GENERAL CONSIDERATIONS

Anatomy & Physiology

•adrenal gland is composed of the medulla and cortex

•adrenal medulla secretes epinephrine and norepinephrine

•adrenal cortex is divided into 3 zones:

•zona glomerulosa: secretes mineralocorticoid and aldosterone

•zona fasciculate: secretes glucocorticoids and androgens

•zona reticularis: secretes glucocorticoids and androgens

Adrenal-Dependent Hyperadrenocorticism

•adrenal-dependent hyperadrenocorticism accounts for 10%-20% cases

•adrenal-dependent hyperadrenocorticism is caused by benign or malignant tumors of the adrenal cortex autonomously secreting excessive quantities of cortisol

•adrenocortical tumors can produce glucocorticoids, but also mineralocorticoids and adrenal sex hormones

•contralateral adrenal gland is often atrophied

•adrenocortical adenoma and ADC occur with equal frequency and are difficult to differentiate with diagnostic tests and imaging techniques

•adrenocortical ADC is more likely to invade regional vascular structures (i.e., caudal vena cava and renal and hepatic veins) (11%-25% cases) and metastasize to lungs, liver, or kidneys

•metastatic rate variable for adrenocortical ADC: 7%-50%

•other findings in cats and dogs with adrenal tumors:

•thrombosis of vessels such as caudal vena cava, iliac, and femoral veins (especially dogs)

•hypersecretion of sex hormones such as progesterone (especially cats) which may contribute to diabetes mellitus due to insulin resistance and antagonism

•bilateral adrenocortical tumors, concurrent adrenocortical tumor and pituitary-dependent hyperadrenocorticism, concurrent adrenocortical tumor and adrenal pheochromocytoma, and concurrent pituitary-dependent hyperadrenocorticism and adrenal pheochromocytoma have been reported and may account for conflicting discriminatory tests and poor response to medical management

CLINICAL SIGNS

General Considerations

•hyperadrenocorticism is usually an insidious and slowly progressive disease

•chronic elevation of cortisol results in a broad range of systemic effects due to gluconeogenesis, lipolysis, protein catabolism, anti-inflammatory effects, and immunosuppression

•clinical signs in cats and dogs with adrenocortical tumors may be associated with secretion of non-glucocorticoid substances, such as mineralocorticoids (i.e., hypokalemia and hypertension) and adrenal sex hormones

Signalment

•median age:

•11.3 years for dogs with adrenal-dependent hyperadrenocorticism

•10.0 years for cats

•breeds: Poodle, Dachshund, Terrier, Beagle, GSD, Labrador Retriever, and Boxer are over-represented

•sex predisposition: female dogs

General Appearance

•pendulous abdomen with varying degrees of hair loss

•abdominal distension reported in up to 95% due to redistribution of body fat into the abdomen, hepatomegaly, and muscle atrophy secondary to catabolic effects of excessive cortisol

•hepatomegaly is caused by accumulation of glycogen and fat

Skin and Hair

•skin and hair changes are frequently observed in feline and canine hyperadrenocorticism

•skin and hair changes include thinning hair coat, bilaterally symmetrical alopecia, thin skin, comedones, hyperpigmentation, pyoderma, and calcinosis cutis

•calcinosis cutis is a raised, cream-coloured plaque surrounded by a zone of erythema and most commonly occurs on the temporal region of the head

Polyuria and Polydipsia

•polyuria and polydipsia are common signs and present in 82% and 97%, respectively

•nocturia, urinary incontinence, and pollakiuria are common findings secondary to polyuria and polydipsia

•concurrent diabetes mellitus in 5%-10% of dogs and 76% of cats due to insulin resistance

•UTI common due to increased residual urine volume, dilute urine and immunosuppression

Panting

•excessive panting and reduced exercise tolerance are frequently reported

Pulmonary Thromboembolism

•pulmonary thromboembolism is caused by hyperadrenocorticism in 17% dogs

•pulmonary thromboembolism should be suspected in hyperadrenocorticoid dogs with respiratory distress

•pulmonary thromboembolism due to hypercoagulable condition characterized by impaired fibrinolysis and increased coagulation factors

•pulmonary thromboembolism is most often seen after initiating medical therapy or following surgery

Neurologic

•neurologic signs may develop secondary to mass effect of pituitary macroadenoma

•clinical signs include inappetance, dullness, disorientation, pacing, head pressing, ataxia, loss of learned behaviour, seizures, visual deficits, anisocoria, and Horner’s syndrome

LABORATORY FINDINGS

Hematology

•mature leukocytosis with neutrophilia, eosinopenia, and lymphopenia in dogs, but not cats

Serum Biochemistry

•elevated ALP (5-20 times normal), ALT (mild), cholesterol, and glucose

•hypothyroidism due to excessive cortisol suppressing thyroid-stimulating hormone release

Urinalysis

•hyposthenuric, but hyperadrenocorticoid dogs can concentrate urine if stressed or deprived of water

•hyperadrenocorticoid cats are able to maintain USG > 1.020

•other urinalysis findings include glucosuria (with concurrent diabetes mellitus), bacteruria, and proteinuria

SCREENING TESTS

General Considerations

•hematology, serum biochemistry, and urinalysis are suggestive of hyperadrenocorticism, but are not diagnostic and do not differentiate between pituitary-dependent and adrenal-dependent hyperadrenocorticism

•routine screening tests include ACTH stimulation test, low-dose dexamethasone suppression test, and urine cortisol-to-creatinine ratio

•however, false-positive results are common in dogs with severe non-adrenal disease with 56% (33/59) having inadequate cortisol suppression at 8 hours following LDDST, 14% (8/59) having high serum cortisol levels after an ACTH stimulation test, and 76% (45/59) having a high urine cortisol-to-creatinine ratio

•ultrasound examination can also increase cortisol levels and hence all screening and differentiation tests should not be performed within 2 hours of abdominal ultrasonography

Urinary Cortisol-to-Creatinine Ratio

•excessive urinary concentration of cortisol in dogs with hyperadrenocorticism will increase urine cortisol-to-creatinine ratio

•advantages: convenient and inexpensive

•disadvantages: high sensitivity but poor specificity

•urine cortisol-to-creatinine ratio can be increased with non-hyperadrenocorticoid diseases such as renal disease, diabetes mellitus, and neoplasia

ACTH Stimulation Test

•ACTH stimulation test evaluates ability of adrenal gland to secrete cortisol after maximal stimulation

•ACTH stimulation test is a screening test as it does not differentiate between pituitary- and adrenal-dependent hyperadrenocorticism, however, it is useful for excluding iatrogenic hyperadrenocorticism

•false negatives (15%-30%) and false positives (in stressed and non-adrenal disease) are common in cats, but up to 70% of cats will have increased cortisol concentrations after ACTH administration

•cortisol production following ACTH stimulation remains excessive with both pituitary- and adrenal-dependent hyperadrenocorticism

•cortisol production may be normal following ACTH stimulation in dogs with adrenal-dependent hyperadrenocorticism and hence a normal result does not exclude a diagnosis of hyperadrenocorticism

•iatrogenic hyperadrenocorticism will have minimal to no response to exogenous ACTH

•2 ACTH stimulation techniques:

•serum cortisol collected for baseline and 1 hour after administering 0.25 mg synthetic ACTH IM

•serum cortisol collected for baseline and 2 hours after administering 2.2 U/kg ACTH gel IM

Low-Dose Dexamethasone Suppression Test

•LDDST is regarded as the most reliable diagnostic test for hyperadrenocorticism

•LDDST is very sensitive but false-positive results are possible

•low-dose dexamethasone will provide sufficient negative feedback at the pituitary level to down-regulate ACTH secretion and result in reduced plasma cortisol concentration

•low-dose dexamethasone will not provide negative feedback with pituitary-dependent hyperadrenocorticism resulting in elevated cortisol levels

•30%-40% dogs with pituitary-dependent hyperadrenocorticism will suppress cortisol production at 3 hours

•cortisol secretion is excessive and autonomous with adrenocortical tumors and is not influenced by the normal pituitary-hypothalamic-adrenal axis and results in persistently high cortisol levels

•serum cortisol collected for baseline and 3 and 8 hours after administering 0.01 mg/kg dexamethasone IV

•serum cortisol should be tested more frequently in cats (i.e., 2, 4, 6, and 8 hours) as may escape suppressive effects of dexamethasone before 8 hours if pituitary-dependent hyperadrenocorticism

•100% of cats with hyperadrenocorticism do not suppress cortisol at 8 hours

PITUITARY- VERSUS ADRENAL-DEPENDENT HYPERADRENOCORTICISM

General Considerations

•discriminatory tests (i.e., HDDST and endogenous plasma ACTH levels) are used to differentiate pituitary- and adrenal-dependent hyperadrenocorticism once the diagnosis of hyperadrenocorticism has been confirmed with screening tests

High-Dose Dexamethasone Suppression Test

•high-dose dexamethasone will supposedly suppress ACTH secretion in dogs with pituitary-dependent hyperadrenocorticism but, due to autonomous secretion of cortisol independent of the hypothalamic-pituitary-adrenal axis, not adrenal-dependent hyperadrenocorticism

•however, 20%-30% of dogs with pituitary-dependent hyperadrenocorticism will not suppress with HDDST

•HDDST can exclude adrenal-dependent hyperadrenocorticism if cortisol production is suppressed but not differentiate between pituitary- and adrenal-dependent hyperadrenocorticism

•serum cortisol collected for baseline and 8 hours after administering 0.1 mg/kg dexamethasone IV

Endogenous ACTH Concentration

•endogenous ACTH secretion is increased in dogs with pituitary-dependent hyperadrenocorticism

•pituitary production of ACTH is suppressed in dogs with adrenal-dependent hyperadrenocorticism

•ACTH is very labile and samples must either be immediately centrifuged and frozen or preserved by addition of protease inhibitor aprotinin

•combination of endogenous ACTH concentration and ultrasonography correctly differentiated pituitary- and adrenal-dependent hyperadrenocorticism in 93% (27/29) dogs

IMAGING

Survey Radiographs

•hepatomegaly, osteoporosis, and soft tissue mineralization are features of hyperadrenocorticism

•perihilar bronchial mineralization is common in hyperadrenocorticoid dogs

•adrenal calcification can be observed in normal old dogs, 30% of normal old cats, and dogs with benign and malignant adrenal neoplasia

•cranial abdominal mass can be detected in up to 54% of dogs with adrenal tumors

Contrast Radiographs

•caudal vena cavogram is useful in delineating presence and extent of invasion or tumor thrombus formation in dogs with adrenocortical ADC

Ultrasound

Normal Adrenal Glands

•left and right adrenal glands can be identified in 96% and 72% of dogs with abdominal ultrasonography

•right adrenal gland is more difficult to visualize due to cranial position and overlying pyloric and duodenal gas

•normal adrenal gland is 0.5-1.4 cm long and 0.3-0.5 cm wide in cats

•normal adrenal gland is 2.0-3.0 cm long, 1.0 cm wide, and 0.5 cm thick in dogs

•adrenal glands show considerable variation in size and shape with resultant overlap between ultrasonographic changes in normal and hyperplastic adrenal glands

Adrenal-Dependent Hyperadrenocorticism

•dogs with adrenal-dependent hyperadrenocorticism have unilateral adrenomegaly, variable and often heterogenous echogenicity, distortion of normal architecture and contour, and may have evidence of vascular invasion or metastatic disease

•atrophy of contralateral gland is not a consistent finding

•benign and malignant adrenal neoplasia cannot be differentiated on the basis of ultrasonographic features such as bilateral involvement, mineralization, and echogenicity

•malignant tumors tended to have a more rounded appearance and poorly encapsulated (compared to nodular and well-encapsulated with benign tumors) with evidence of vascular extension or thrombus formation

•bilateral adrenal tumors and pituitary-dependent hyperadrenocorticism with either adrenocortical tumor or pheochromocytoma have been reported and must be interpreted with laboratory results

•combination of endogenous ACTH concentration and ultrasonography correctly differentiated pituitary- and adrenal-dependent hyperadrenocorticism in 93% (27/29) dogs

Computed Tomography and Magnetic Resonance Imaging

•CT and MRI can be used to identify pituitary macroadenomas, adrenal tumors, and evidence of vascular invasion and metastatic disease

MEDICAL MANAGEMENT

General Considerations

•drugs used for medical management of hyperadrenocorticism include:

•mitotane (o,p'-DDD)

•ketaconazole is an anti-fungal agent which inhibits adrenal steroidogenesis with minimal affect on mineralocorticoid synthesis (5-15 mg/kg/day), but up to 50% dogs fail to respond

•bromocriptine is a dopamine agonist with limited success

•selegiline is a monoamine oxidase inhibitor which enhances dopaminergic tone to the hypothalamic-pituitary axis and inhibits ACTH secretion (1 mg/kg/day)

•metyrapone is an inhibitor of 11-β-hydroxylase which converts 11-deoxycortisol to cortisol and has shown good short-term results in cats with hyperadrenocorticism and can be used for preoperative stabilization prior to adrenalectomy

•aminoglutethimide inhibits conversion of cholesterol to pregnenolone and has been associated with short-term improvement in 1 cat and suppresses adrenal steroid hormones in normal dogs

•trilostane

Mitotane

General Considerations

•mitotane (o,p’-DDD) which is an adrenolytic agent which reduces cortisol secretion through selective necrosis of zona fasciculata and reticularis (i.e., glucocorticoid-producing portions of the adrenal cortex) and spares the aldosterone-producing zona glomerulosa

•adverse effects are common and include glucocorticoid and mineralocorticoid (rare) deficiency during induction therapy and toxic effects on GI, liver, and CNS (i.e., weakness, disorientation, and ataxia)

•response rate with adrenal-dependent hyperadrenocorticism is poor with 56% responding to induction therapy (although better response if no evidence of metastatic disease) with higher doses required for longer duration

•mitotane has been used in cats although they are traditionally sensitive to chlorinated hydrocarbons, response rate is less, and incidence of adverse effects higher

Induction Therapy

•aim: reduce serum cortisol levels to within reference range for both basal and post-ACTH stimulation

•mitotane: 50 mg/kg/day for 7-10 days or until end-point of induction phase is achieved

•response to mitotane is variable with adrenal reserves diminished in 5-60 days

•water intake, appetite, and general health should be closely monitored

•mitotane is stopped and treatment reassessed if dog becomes listless, inappetant, or develops GI signs

•success of mitotane induction therapy can be measured directly with ACTH stimulation test or indirectly with an eosinophil count or reduction in water intake (especially if pre-existing polydipsia)

•10%-15% dogs will not respond within 7-10 days and will require further induction therapy and repeat ACTH stimulation test in 7-10 days

•33% dogs will rebound with subnormal cortisol levels and may require glucocorticoid supplementation until cortisol levels are within the reference range (usually 2-6 weeks although can be months)

Maintenance Therapy

•mitotane: 25-50 mg/kg/week divided into 2-3 doses

•physical examination and ACTH stimulation test should be performed every 3-6 months for monitoring

•pituitary secretion of ACTH continues despite clinical control of hyperadrenocorticism

•40%-50% recurrence rate of clinical signs of hyperadrenocorticism within 12 months

•daily induction therapy restarted for short period followed by maintenance therapy if recurrence

Prognosis

•MST for dogs with adrenal-dependent hyperadrenocorticism is 11.5 months

ADRENALECTOMY

Indications

•unilateral adrenalectomy is recommended for treatment of adrenal tumors and some have recommended bilateral adrenalectomy for management of pituitary-dependent hyperadrenocorticism

Preoperative Management

•glucocorticoid therapy is considered necessary due to functional atrophy of contralateral adrenal gland:

•dexamethasone: 0.1-0.2 mg/kg bolus or 0.02-0.03 mg/kg/hr CRI for 6 hours

•prednisolone sodium succinate 1.0-2.0 mg/kg

•hydrocortisone: 625 µg/kg/hr (glucocorticoid and mineralocorticoid support)

•coagulation profile important in screening for animals with potential for thromboembolic disease

•preoperative anticoagulant therapy can be considered although benefit unknown

•± heparin (35 U/kg) in plasma to minimize the risk of pulmonary thromboembolism

•metyrapone inhibits conversion of 11-deoxycortisol to cortisol and has been used in cats for preoperative stabilization prior to adrenalectomy

General Anesthesia

•anesthetic considerations for animals with hyperadrenocorticism include:

•fluid and sodium retention

•hypokalemia

•hypertension

•impaired respiratory function due to muscle weakness, hepatomegaly, and excessive fat deposition

•hypertension occurs in 86% of dogs with untreated hyperadrenocorticism, and treatment does not always correct hypertension

•hyperglycemia (± diabetes mellitus) is common

•pulmonary thromboembolism is a risk during anesthesia and surgery and, although the mechanisms are not fully understood, include obesity, hypertension, increased red blood cell volume, and hypercoagulability

Surgical Technique

General Considerations

•abdominal exploration to examine for metastatic disease and bilateral adrenal involvement

•caudal vena cava is examined for tumor thrombus, but should be done with caution to maximize venous return

•liver, stomach and intestines, spleen, and kidneys are retracted with large hand-held retractors

•phrenicoabdominal vein is isolated, ligated, and divided, although this may be difficult in large adrenal tumors

•adrenal gland is bluntly dissected from surrounding tissue

•hemostatic clips are preferred for ligation because of difficulty hand-ligating deep in the abdominal cavity

•ipsilateral nephrectomy may be required with adrenal invasion of renal parenchyma or vasculature

Thrombectomy Techniques

•extraction of tumor thrombus may be required with the caval defect repaired primarily or with a patch graft or segmental reconstruction with autogenous or prosthetic graft material

•abdominal ultrasonography is 80% sensitive and 90% specific for identifying caval thrombosis

•tumor thrombus is detected in up to 32% (13/40) of dogs with adrenal tumors, including 21% (6/28) with adrenocortical tumors and 55% (6/11) with pheochromocytomas

•majority of tumor thrombi extend beyond the phrenicoabdominal vein and into the prerenal ± intrahepatic and post-hepatic caudal vena cava with caval thrombus detected in up to 25% (10/40) of dogs with adrenal tumors, including 11% (3/28) with adrenocortical tumors and 55% (6/11) with pheochromocytomas

•tumor thrombus arise from left-sided adrenal tumors in 22% (5/23) and right-sided tumors in 40% (8/20)

•caval thrombus arise from left-sided adrenal tumors in 20% (4/20) and right-sided tumors in 35% (6/17)

•tumor thrombus is 2.73-times more likely to develop in right-sided adrenal gland tumors and 7.55-times more likely to be associated with a pheochromocytoma than an adrenocortical tumor

•tumor thrombi are classified into 3 groups:

•thrombus confined to the phrenicoabdominal vein

•thrombus extending into the prehepatic caudal vena cava

•thrombus extending into the intrahepatic ± post-hepatic caudal vena cava

•adrenalectomy with tumor thrombus confined to the phrenicoabdominal vein is performed with ligation of the phrenicoabdominal vein adjacent to the junction of the caudal vena cava and phrenicoabdominal vein

•thrombectomy techniques in dogs with caval thrombi involves:

•Rumel tourniquets placed cranial and caudal to the adrenal gland tumor

•cranial Rumel tourniquet immediately caudal to the liver

•caudal Rumel tourniquet cranial to the renal veins or caudal to the right renal vein with a separate Rumel tourniquet on the right renal vein

•caudal vena cava is incised around the base of the phrenicoabdominal vein

•cranial Rumel tourniquet tightened to control hemorrhage after removal of extensive caval thrombus

Postoperative Management

•monitor systemic blood pressure, oxygenation, serum electrolytes, and other biochemical parameters

•± heparin (35 U/kg q 12 hr SC and tapering to 10 U/kg over 3-4 days)

Complications

Adrenal Insufficiency

•adrenal insufficiency may occur following unilateral adrenalectomy for adrenal neoplasia and bilateral adrenalectomy

•prednisone (0.5 mg/kg q 12 hr PO) should be tapered down to 0.2 mg/kg q 12 hr PO within 7-10 days

•ACTH stimulation tests can be used to guide cessation of glucocorticoid therapy

•mineralocorticoid deficiency can also occur and electrolytes should be monitored

•mild hyponatremia and hypokalemia has been reported in > 40% dogs after unilateral adrenalectomy

•mineralocorticoid supplementation: fludrocortisone acetate or desoxycorticosterone pivalate

Pulmonary Thromboembolism

•pulmonary thromboembolism may present with acute dyspnea, respiratory arrest, hypoxia ± jugular pulse

•diagnosis of pulmonary thromboembolism:

•normal thoracic radiographs to blunting of pulmonary arteries

•decreased arterial PaO 2 (< 80 mm Hg) and increased PaCO 2

•evidence of pulmonary hypertension of echocardiography

•treatment of pulmonary thromboembolism:

•oxygen and cage rest

•heparin therapy to prevent thrombus formation: 200 IU/kg then 10-150 IU/kg q 6 hrs

•fresh frozen plasma if AT-III low

•prevention of pulmonary thromboembolism:

•aspirin 5 mg/kg q 12 hrs for 5 days prior to surgery

•heparin 10 IU/kg q 6 hrs for 48 hrs following surgery

Other Complications

•pancreatitis (common especially with ventral midline celiotomy)

•recurrence of clinical signs due to incomplete resection, metastatic disease, or concurrent pituitary-dependent hyperadrenocorticism in 31% with median time to recurrence 16 months (range, 5-43 months)

•others complications in dogs include iatrogenic vascular trauma and hemorrhage, ventricular tachycardia, pneumonia, renal failure, wound dehiscence, infection, and sepsis

•complications in cats include electrolyte abnormalities, skin lacerations, pancreatitis, hypoglycemia, pneumonia, and venous thrombosis and pulmonary thromboembolism

Prognosis

Cats

•82% (9/11) cats responded well to bilateral adrenalectomy and appropriate postoperative management with resolution of clinical signs and either improvement or resolution of diabetes mellitus

Dogs

•19%-44% perioperative mortality rate

•14%-50% metastatic rate with metastasis to the liver common

•12%-31% local tumor recurrence rate

•resolution of clinical signs in 69%-89% dogs following unilateral adrenalectomy for adrenocortical tumor

•MST for adrenocortical carcinomas: 778 days (range, 1-1,593 days) and 992 days if they survived 14 days

•MST for adrenocortical adenomas: > 730 days (range, 11-730 days)

•no prognostic factors, including presence of tumor thrombus, histopathologic diagnosis, histopathologic features, age, tumor size, or presence of metastatic disease

Ferrets

•splenomegaly (82%, 46/56) and insulinoma (21%, 12/56) were common concurrent conditions

•operative mortality < 2 %

•5% ferrets required mineralocorticoid or glucocorticoid therapy after bilateral adrenalectomy

•15% recurrence rate with a mean follow-up of 30 months