Canine Hyperadrenocorticism (HAC)

Canine Hyperadrenocorticism (HAC) is caused by excess circulating cortisol or other steroid hormones. It is also known as Cushing’s syndrome.

Etiology

• Endogenous HAC is caused by an ACTH-secreting pituitary tumor (~85% of dogs) or a benign or malignant adrenal tumor (~15% of dogs).
• Endogenous HAC may rarely be caused by ectopic ACTH secretion from a nonpituitary tumor or food-dependent hypercortisolemia.
• Iatrogenic HAC is caused by administration of exogenous glucocorticoids of any form.

Pathophysiology

Syndrome characterized by chronic excess of systemic cortisol:

• Pituitary tumor making excess ACTH (most common)
• Pituitary hyperplasia due to excess CRH (not dogs and cats)
• Autonomous adrenocortical tumor
• ACTH from non-pituitary sources– very rare in dogs and cats
• Iatrogenic
• Excess ACTH (rare)
• Excess glucocorticoids (common)

Risk factors

• Endogenous HAC occurs in middle aged to older dogs.
• Although the reported age range is 6 months to 20 years, almost all dogs with HAC are over 6 years of age.
• Poodles, dachshunds, boxers, and various terrier breeds may have a greater risk of pituitary-dependent hyperadrenocorticism (PDH).
• PDH occurs more frequently in smaller dogs, with 75% of dogs with PDH weighing <20 kg. There is no sex predilection for PDH.
• Female dogs may have increased risk for adrenal-dependent hyperadrenocorticism(ADH)

Clinical Signs

• Polyphagia (> 90%)
• PUPD (80-85%)
• Abdominal enlargement (>80%)– “pot-bellied”
• Hepatomegaly
• Redistribution of fat
• Abdominal muscle weakness
• Muscle weakness (75-85%)
• Panting
• Lethargy
• Obesity
• Heat intolerance
• Alopecia: Truncal / Bilaterally symmetrical
• Calcinosis cutis
• Thin skin, bruising, striate
• Seborrhea, pyoderma
• Comedones
• Hyperpigmentation
• Anestrus, Testicular atrophy Facial paralysis Pseudomyotonia

Neurological signs associated with pituitary macroadenoma:

• Dull
• Decreased appetite
• Aimless wandering
• Pacing, circling
• Behavioral changes
• Seizures rare

Clinicopathological Findings

CBC

• Stress leukogram: Neutrophilia, Monocytosis, Lymphopenia and Eosinopenia
• Thrombocytosis
• Mild erythrocytosis (females- androgens)

Serum Biochemistry

• Increased AP (90-95%) (can be then 1000)
• Increased ALT (< 400)
• Mildly increased fasting BG
• Normal to reduced BUN
• increased cholesterol and triglycerides
• Mildly increased bile acids
• Mild increased Na
• Mild decreased K

Urinalysis

• SG < 1.015, often < 1.008
• Mild increase in UP:C (less than 5)
• Urinary Tract Infection (UTI) in 40-50%
• UTI often “silent”

Diagnostic Imaging

Abdominal Radiographs:

• Excellent detail
• Hepatomegaly
• Distended urinary bladder
• Urolithiasis
• Dystrophic calcification of soft tissues
• Osteoporosis of vertebrae
• Calcified adrenal gland

Thoracic Radiographs:

• Calcification of airways
• Osteoporosis of vertebrae
• Pulmonary metastases
• Evidence of pulmonary thromboembolism

Abdominal Ultrasound Examination:

• Adrenomegaly (PDH)
• Adrenal mass with small contralateral adrenal (AT)
• Calcified adrenal gland (AT)
• Tumor thrombus or metastasis
• Hepatomegaly
• Hyperechoic liver
• Distended urinary bladder
• Urolithiasis
• Dystrophic calcification of soft tissues

Advanced Imaging:

• Brain CT or MRI may reveal pituitary tumor

Complications of Hyperadrenocorticism

• Hypertension (> 50%)
• Urinary tract infection (UTI)
  • Pyelonephritis
  • Cystitis (clinically silent)
• Urolithiasis
  • Calcium-containing
  • Struvite related to UTI
• Congestive heart failure, Diabetes mellitus , Poor wound healing , Recurrent infections, Joint laxity, Hypercoagulability, Pulmonary thromboembolism and Aortic thromboembolism.

Diagnosis of Canine Hyperadrenocorticism

Screening tests

• Basal Cortisol: Typical reference range: 1-5 ug/dl
• Urine Cortisol: Creatinine Ratio
• ACTH Stimulation Test
  • Pre-ACTH cortisol: normal: 0.5 – 6.0 µg/dl
  • Post-ACTH cortisol
  • Normal: <18 µg/dl
  • Exaggerated: >22 µg/dl
  • Grey zone: 18 – 22 µg/dl

Discrimination test

• Low-Dose Dexamethasone Suppression Test (LDDST)
• Normal patient:
  • 0 hour: Cortisol = 1-5 mg/dl
  • 4 hour: Cortisol < 1.4 mg/dl
  • 8 hour: Cortisol < 1.4 mg/dl
• Cushing’s patient:
  • 8 hour: Cortisol > 1.5 mg/dl
• High Dose Dexamethasone Suppression Test (HDDST)
• Endogenous ACTH
• Abdominal Ultrasound

Treatment of Hyperadrenocorticism

Before commencing treatment be confident of the diagnosis; Patient must have consistent clinical signs, clinicopathological findings, and positive diagnostic testing.

Trilostane and mitotane are used most commonly used in canine hyperadrenocorticism (HAC); both have similar effect.

Trilostane

• Competitive inhibitor of 3-β- hydroxysteroid dehydrogenase. It reaches peak concentrations 2 hours after administration with return to baseline at 10–18 hours.
• Administration with food enhances absorption
• Starting dose of 3–6 mg/kg PO q24h.

Mitotane

• Adrenocorticolytic agent predominately targeting the zonas fasciculata and reticularis
• Treatment includes 2 phases: Induction and maintenance.
• Induction: Initial dose is 30–50 mg/kg PO per day, usually split q12h.
• Maintenance: Total daily induction dose is used as the total weekly maintenance dose, typically split over 3–4 days per week.

Surgical

• Adrenalectomy- First choice for ADH
• Hypophysectomy- Can be used for treatment of PDH.

Alternative Therapy

• Ketoconazole inhibits the synthesis of glucocorticoids and androgens and has been used for PDH or ADH treatment but has a much lower efficacy.
• L-deprenyl inhibits monoamine oxidase type B, resulting in increased dopamine concentrations in the pituitary and inhibiting secretion of ACTH from the pars intermedia.
• Radiation therapy.