. At this time he had glycosuria, a fasting blood sugar of 214 mg/100 ml, a normal alkaline and acid phosphatase, including prostatic fraction, NPN of 36, Na of 136, K of 4.4, chloride of 85 and CO2 of 39.9. His behavior was boister- ous, hypomanic and at times agitated and disoriented. He was transferred to McLean Hospital.
On admission physical examination showed peripheral edema, hepatomegaly and induration of the prostatic bed. There was uncontrolled hyperglycemia at 228; K+ was 2.6; Cl was 84; Na was 132 and CO2 was 31. He was given tranquilizers and placed on a “by-test” regimen of regular insulin. A low- salt diet and mercurial diuretics and oral KCI were started. He lost 20 pounds of
edema fluid; his hyperglycemia was controlled and his hypomania disappeared. During one week normal behavior was succeeded by sluggishness and, finally, progressive weakness and stupor. Because of the possibility that a fall might have occurred unobserved, skull films were taken which were interpreted as showing a calcified pineal shifted from the midline. Lumbar puncture showed xantho- chromia and a protein of 55 mg/100 ml. EEG showed diffuse slowing without locali- zation. Neurologic and neurosurgical con- sultants thought a subdural hematoma likely and recommended burr holes; the patient’s head was shaved and he was prepared for neurosurgery on the ninth postadmission day. During his course to this point, serial bio- chemical determinations had been taken every third day. These showed a progressive fall in his potassium from 4.4 to 2.6, 2.1 and finally 2.0 meq per liter. This was accom- panied by a fall of chlorides from 85 to 68 meq per liter and a rise of CO2 to 31 meq per liter. NPN had risen from 39 to 49 mg per 100 ml.
Operation was cancelled and K replace- ment instituted which corrected his hypoka- lemic alkalosis. His mental state then re- turned to normal. Review of the skull films showed an intradiploic bone island which mimicked displacement of the pineal.
Thereafter diabetes remained difficult to control and mercurial diuretics, which were effective in controlling peripheral edema, ag- gravated a tendency to hypokalemia; mild alkalosis continued with CO2 of 41 and pH of 7.6. Oral intake of K exceeded 100 meq per day and urinary K output continued high at 60 meq per liter. Glycosuria in excess of 50 Gm per day persisted in spite of good control of blood sugars with NPH insulin. Hypokalemic alkalosis increased in spite of 70 meq of dietary K supplemented by 160 meq K daily orally. Muscle wasting and weak- ness appeared but hypertension and a Cush- ing’s disease facies were absent.
Because of persistent hepatomegaly a search for evidence of active metastatic can- cer was undertaken; IVP, upper GI series, small bowel follow-up and barium enema were all negative. A chest film showed full- ness of the right hilum. Repeat EEG showed an abnormal tracing with diffuse theta and random sharp waves in the right temporal activity. A percutaneous liver biopsy was per- formed which showed mild fatty infiltration
and no tumor nor hemochromatosis. A repeat examination of the prostatic bed showed changes suggestive of progressive disease dur- ing two months. Urinary 17 oxosteroids were reported as elevated to 30 mg per 24 hours. His final chemistries showed FBS 131, Na 140, K 5, CO2 34 and NPN 50. He became coma- tose, hypotensive and died quietly 2 months after the onset of hyperglycemia and 6 weeks after plans to drill burr holes had been can- celled.
Postmortem examination showed diffuse pelvic extension of prostatic adenocarcinoma. There was almost complete replacement of the liver by metastases from the prostate; the needle track of the liver biopsy could be seen passing between the nodular metastases. The right and left adrenals were hypertrophic, weighing 18 Gm each but showing no involve- ment by tumor; this is over twice the average total adrenal weight for patients with pro- static cancer.8 The chest was free of tumor.
DISCUSSION
Metastatic carcinoma may cause hyperad- renocorticism. Hyperadrenocorticism may cause hypokalemic alkalosis. The vigorous treatment of diabetes may cause severe hypo- kalemic alkalosis.3 Lubash et al. have reported that the latter causes stupor mimicking sub- dural hematoma.” The present case is the first in which the three clinical possibilities have been reported within one patient and in which the latter two have responded to vigorous metabolic replacement therapy. This patient is unusual because of the rarity of hyperadrenocorticism in prostatic carcinoma; in one other reported case the secretion of an ACTH-like substance was postulated be- cause of findings similar to those in the present patient-no direct involvement of the adrenal by tumor, elevated 24-hour ex- cretion of adrenal cortical hormones and hypokalemic alkalosis.10 In the present pa- tient evidence for overproduction of glucocorticoids included the appearance of insulin-refractory diabetes and excessive glu- coneogenesis with hypoglycemia and muscle wasting.
Replacement treatment of the hypokalemic alkalosis resulted in restoration of mental function, in spite of continued high K losses in urine. Hence, it appears that neither dia- betes alone nor the mineralocorticoid action of the adrenals was sufficient to induce the
clinical signs of mania, disorientation and stupor.
Two tests which gave wrong leads as to the pathophysiologic mechanism involved were the lumbar puncture and skull films which indicated the likelihood of a subdural hematoma and the percutaneous liver biopsy which was negative in spite of almost com- plete replacement of the liver.
CONCLUSIONS
Sudden metabolic disturbances occurring in patients with cancer may herald the onset of a “paraneoplastic syndrome.” The proper management of such metabolic consequences of the neoplastic state is an important part of the total care of the patient with cancer.
REFERENCES
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2. Hallwright, G. P., North, K. A. K., and Reid, J. D .: Pigmentation and Cushing’s syndrome due to malignant tumor of the pancreas. J. Clin. Endocr. 24:496-500, 1964.
3. Harrison, T. R .: Principals of Internal Medicine, 4th ed. N.Y., McGraw-Hill Book Co., 1962; p. 654.
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5. Law, D. H., Liddle, G. W., Scott, H. W., Jr., and Tauber, S. D .: Ectopic production of multiple hor- mones (ACTH, MSH and Gastrin) by a single ma- lignant tumor. New Eng. J. Med. 273:292-296, 1965.
6. Lubash, G. D., Cohen, B. D., Young, C. W., Silver- man, G. M., and Rubin, A. L .: Severe metabolic alka- losis with neurologic abnormalities. Ibid. 258:1050- 1052, 1958.
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8. Sommers, S. C .: Endocrine changes with prostatic carcinoma. Ibid. 10: 345-358, 1957.
9. Thorne, M. G .: Cushing’s syndrome associated with bronchial carcinoma. Guy’s Hosp. Rep. 101:251- 272, 1952.
10. Webster, G. D., Jr., Touchstone, J. C., and Suzuki, M .: Adrenocortical hyperplasia occuring with metastatic carcinoma of the prostate-Report of a case exhibiting increased urinary aldosterone and gluco- corticoid excretion. J. Clin. Endocr. 19:967-979, 1959.