Hyperaldosteronism and Hyperprogesteronism in a Cat with an Adrenal Cortical Carcinoma
Amy E. DeClue, Lee A. Breshears, Ingrid D. Pardo, Marie E. Kerl, Jonathan Perlis, and Leah A. Cohn
A 12-year-old castrated male, domestic long-haired cat weighing 4.93 kg was evaluated for weight loss and an abdominal mass. The cat had a 3-month history of di- abetes mellitus treated with 2 units of ultralente insulina twice daily. Hypokalemia, mild azotemia, mild hypergly- cemia, and glucosuria were noted on recent laboratory eval- uations.
Physical examination findings included a thin, greasy haircoat, dermal and epidermal atrophy, cutaneous fragility, a III/VI left peristernal systolic heart murmur, and a cranial abdominal mass. Clinicopathologic abnormalities included hyperglycemia (460 mg/dL, reference range 52-153 mg/ dL), azotemia (blood urea nitrogen 76 mg/dL, reference range 17-35 mg/dL; creatinine 3.1 mg/dL, reference range 0.50-2.20 mg/dL), hypokalemia (2.5 mmol/L, reference range 3.0-4.0 mmol/L), hypochloremia (110 mmol/L, ref- erence range 114-122 mmol/L), hyperphosphatemia (6.1 mmol/L, reference range 2.0-5.3 mmol/L), increased total CO2 (27 mmol/L, reference range 11-22 mmol/L), and glu- cosuria. Venous blood gas analysis was consistent with a metabolic alkalosis (pH 7.38, HCO3 = 28.2 mmol/L) with respiratory compensation (partial pressure of carbon diox- ide [Pco2] = 48.7). Serum total thyroxine (T4) concentra- tion, magnesium concentration, creatine phosphokinase ac- tivity, and CBC were within reference ranges. A mass cra- nial to the right kidney (Fig 1) and mild cardiomegaly were noted on abdominal and thoracic radiographs, respectively. The mass, measuring 2 × 2.5 cm by ultrasound, was iden- tified as the right adrenal gland (Fig 2). Echocardiography was unremarkable. Mild hypertension was identified on an initial reading (blood pressure 170 mm Hg, systolic). How- ever, considering the fractious nature of this cat during blood pressure measurement and a lack of ocular manifes- tations of hypertension, therapy was deemed unnecessary at the time.
Endocrinologic testing was performed to investigate functionality of the adrenal tumor. Results of low-dose dexamethasone suppression testing (0.01 mg/kg IV)b (rest- ing 0.6 µg/dL [16.6 nmol/L], reference range 0.0-5.0 µg/ dL [0.0-137.9 nmol/L]; 4 hours after 0.4 µg/dL [11.0 nmol/ L], reference range <1.4 µg/dL [<38.6 nmol/L]; 8 hours after 0.4 µg/dL [11.0 nmol/L], reference range <1.4 µg/ dL [<38.6 nmol/L]) were within reference ranges. Serum
aldosterone concentrationb was markedly increased (>3,329 pmol/L, reference range 194-388 pmol/L). Serum cortisol and androgen concentrations were measurede be- fore, 30 minutes after, and 1 hour after injection of synthetic ACTHª (150 µg IV). Progesterone was increased before ACTH (9.95 ng/ml, reference range 0.06-0.70 ng/ml), 30 minutes after ACTH (14.7 ng/mL, reference range 0.9-4.6 ng/ml), and 1 hour after ACTH (16.8 ng/ml, reference range 0.9-4.6 ng/ml). Cortisol concentrations were below the reference range before (6.1 ng/ml [16.8 nmol/L], ref- erence range 9.8-59 ng/ml [27.0-162.8 nmol/L]), 30 min- utes after (6.7 ng/mL [18.48 nmol/L], reference range 95- 183 ng/mL [262.1-504.9 nmol/L]), and 60 minutes after (7.0 ng/ml [19.31 nmol/L], reference range 9.8-59 ng/ml [27.0-162.8 nmol/L]) administration of ACTH. No increas- es in testosterone, androstenedione, estradiol, or 17-OH progesterone were noted before or after ACTH stimulation.
Surgical exploration and tumor removal was planned. Potassium gluconatee supplementation was initiated (2 mEq q24h PO) and insulin therapy continued pending surgery. Serum potassium concentrations did not normalize before surgery despite supplementation. At surgery, the right ad- renal gland contained a 1.5 × 2.0-cm mass that appeared encapsulated but closely associated with the vena cava. Ex- tension of tumor thrombi was evident into the phenicoab- dominal vein but not into the vena cava. The phenicoab- dominal vein was ligated at the level of the vena cava and tumor excision was accomplished with a combination of blunt dissection and the use of hemoclips. The left adrenal gland was grossly normal, and no evidence was found of gross metastasis to any abdominal organ. Histopathology of the right adrenal gland (Fig 3) was consistent with a cortical adrenal gland carcinoma.
Initial postoperative treatment included insulin, dexa- methasonef (0.25 mg/kg q24h IV), and a balanced electro- lyte solutions with potassium supplementation (20 mEq/L IV). Insulin administration was discontinued after the 1st postoperative day because glucose concentrations normal- ized. Mild anemia was apparent the day after surgery (PCV 20%, reference range 25-35%) but the cat’s appetite and attitude were good. Two days postoperatively, serum al- dosterone concentration was below the reference range (28.0 pmol/L, reference range 194-388 pmol/L), serum po- tassium was within the reference range, and serum sodium was increased (163 mmol/L, reference range 149-159 mmol/L). On the 3rd postoperative day, the cat developed mild abdominal transudate and hematocrit decreased (15%, reference range 25-35%), although activity and appetite re- mained normal. Overhydration was suspected and IV fluids were discontinued. Twelve hours later, the cat became acutely stuperous. Cardiac arrest ensued and resuscitation was unsuccessful. Postmortem examination was not per- mitted by the owners.
Carcinoma of the adrenal cortex secreting either cortisol,
From the Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, (DeClue, Breshears, Kerl, Perlis, Cohn), and the Department of Pathobiology, Veterinary Medical Diagnostic Lab- oratory (Pardo), University of Missouri, Columbia, MO.
Reprint requests: Leah A. Cohn, DVM, PhD, DACVIM, 379 E Cam- pus Drive, University of Missouri, Columbia, MO 65211; e-mail: cohnl@missouri.edu.
Copyright @ 2005 by the American College of Veterinary Internal Medicine
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b
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progesterone, cortisol and progesterone, aldosterone, or tes- tosterone have been reported in cats.1-4 Pheochromocytoma, a tumor of the adrenal medulla, also has been reported.4 In this case, primary hyperaldosteronism and hyperprogester- onism were diagnosed based on appropriate clinicopatho- logic abnormalities, increased serum aldosterone and pro- gesterone concentration, identification of an adrenal mass, histopathologic confirmation of a cortical adrenal gland car- cinoma, and decrease in aldosterone concentrations post- operatively.
Because a tumor secreting these 2 differing hormones would be unusual, secondary hyperaldosteronism via acti- vation of the renin-angiotension system by cardiac or renal
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disease was suspected initially. Ideally, serum renin con- centrations would have been measured to differentiate pri- mary from secondary hyperaldosteronism.5 Unfortunately, renin measurement in cats is no longer commercially avail- able. Cardiac disease was ruled out based on normal echo- cardiogram. Although the cat did have moderate azotemia, chronic renal failure was considered an unlikely cause of the magnitude of hyperaldosteronism demonstrated in this cat.6 Other causes of increased renin, including hepatic cir- rhosis, Bartter syndrome, and renal artery stenosis seemed unlikely for a variety of reasons. The dramatic decline in aldosterone concentration after adrenalectomy further sup- ported the diagnosis of primary hyperaldosteronism in this cat. Had hyperaldosteronism been simply a secondary re-
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sponse to increased renin concentration, the remaining functional adrenal gland would have been expected to con- tinue to secrete excess aldosterone.
Although different adrenal cortical cell types normally produce aldosterone and progesterone, adrenal cortical ad- enomas in humans have been demonstrated to produce combinations of aldosterone, 18-hydroxycorticosterone, corticosterone, deoxycorticosterone, 18-hydroxydeoxycor- ticosterone, cortisol, 17-hydroxyprogesterone, and proges- terone.7 The tumor in this cat may have been producing multiple hormones. Alternatively, hyperprogesteronism may represent excess intermediates of aldosterone produc- tion. The pathway for aldosterone production in human al- dosterone-secreting adrenal tumors is cholesterol → pro- gesterone → 11-deoxycorticosterone → corticosterone → 18-hydroxycorticosterone → aldosterone.8 In humans with primary hyperaldosteronism, the intermediate steps in al- dosterone biosynthesis (progesterone, deoxycorticosterone, and corticosterone) and other steroid hormones (17a-hy- droxyprogesterone, 11-deoxycortisol, and cortisol) may be hypersensitive to ACTH.9,10
Aldosterone is the major mineralocorticoid produced in the zona glomerulosa of the adrenal cortex.11 Secretion of aldosterone is principally controlled by increases in serum potassium concentrations and activation of the renin-angio- tensin system with minimal stimulation from ACTH secre- tion or hyponatremia.11 Aldosterone promotes renal potas- sium secretion while conserving sodium.11,12 Secretion of magnesium, hydrogen, and ammonia also are effected by aldosterone.2
Although not observed in this case, clinical signs of weakness, cervical ventroflexion, hypertension, mydriasis, and retinal detachment have been reported in cats with hy- peraldosteronism.2,4,5 Hypokalemia is the most consistent laboratory finding; alkalosis, hypophosphatemia, hypomag- nesemia, and increased serum creatine phosphokinase ac- tivity may be found as well.2,4,5,11,13 In this case, persistent hypokalemia, hypernatremia (after correction for hypergly- cemia), and metabolic alkalosis were observed. Despite the sodium-retaining effects of aldosterone, normonatremia is typically maintained through water conservation and the effects of atrial naturetic peptide.2,4,5,13 Hypertension was not observed but may occur secondary to intravascular vol- ume expansion from sodium and water conservation.4
Progesterone is produced in the zona fasciculata and re- ticularis of the adrenal cortex and serves as a precursor for androgens, estrogens, and cortisol. Progesterone may com- petitively bind to cortisol-binding proteins in the circulation resulting in increased free cortisol and, therefore, may sim- ulate the actions of cortisol.3,4 Dermal and epidermal atro- phy along with cutaneous fragility observed in this cat are classically associated with hyperprogesteronism. Symmetric alopecia is also common but was not observed in this case.3 Because of the suppressive effects of progesterone on the adrenocortical axis, cortisol concentrations were below the reference range in this cat before and after ACTH stimu- lation, as has been reported in other cats with hyperpro- gesteronism.3,4,14
Diabetes mellitus was likely secondary to hyperproges- teronism, hyperaldosteronism, or both in this cat because hyperglycemia resolved after adrenalectomy. Carbohydrate
intolerance results from progesterone-mediated insulin an- tagonism3,4,15 and poorly regulated diabetes mellitus is a common finding in cats with hyperprogesteronism. Insulin resistance was suspected in a previous case report of a cat with primary hyperaldosteronism.2 Although it is likely that hyperprogesteronism contributed to diabetes mellitus in this case, it is unknown if hyperaldosteronism contributed as well.
Surgical removal of functional adrenal tumors is gener- ally considered the treatment of choice.4,16 Aminogluteth- iamide has been used to decrease progesterone production in cats before surgery or for cats that are poor surgical candidates.1 Cats with primary hyperaldosteronism have been managed in the short term with potassium supple- mentation and spironolactone administration.2,5,12,13 Surgical removal of the adrenal mass was attempted in this case with the goal of attaining cure. The cause of death was unknown. Although hematocrit had decreased over the last 2 days of life, there was little reason to believe that massive hemor- rhage occurred 3 days after surgery. Given the acute dete- rioration, a thromboembolic event was suspected. Although hypercortisolemia is known to increase the likelihood of thromboembolism, the effects of hyperprogesteronemia and hyperaldosteronemia on thromboembolism formation in cats are not known.
Footnotes
a Humulin U, Lilly, Indianapolis, IN
b Endocrinology section, Animal Health Diagnostic Laboratory, Mich- igan State University, East Lansing, MI
” Clinical Endocrinology Service, College of Veterinary Medicine, University of Tennessee, Knoxville, TN
d Cortrosyn, Organin, West Orange, NJ
e Tummil K, Daniels, St Petersburg, FL
f Dexamethasone injectable, Phoenix Pharmaceuticals, St Joseph, MO
& Normosol-R, Abbott Laboratories, North Chicago, IL
Acknowledgment
All work was completed at the University of Missouri.
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