Feline Addison's disease (Adrenal Insufficiency) See also, Adrenal gland
© Rand, J (2006) Problem-based feline medicine. Saunders Elsevier, Sydney
Hypoadrenocorticism, also known as Addison’s disease, is a very rare disease in cats. It has been reported in young to middle age cats, and neither a sex or breed predilection has been observed.
Causes
The disease is characterized by insufficient production of mineralocorticoids (primarily aldosterone) by the adrenal cortex (Fig.1). Mineralocorticoids regulate body water and electrolyte homeostasis by promoting renal retention of sodium and excretion of potassium and/or glucocorticoids (cortisol). Hypoadrenocorticism usually results from disease affecting both adrenal cortices and requires destruction of 85-90% of the adrenocortical cells before clinical signs of glucocorticoid and mineralocorticoid deficiency become obvious. Two types of adrenocortical insufficiency exist and are designated as primary hypoadrenocorticism and secondary hypoadrenocorticism based on causative agents.
Primary hypoadrenocorticism occurs from destruction of the adrenal cortex with resultant atrophy and fibrosis (Fig. 2). In humans, the most common cause is immune-mediated destruction of the adrenal cortex. In dogs, the aetiology usually is unknown but an immune-mediated cause is suspected. This form of disease is termed idiopathic hypoadrenocorticism. Other causes of primary hypoadrenocorticism include iatrogenic destruction of the adrenal cortex from Lysodren (o,p'DDD) therapy for Cushing’s disease (common), adrenal haemorrhage or infarction (rare), fungal infection (rare), trauma (rare), effacement of the adrenal gland by metastatic neoplasia (rare), and surgical adrenalectomy (uncommon). Regardless of the cause of primary hypoadrenocorticism, the results of the disease are a deficiency of mineralocorticoid and glucocorticoid production by the adrenal cortices, as well as an increased plasma concentration of adrenocorticotropic hormone (ACTH) due to the absence of negative feedback on the pituitary secretion of this hormone. The possibility exists that the outermost layer of the adrenal cortex (zona glomerulosa), which is responsible for mineralocorticoid production, may be spared. This condition results only in a glucocorticoid deficiency with an atypical presentation of primary Addison’s disease (hypoadrenocorticism).
|
 |
| Figure 1. Histologic section of the adrenal gland, demonstrating the three zones of the cortex (zona glomerulosa, zona fasiculata and zona reticularis ) and the medulla (hematoxylin and eosin stain, 2.5x magnification). | Figure 2. Small adrenal glands from a dog that developed hypoadrenocorticism following treatment for Cushing's disease with o,p'DDD. |
Secondary hypoadrenocorticism results from hyposecretion of glucocorticoids by the two innermost layers of the adrenal cortex (zona fasciculata and zona reticularis). In secondary hypoadrenocorticism, decreased secretion of ACTH by the pituitary occurs directly or as a consequence of decreased release of corticotropin releasing hormone (CRH) by the hypothalamus. Dogs with secondary hypoadrenocorticism usually do not have mineralocorticoid deficiency because ACTH has little trophic effect on the zona glomerulosa. Although rare, spontaneous disease may result from destructive lesions of the pituitary or hypothalamus including neoplasia, inflammation, or trauma. The most common of these possibilities is a large pituitary tumour that ultimately may result in simultaneous hypofunction of other endocrine organs such as the thyroid gland. A more common cause of secondary hypoadrenocorticism is iatrogenic disease. Long-term glucocorticoid administration may suppress ACTH secretion by the pituitary, resulting in atrophy of the adrenal glands. Cats may also develop adrenocortical atrophy after receiving megestrol acetate, but spontaneously occurring secondary hypoadrenocorticism has not been reported in cats.
Clinical Signs
The most common symptoms of Addison's in cats included lethargy, anorexia, occasional vomiting, dehydration, polyuria/polydipsia, and weight loss. Some cats show a waxing and waning clinical course, including temporary 'remissions' associated with parenteral fluid and/or corticosteroid administration.
Some cats can worsen with time, and present as an 'Addisonian crisis', in severe shock with weak pulses, slow capillary refill times, and extreme weakness or collapse. The duration of clinical signs preceding the diagnosis of hypoadrenocorticism can range from 1 - 3 months post-diagnosis. An Addisonian crisis is the result of severe hyponatraemia and hyperkalemia, which are the precursors for hypovolaemia, prerenal azotemia and cardiac arrhythmias.
Pathological signs
Similar to what is seen in dogs, serum electrolyte changes characteristic of mineralocorticoid deficiency is evident. Serum sodium:potassium ratios are usually less than 24:1. Cats are often hyponatremia, hypochloremic, and hyperkalemic. Mild to severe azotemia as a result of renal hypoperfusion (blood urea nitrogen 31–80 mg/dl, normal range 5-30 mg/dl; creatinine 1.6–6.0 mg/dl, normal range 0.5–1.5 mg/dl), and hyperphosphatemia (inorganic phosphorus 6.1-9.1 mg/dl; normal range 3.0–6.0 mg/dl) is present. Hypercalcemia is sometimes observed as well. Despite signs of dehydration and prerenal azotemia, urine specific gravity is rarely greater than 1.030. The loss of renal medullary solutes, particularly sodium, is believed to result in impaired renal concentrating ability.
Survey radiographs of dogs with hypoadrenocorticism may have one or more of the following abnormalities including microcardia, a narrow descending aorta or caudal vena cava, small cranial lobar pulmonary artery, hypoperfusion of the lung fields, and microhepatica.6 The severity of these changes usually reflects the severity of hypovolemia. These radiographic findings are not specific for hypoadrenocorticism but reflect hypovolemia of any origin.
 |
 |
| Figure 5. Lateral (left) and ventrodorsal (right) survey thoracic radiographs of a dog with microcardia (a small cardiac shadow) secondary to hypoadrenocorticism and severe hypovolemia. | |
A secondary megaoesophagus occasionally has been observed and is thought to originate from abnormal electrolyte levels that interfere with normal neuromuscular function or from decreased cortisol concentrations that result in muscular weakness. Megaoesophagus usually resolves following treatment of hypoadrenocorticism, but the presence of this condition is important in initial management of the patient.
Ultrasound examination of the adrenal glands may be of benefit when hypoadrenocorticism is suspected in a critically ill patient. Ultrasound studies may demonstrate shorter and thinner adrenal glands in dogs with hypoadrenocorticism. Both poles of the left adrenal may be considerably thinner than normal, while the right adrenal gland may appear straight, losing its characteristic peanut shape. The two layer internal structure (cortex and medulla) of the adrenal gland may not be visualized on ultrasound examination of dogs with hypoadrenocorticism. Histopathology of the adrenal gland usually demonstrates adrenal atrophy and fibrosis. In humans with autoimmune hypoadrenocorticism, mononuclear cell infiltrates (lymphocytes, plasma cells, and macrophages) may be observed within the adrenal cortex on histologic sections. Several reports have described mononuclear cell infiltrates in dogs in addition to adrenal atrophy and fibrosis indicating a possible immune-mediated component of the disease.
|
|
|
Figure 6. Histologic section of an adrenal gland from a dog with hypoadrenocorticism. The adrenal cortex is diminished in width and contains a lymphocytic infiltrate. Hematoxylin and eosin stain, 40x magnification. |
Diagnosis
Diagnosis is based on clinical signs of vomiting, dehydration, plus azotemia, hyperphosphatemia and a sodium:potassium ration <24:1. Also, 70% of Addisonian cats have USG < 1.030 due to medullary washout from hyoaldosteronism.
Although certain diagnostic findings may be suggestive of hypoadrenocorticism, specific disease diagnosis requires determination of plasma cortisol concentrations before and after an ACTH stimulation test. This test measures the ability of the adrenal cortex to secrete endogenous cortisol in response to exogenous ACTH. A blood sample is collected prior to administration of ACTH to determine the baseline plasma cortisol concentration. ACTH gel (20 U) is administered intramuscularly or synthetic ACTH (Cosyntropin, 250 micrograms or one reconstituted vial) is administered intramuscularly or intravenously (it also has been reported that an intravenous dose of 0.125 mg/cat IM with blood samples collected at 0, 30 and 60 mins or IV with samples at 0, 60 and 90 mins or ACTH gel (2.2 mg/kg) IM with samples at 0, 60 and 120 mins.
Cortisol concentrations pre- and post-ACTH < 55 nmol/L (2 µg/dL) is diagnostic.
If the patient presents in an acute adrenal crisis with hypovolemic shock, the ACTH stimulation test can be performed several hours after the patient is stabilized. If glucocorticoids are to be used in the initial treatment of such patients, dexamethasone sodium phosphate will not interfere with plasma cortisol determinations. Other glucocorticoids, such as prednisone and prednisolone, may cross react with the cortisol assay. If the patient has been on glucocorticoids prior to presentation, dexamethasone sodium phosphate should be administered as an alternative therapy at least 24 hours before performing the ACTH stimulation test. Severe hypovolemia, if present, may interfere with absorption of the intramuscular ACTH because of decreased tissue perfusion, produce inaccurate ACTH stimulation test data.
When interpreting the results of the ACTH stimulation test, absolute cortisol values should be interpreted rather than relative increases in plasma cortisol concentration. The resting cortisol concentration may be low or within the reference interval. Administration of ACTH incites a subnormal or negative response in dogs with hypoadrenocorticism. Baseline and post-ACTH samples with cortisol concentrations of < 2 micrograms/dl are diagnostic for hypoadrenocorticism. Occasionally in dogs that have incomplete destruction of the adrenal cortex, the post-ACTH cortisol concentration may be >2 micrograms/dl. The ACTH stimulation test does not differentiate between primary and secondary hypoadrenocorticism. In order to distinguish adrenal dependent from pituitary dependent disease in dogs with abnormally decreased ACTH stimulation test results and normal electrolyte concentrations, the endogenous plasma ACTH concentration should be measured. Dogs with primary hypoadrenocorticism will have an increased plasma ACTH concentration due to the absence of negative feedback on the pituitary from cortisol secretion by the adrenal cortex. Dogs with secondary hypoadrenocorticism will have very low to undetectable plasma ACTH levels due to destruction of the pituitary or hypothalamus.
The corticotropin releasing hormone (CRH) stimulation test also is available. This test may provide useful information by measuring endogenous plasma ACTH concentration. Dogs with primary hypoadrenocorticism will have ACTH levels that appear hyperresponsive to CRH. In contrast, dogs with secondary hypoadrenocorticism will not respond to CRH stimulation. If secondary hypoadrenocorticism is suspected, visualization of the pituitary should be attempted to determine the aetiology of disease.
Differential diagnosis
Renal failure has very similar signs, and also presents with dehydration, azotemia and USG < 1.030. The ACTH test is normal in renal cats, who are commonly over 10 years of age and have a more chronic history of weight loss, PU/PD and renal related symptoms.
Addisonian cats also ned to be differentiated from cats with diabetic ketoacidosis, necrotising pancreatitis and septic shock.
Treatment
Long-term management of cats with primary hypoadrenocorticism requires lifetime mineralocorticoid and glucocorticoid supplementation. Oral fludrocortisone acetate (0.1 mg/day) or intramuscular injections of repositol desoxycorticosterone pivalate (DOCP; 10–12.5 mg/month) have been successful in maintaining Addisonian cats. The dose of mineralocorticoid is adjusted as needed based on follow-up serum electrolyte concentrations monitored every one to two weeks during the initial maintenance period. Normal electrolyte parameters two weeks following DOCP suggests adequate dosing, but does not provide information concerning the duration of action of each injection. Eighty percent of dogs require DOCP more frequently than every 30 days (5% need to receive DOCP every three weeks), so frequent sampling during the early management period is recommended. Prednisone, 1.25 mg orally once per day, or intramuscular methylprednisolone acetate, 10 mg once a month, can be used to provide adequate long-term glucocorticoid supplementation. Cats surviving the initial adrenal crisis can be managed successfully for many years. Six of the 10 cats diagnosed with primary hypoadrenocorticism were alive a median of 2ľ years after diagnosis. With appropriate glucocorticoid and mineralocorticoid supplementation, cats with adrenocortical insufficiency should have a normal life expectancy10.
1. Rijnberk A (ed): Clinical Endocrinology of Dogs and Cats. Kluwer Academic Publishers, The Netherlands, 1996, pp. 61-73.
2. Feldman EC, Nelson RW: Canine and Feline Endocrinology and Reproduction, 2nd ed. W. B. Saunders Co., Philadelphia, 1996, pp. 267-305
3. Ettinger SJ, Feldman EC: Textbook of Veterinary Internal Medicine, 5th ed, vol 2. W. B. Saunders Co., Philadelphia, 2000, pp.1488-1498.
4. Kintzer PP, Peterson ME: Primary and secondary canine hypoadrenocorticism. Vet Clin N Am: Small Anim Pract 1997; 27:349-357.
5. Phillips SL, Polzin DJ: Clinical disorders of potassium homeostasis. Vet Clin N Am: Small Anim Pract 1998; 28:552.
6. Melian C, Stefanacci J, Peterson ME, Kintzer PP: Radiographic findings in dogs with naturally occurring primary hypoadrenocorticism. J Am Vet Med Assoc 1999
7. Hoeranf A, Reusch C: Ultrasonographic evaluation of the adrenal glands in six dogs with hypoadrenocorticism. J Am Vet Med Assoc 1999; 35: 214-218.; 35:208-212.
8. Tidwell AS, Penninck DG, Besso JG: Imaging of adrenal gland disorders. Vet Clin N Am: Small Anim Pract 1997; 27: 246.
9. Ferguson DC, Hoenig M: Endocrine system. In: Latimer KS, EA Mahaffey, KW Prasse. Duncan and Prasse's Veterinary Laboratory Medicine: Clinical Pathology, 4th ed. Iowa State Press, Ames, 2003, pp. 295-300
10. Bruyette, D. http://www.vin.com/VINDBPub/SearchPB/Proceedings/PR05000/PR00106.htm