Definition

• Hypoadrenocorticism is an endocrine disorder resulting from deficient production of glucocorticoids and/or mineralocorticoids.
• Primary hypoadrenocorticism is due to destruction of the adrenal cortices, typically resulting in glucocorticoid and mineralocorticoid deficiency.
• Addison's disease refers to a deficiency of both glucocorticoids and mineralocorticoids resulting from idiopathic (immune-mediated) primary hypoadrenocorticism.
• The term atypical hypoadrenocorticism has been applied to the subset of dogs with primary hypoadrenocorticism that present with normal electrolytes. Recent work, however, has demonstrated that most of these dogs are mineralocorticoid deficient and thereby may not be so atypical.
• Secondary hypoadrenocorticism is results from pituitary ACTH insufficiency, resulting in inadequate glucocorticoid production by the adrenal cortices.

Pathophysiology

• Mineralocorticoid (aldosterone) deficiency results in a diminished ability to excrete potassium and retain sodium, disrupting sodium and potassium balance in the body.
• Sodium deficiency leads to diminished effective circulating volume. This then contributes to pathophysiologic changes and clinical abnormalities including prerenal azotemia, hypotension, dehydration, weakness, and depression.
• Hyperkalemia can contribute to clinical abnormalities including weakness, lethargy and anorexia. In combination with other electrolyte and metabolic derangements, it may result in myocardial toxicity as evidenced by bradycardia and various arrhythmias.
• Glucocorticoid (cortisol) deficiency contributes to the occurrence of anorexia, vomiting, diarrhea, melena, lethargy, and weight loss. Due to its role in glucose homeostasis hypocortisolemia predisposes to hypoglycemia. In addition, free water excretion is impaired.

Systems Affected

• Gastrointestinal
• Musculoskeletal
• Cardiovascular
• Renal/Urologic
• Skin

Genetics

A genetic basis has been determined in standard poodles, bearded collies and Leonbergers.

Incidence/Prevalence

No exact figures available; considered uncommon to rare in dogs and very rare in cats.

Signalment

Signs

Causes

• Primary hypoadrenocorticism-idiopathic (immune-mediated), mitotane overdose, trilostane overdose, granulomatous disease, metastatic tumors, fungal disease, coagulopathy
• Secondary hypoadrenocorticism-iatrogenic following withdrawal of long-term glucocorticoid administration, isolated ACTH deficiency, panhypopituitarism, pituitary or hypothalamic lesions

Risk Factors

N/A

Differential Diagnosis

• Signs are nonspecific and are seen in other, more common medical disorders, particularly gastrointestinal and renal diseases.
• Although no signs are pathognomonic, a waxing and waning course and previous response to nonspecific medical intervention (“fluids and steroids”) should alert the clinician to consider the diagnosis.

CBC/Biochemistry/Urinalysis

• Hematologic abnormalities may include anemia, eosinophilia, and lymphocytosis.
• The absence of a stress (glucocorticoid influence) leukogram in a patient that has been ill for a few days should prompt consideration of hypoadrenocorticism.
• Serum biochemical findings may include hyperkalemia, azotemia, hyponatremia, hypochloremia, decreased total CO₂, hyperphosphatemia, hypercalcemia, increased ALT, increased serum alkaline phosphatase, and hypoglycemia.
• Urinalysis often reveals impaired urine-concentrating ability and in some cases isothenuria. Some patients with isothenuria are also azotemic, potentially causing confusion with primary renal disease.
• Some patients with hypoadrenocorticism exhibit normal electrolyte levels (so-called atypical hypoadrenocorticism).

Other Laboratory Tests

• Definitive diagnosis is by demonstration of undetectable-to-low baseline serum cortisol concentrations that fail to increase appropriately following ACTH administration. We prefer to determine cortisol concentrations before and 1 hour after administration of synthetic ACTH IV (5 µg/kg in dogs, 0.125 mg in cats). Alternatively, ACTH gel can be given IM (2 U/kg in dogs, 10 U in cats). ACTH gel (usually 40 U/mL) is available from several compounding pharmacies. Based on a recent study performed in normal dogs, it was recommended determine serum cortisol concentrations at both 1 and 2 hours post-ACTH administration when using a compounded ACTH gel.
• In hypovolemic dehydrated animals, use synthetic ACTH IV or delay testing until after initial fluid administration is completed and tissue perfusion restored.
• If IV synthetic ACTH is used, the ACTH stimulation test can be performed during initial stabilization and treatment if dexamethasone is used since it does not cross-react with the cortisol assay.
• If prednisone, prednisolone, or hydrocortisone have been administered, these treatments must be discontinued, and the ACTH stimulation test performed at least 24 hours after changing the glucocorticoid to dexamethasone.
• A recent study demonstrated that a resting cortisol concentration above 2 µg/dL would make hypoadrenocorticism very unlikely in a dog that had not recently received glucocorticoids. Please note that this cutoff is a guideline and may vary a little based on methodology of the cortisol assay used, as well as from laboratory to laboratory using the same methodology. Also, a low resting cortisol does not confirm hypoadrenocorticism; an ACTH stimulation test is required. Determine the plasma ACTH concentration in patients with normal electrolyte levels to differentiate primary from secondary hypoadrenocorticism; must collect sample before initiating therapy, especially glucocorticoids. Carefully follow sample handling instructions from the laboratory being used. Plasma ACTH concentrations are high with primary hypoadrenocorticism and undetectable-to-low with secondary hypoadrenocorticism.

Imaging

Radiographs may reveal microcardia, narrowed vena cava or descending aorta, hypoperfused lung fields, less commonly microhepatica, and very rarely megaesophagus. Abdominal ultrasound may reveal small adrenal glands.

Pathologic Findings

• Gross examination-atrophy of the adrenal glands.
• Microscopically-lymphocytic-plasmacytic adrenalitis and/or adrenocortical atrophy. Other abnormalities may be present depending on etiology (neoplasia, fungal disease, etc.).

Appropriate Health Care

• An acute Addisonian crisis is a medical emergency requiring intensive therapy and 24 hour observation and care. The diagnostic workup is performed while initial treatment and stabilization are ongoing. Cats often respond more slowly than dogs.
• The intensity of treatment for patients with chronic hypoadrenocorticism depends on the severity of clinical signs; usually initial stabilization and therapy are conducted on an inpatient basis.

Nursing Care

• Treat acute Addisonian crisis with rapid correction of hypovolemia and restoration of volume status using isotonic fluids (preferably 0.9% NaCl).
• Monitor hydration status, blood pressure, urine output, temperature and heart rate and rhythm.

Activity

Avoid unnecessary stress and exertion during an Addisonian crisis.

Diet

No need to alter

Client Education

• Life-long glucocorticoid and/or mineralocorticoid replacement therapy is required.
• Increased dosages of glucocorticoid (above maintenence requirements) are required during periods of stress such as travel, boarding, hospitalization, and surgery.

Drug(s) Of Choice

• Chronic primary hypoadrenocorticism-most patients will need daily glucocorticoid replacement (prednisone, 0.1–0.2 mg/kg/day), as well as mineralocorticoid replacement (DOCP, Percorten, 2.2 mg/kg IM or SC typically given monthly, and adjusted as needed on the basis of serial electrolyte determinations). The initial monthly DOCP dose for an average size cat is 12.5 mg. Though not preferred, an alternative means of administering glucocorticoid replacement to cats is Depo-Medrol (10 mg IM monthly).
• Alternatively an oral mineralocorticoid replacement can be used (fludrocortisone acetate, Florinef, 5–10 µg/kg q12h, adjusted by 0.05- to 0.1-mg increments on the basis of serial electrolyte determinations). Fludrocortisone acetate has some glucocorticoid activity and the maintenance dose of prednisone for patients receiving fludrocortisone may be lower than for dogs receiving DOCP. A few dogs develop PU/PD and/or polyphagia on fludrocortisone acetate.
• In an Addisonian crisis, parenteral administration of a rapidly acting glucocorticoid such as dexamethasone sodium phosphate or prednisolone sodium succinate is indicated; dexamethasone sodium phosphate is preferred because prednisolone cross-reacts with cortisol assays. Dexamethasone sodium phosphate is given at a dose of 2–4 mg/kg IV; this dose can be repeated in 2–6 hours if necessary. Glucocorticoid is gradually tapered as the condition improves. If prednisone, prednisolone, or hydrocortisone have been given, ACTH stimulation testing will need to be delayed until the glucocorticoid has been switched to dexamethasone for at least 24 hours.
• Fluid therapy with 0.9% NaCl as needed based on the patient's hydration, volume status and blood pressure. In an Addisonian crisis, fluids are typically initiated at a rate of 60–80 mL/kg/h for the first 1–2 hours, then tapered based on the clinical status and discontinued when appropriate. If severe hyponatremia is noted on preliminary lab work, correct no quicker than 10–12 mEq/L per day over the first 48 hours of therapy.
• If necessary a colloid also can be given to help treat hypotension and hypovolemia,
• Treat hypoglycemia if present with IV dextrose.
• Sodium bicarbonate therapy is rarely needed; reserve for severe acidosis.
• Treat hyperkalemic myocardial toxicity with an intravenous insulin and glucose protocol. Alternatively use intravenous calcium chloride or calcium gluconate (cardioprotective only).
• Patients with confirmed secondary hypoadrenocorticism require only glucocorticoid supplementation (prednisone, 0.1–0.2 mg/kg/day).

Precautions

N/A

Alternative Drug(s)

• See Hyperkalemia chapter for specific recommendations for emergency management of severe hyperkalemia.
• See Hyponatremia chapter for specific recommendations for emergency management of severe hyponatremia.

Patient Monitoring

• Depending on their clinical presentation, patients hospitalized for treatment of hypoadrenocorticism may require intensive monitoring and frequent laboratory evaluations. Monitor clinical status, urine output, CBC, blood chemistry, and ECG as needed. Blood glucose and electrolytes may need to be evaluated several times daily during initial therapy. Determine blood gas status when necessary.
• After the first 2 injections of DOCP, ideally measure electrolyte levels at 2, 3, and 4 weeks to determine the duration of effect; thereafter, check electrolyte levels at the time of injection for the next 3–6 months (and adjust the dosage of DOCP if necessary) and then every 6 months.
• DOCP is usually required at monthly intervals; rare patients need injections as often as every 2 or 3 weeks. On the other hand, an occasional dog will require DOCP as infrequently as every 6 weeks. Less than 5% of dogs require a dose of DOCP higher than 2.2 mg/kg per injection.
• The large majority of dogs with hypoadrenocorticism will be well controlled on a maintenance DOCP dose of 2.2 mg/kg/injection every month. If necessary, the DOCP dosage can be sequentially decreased based on electrolyte determinations as some dogs can be controlled on a monthly dosage that is significantly less than 2.2 mg/kg. Alternatively, the interval between injections can be increased while monitoring electrolyte concentrations.
• Adjust the daily dose of fludrocortisone by 0.05- to 0.1-mg increments as needed, based on serial electrolyte determinations; following initiation of therapy, check electrolyte levels weekly until they stabilize in the normal range; thereafter, check electrolyte concentrations monthly for the first 3–6 months and then every 3–12 months.
• In many dogs given fludrocortisone, the daily dose required to control the disorder increases incrementally, usually during the first 6–24 months of therapy; in most dogs, the final fludrocortisone dosage needed is 20–30 µg/kg/day; very few can be controlled on 10 µg/kg/day or less.
• In patients that were initially azotemic, monitor creatinine concentrations as needed following discharge from the hospital.

Prevention/Avoidance

• Continue hormonal replacement therapy for the lifetime of the patient.
• Increase the dosage of replacement glucocorticoid during periods of stress such as travel, boarding, hospitalization, and surgery.

Possible Complications

• PU/PD may occur from prednisone administration, necessitating decreasing or discontinuing the drug or trying an alternative glucocorticoid.
• PU/PD may occur from fludrocortisone administration, necessitating a change to DOCP therapy.
• Side effects from DOCP are very uncommon; rarely weight gain is seen and very rarely PU/PD.

Expected Course and Prognosis

Except for patients with primary hypoadrenocorticism caused by granulomatous or metastatic disease and secondary hypoadrenocorticism caused by a pituitary mass, the vast majority of patients carry a good to excellent prognosis following with proper stabilization, treatment, and monitoring.

Associated Conditions

Concurrent endocrine gland failure occurs in up to 5% of dogs-hypothyroidism, diabetes mellitus, and/or hypoparathyroidism.

Age-Related Factors

N/A

Zoonotic Potential

None

Synonyms

Addison's disease (primary hypoadrenocorticism)

See Also

• Hyperkalemia
• Hyponatremia

Abbreviation

PU/PD = polyuria/polydipsia

Internet Resources

None