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Standards of Care October 2009 (Vol 11, No 8)

Hypoadrenocorticism

by Christine Bryan, Jeffery P. Simmons, DVM, MS, DACVECC, Patty Lathan, VMD, MS, DACVIM

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    Introduction

    In partnership with the Veterinary Emergency and Critical Care Society

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    Hypoadrenocorticism is a deficiency of adrenocortical hormones. Primary hypoadrenocorticism, termed Addison's disease, occurs when the destruction of both adrenal cortices results in the deficiency of glucocorticoids (cortisol) and mineralocorticoids (aldosterone). Rarely, hypoadrenocorticism results in cortisol deficiency without aldosterone deficiency (atypical hypoadrenocorticism or atypical Addison's disease). Secondary hypoadrenocorticism results from decreased pituitary production of adrenocorticotropic hormone (ACTH), leading to adrenocortical atrophy and decreased cortisol secretion. Iatrogenic hypoadrenocorticism can occur when a patient is rapidly removed from chronic glucocorticoid therapy or after mitotane or trilostane therapy. Tertiary hypoadrenocorticism, resulting from deficient hypothalamic production of corticotropin-releasing hormone, has not been reported in dogs or cats. A large amount of research regarding relative cortisol deficiency during critical illness is ongoing; however, this subject is beyond the scope of this article.

    Aldosterone is synthesized in the zona glomerulosa of the adrenal cortex. Its primary function is to promote sodium, chloride, and water reabsorption and potassium excretion in the distal renal tubules. Hyponatremia, hypochloremia, and hyperkalemia occur with aldosterone deficiency. Renal water loss accompanies sodium loss, leading to hypovolemia, hypotension, reduced cardiac output, and decreased perfusion of the kidneys and other tissues. Cortisol is synthesized primarily by the zona fasciculata of the adrenal cortex. It has multiple physiologic functions, including the stimulation of gluconeogenesis and erythropoiesis, suppression of the inflammatory response, and maintenance of normal blood pressure and cardiac contractility. Cortisol also has a role in maintaining the integrity of the gastrointestinal (GI) tract. Cortisol deficiency may result in predominantly GI signs, in addition to hypoglycemia and hypotension. Cortisol deficiency may become obvious when a patient is under stress (e.g., boarded away from home, unrelated illness).

    The clinical presentation of a dog with hypoadrenocorticism depends on the chronicity of disease. Some dogs are stable at presentation, with a history of lethargy, weight loss, and chronic GI disease. Other dogs present in hypovolemic shock with or without a history of chronic illness. Veterinarians must be particularly aware of the various clinical presentations of hypoadrenocorticism because the consequences of a missed diagnosis may be fatal.

    Cats may also be affected by hypoadrenocorticism; however, it is a much rarer diagnosis than in dogs. The clinical signs, physical examination and laboratory findings, and treatment recommendations for cats with hypoadrenocorticism are similar to those for dogs. Like dogs, with appropriate treatment and management, cats have a good prognosis following a diagnosis of hypoadrenocorticism.

    Diagnostic Criteria

    Historical Information

    • Waxing and waning illness.
    • Failure to thrive.
    • Acute, intermittent, or chronic GI signs.
      — Vomiting.
      — Diarrhea.
      — Decreased appetite.
      — Weight loss.
    • Response to fluid and/or corticosteroid therapy.
    • Exacerbation of clinical signs by stressful situations.
    • Episodic weakness and collapse.
    • Owners may not report any clinical signs before acute illness.

    Gender Predisposition

    • Most dogs (50% to 70%) with naturally occurring hypoadrenocorticism are female. The incidence seems to be higher in intact females than in spayed females.

    Age Predisposition

    • Young to middle-aged dogs are most commonly affected. Reported age at diagnosis ranges from 2 months to 14 years.

    Breed Predisposition

    • A genetic predilection has been confirmed in standard poodles, bearded collies, Portuguese water dogs, Nova Scotia duck tolling retrievers, and Leonbergers.
      — Male and female standard poodles, bearded collies, and Portuguese water dogs appear equally affected.
      — Nova Scotia duck tolling retrievers are often diagnosed at a younger age.
    • West Highland white terriers, Great Danes, rottweilers, soft-coated wheaten terriers, and Saint Bernards are also predisposed.

    Owner Observations

    • Waxing and waning signs.
    • Nonspecific signs of illness.
    • Weakness, lethargy.
    • Anorexia, weight loss.
    • Vomiting.
    • Diarrhea.
    • Hematemesis.
    • Hematochezia, melena.
    • Polyuria/polydipsia.
    • Shaking/shivering.
    • Collapse.
    • Regurgitation.

    Other Historical Considerations/Predispositions

    • Response to nonspecific therapy, including fluid support and corticosteroid administration.
    • Clinical signs exacerbated by stressful situations.
    • May be acute or chronic.
    • History of treatment for hyperadrenocorticism or treatment with corticosteroids or ketoconazole.
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    Physical Examination Findings

    • Hypovolemic shock (if acute).
      — Weak pulses.
      — Hypothermia.
      — Pale mucous membranes.
      — Prolonged capillary refill time.
    • Dehydration.
    • Bradycardia or inappropriately "normal" heart rate in a dog in hypovolemic shock.
    • Depression, weakness.
    • Abdominal pain.
    Key To Costs

    Laboratory Findings

    Serum Biochemical Profile $

    Most Common Abnormalities

    • Hyperkalemia.
      — Usually >5.5 mEq/L.
      — Suggestive of hypoadrenocorticism when found alone; hallmark sign when combined with hyponatremia.
    • Hyponatremia.
      — Usually <135 mEq/L.
      — Suggestive of hypoadrenocorticism when found alone; hallmark sign when combined with hyperkalemia.
    • Prerenal azotemia.
      — Increased blood urea nitrogen, creatinine, and phosphate.
      — May lead to misdiagnosis of primary renal failure when isosthenuria is also present.
    • Decreased sodium:potassium ratio.
      — Usually <27:1 (normal: 27:1 to 40:1).
      — Other conditions can lead to a decreased ratio; however, the lower the ratio, the more specific for hypoadrenocorticism.
      — A decreased ratio is not required for diagnosis of hypoadrenocorticism.

    Common Abnormalities

    • Metabolic acidosis.
      — Reduced bicarbonate and total CO2 concentrations.
      — Elevated lactate level (lactic acidosis).
    • Hypochloremia.

    Less Common Abnormalities

    • Hypercalcemia.
    • Hypoglycemia.
    • Elevated alanine aminotransferase, alkaline phosphatase, and aspartate aminotransferase.
    • Hypoalbuminemia and hypocholesterolemia are more common in patients with atypical hypoadrenocorticism.

    Complete Blood Count $

    • Normocytic, normochromic, nonregenerative anemia. May be severe, depending on severity of GI hemorrhage.
    • Lack of stress leukogram (i.e., normal lymphocyte and neutrophil counts) in a stressed patient.
    • Eosinophilia.
    • Lymphocytosis.

    Urinalysis $

    • Urine specific gravity between 1.015 and 1.030.
      — May lead to inappropriate diagnosis of primary renal failure in azotemic patients with hypoadrenocorticism.

    Fecal Examination $

    • To rule out intestinal parasites that can cause similar clinical signs (Trichuris vulpis).

    Other Diagnostic Findings

    Electrocardiographic Findings $

    • Electrocardiographic abnormalities are not present in all patients with hypoadrenocorticism.
    • Bradycardia or "normal" heart rate despite hypovolemia.
    • Abnormalities associated with elevated potassium levels include (in order of increasing severity):
      — Increased T-wave amplitude.
      — Shortened Q-T interval.
      — Decreased P-wave amplitude.
      — Prolonged P-R interval.
      — Absent P wave (sinoatrial standstill).
      — Severe bradycardia.
      — Asystole.
    • Bizarre QRS complexes may also be seen.

    Radiographic Findings $

    • Radiography provides little help in the diagnosis of hypoadrenocorticism but is useful to rule out diagnostic differentials.
    • Signs consistent with hypovolemia:
      — Microcardia.
      — Decreased size of caudal vena cava.
      — Decreased size of pulmonary vessels.
      — Microhepatia.
    • Dilated esophagus (if megaesophagus is present).

    Ultrasonographic Findings $

    • Adrenal glands in dogs with hypoadrenocorticism may be smaller than normal.
      — Decreased length (median values: left, 12.1 mm; right, 13.1 mm).
      — Decreased thickness (median values: left, 2.4 mm; right, 2.5 mm).
      — Do not rule out hypoadrenocorticism based on ultrasonographic findings of normal-sized or enlarged adrenal glands.

    Endocrine Testing

    ACTH Stimulation Testing $

    • Gold standard for diagnosis of hypoadrenocorticism.
    • Obtain a serum sample for baseline cortisol measurement.
    • Administer cosyntropin 5 µg/kg IV, up to 250 µg/patient.
    • Obtain a serum sample 60 minutes after cosyntropin administration.
    • A post-ACTH serum cortisol concentration of <2.0 µg/dL confirms the diagnosis of hypoadrenocorticism.
    • Previously administered glucocorticoids can interfere with ACTH stimulation testing.
    • Most synthetic glucocorticoids (including prednisone and methylprednisolone, but not dexamethasone) will cross-react with the cortisol assay, leading to a value that is falsely elevated or within normal limits. For this reason, short-acting glucocorticoids (such as prednisone and methylprednisolone succinate) should be withheld for 48 hours, and longer-acting glucocorticoids (such as methylprednisolone acetate) should be withheld for approximately 1 month before ACTH-stimulation testing.
    • Additionally, short-term administration of short-acting glucocorticoids, or an injection of a longer-acting glucocorticoid, within a month of ACTH stimulation testing will suppress the adrenocortical axis and may lead to a subnormal response to ACTH (3.0-5.0 µg/dL), but usually not <2.0 µg/dL.
    • Dexamethasone can be administered up to 48 hours before an ACTH stimulation test without affecting measured cortisol levels. This does not include long-acting steroids, like injectable methylprednisolone.

    Baseline Cortisol Levels $

    • Used to rule out, but never to definitively diagnose, hypoadrenocorticism.
    • Almost all patients with hypoadrenocorticism have a baseline cortisol level ≤ 2.0 µg/dL.
      — An ACTH stimulation test must be performed to confirm hypoadrenocorticism.
    • If baseline cortisol is >3 µg/dL, the diagnosis of hypoadrenocorticism can be ruled out.
    • Most useful in stable patients for which there is a moderate index of suspicion for hypoadrenocorticism because it is much less expensive than the ACTH stimulation test.

    Endogenous Plasma ACTH Concentration $

    • Measured after the diagnosis of hypoadrenocorticism has been confirmed.
    • Used to differentiate between primary and secondary hypoadrenocorticism.
    • Should be measured in patients with normal potassium and sodium levels if hypoadrenocorticism is suspected.
    • Patients with primary hypoadrenocorticism have elevated endogenous ACTH concentrations (usually >500 pg/mL).
    • Patients with secondary hypoadrenocorticism have decreased or undetectable endogenous ACTH concentrations (<5 pg/mL).

    Summary of Diagnostic Criteria

    • Diagnostic tests:
      — ACTH stimulation test: a post-ACTH serum cortisol concentration of <2.0 µg/dL is diagnostic of hypoadrenocorticism.
      — Serum chemistry profile: presence of hyperkalemia and/or hyponatremia warrants further investigation of hypoadrenocorticism, even in the absence of overt clinical signs.
    • Clinical signs, especially waxing and waning symptoms.
    • Response to nonspecific therapy, especially fluids and corticosteroids.
    • Patients with atypical hypoadrenocorticism (pure cortisol deficiency) present with similar clinical signs; however, they usually have normal electrolyte levels and are less likely to be in hypovolemic shock.

    Diagnostic Differentials

    • Primary or secondary GI disease.
      — Trichuriasis may produce similar clinical signs.
    • Renal disease causing azotemia and isosthenuria.
    • Urinary tract disease.
    • Myasthenia gravis.
    • Additional causes of hyperkalemia:
      — Insulin deficiency (diabetic ketoacidosis).
      — Acute tumor lysis syndrome.
      — Acidosis.
      — Drugs (nonspecific β blockers, cardiac glycosides, angiotensin-converting enzyme inhibitors).
    • Additional causes of hyponatremia:
      — Severe liver disease.
      — Congestive heart failure.
      — Nephrotic syndrome.
      — Psychogenic polydipsia.
      — Third space loss (may also cause hyperkalemia).
      — Diuretic therapy.

    Treatment Recommendations

    Initial Treatment

    • If hypoadrenocorticism is acute (addisonian crisis), treat as a medical emergency.
    • Treatment of arrhythmia, hyperkalemia, hypovolemia, hypoglycemia, and acidosis should be the initial goal.
      — Fluid resuscitation is the priority in treating an addisonian crisis; it corrects hypovolemia and most cases of hyperkalemia and metabolic acidosis. One-third to one-half of the shock dose (90 mL/kg total) of an isotonic replacement crystalloid (0.9% sodium chloride) ($) should be given as a rapid IV bolus initially; additional boluses may be administered as indicated by physical examination and other clinical parameters, such as heart rate and blood pressure. The fluid rate is decreased as signs of shock and hyperkalemia dissipate but is kept at a level that maintains daily metabolic needs and replaces interstitial fluid and ongoing losses.
      — 0.9% Sodium chloride has been the isotonic crystalloid fluid of choice for many years, but buffered isotonic crystalloid fluids such as lactated Ringer's solution (LRS) and Normosol-R are also valid choices and may be preferred because they do not worsen acidosis to the same degree as 0.9% sodium chloride. The low potassium concentration in Normosol-R and LRS should not worsen hyperkalemia.
      — Hydroxyethyl starch (hetastarch) may also be used to treat hypovolemic shock, particularly if hypoproteinemia is present. Benefits include a more rapid and prolonged correction of hypovolemia than with crystalloids alone. The dose for shock is 5-20 mL/kg, with a maintenance dose of 0.8 mL/kg/h.
      — If hyponatremia is present, care should be taken not to increase the sodium more than 0.5 mEq/hr to help prevent an abrupt change in serum osmolarity and resulting neurologic damage.
      — A dose of intravenous dexamethasone may be needed in severely hypotensive and/or bradycardic patients and cases refractory to fluid resuscitation.
    • If hypoglycemia is present, an IV dose of 1 mL/kg 25% dextrose in 0.9% sodium chloride can be administered, followed by a 1.25% to 5% dextrose solution in 0.9% sodium chloride (do not use 5% dextrose [D5W] alone because its conversion to a hypotonic fluid does not adequately expand intravascular volume).
    • Typically, fluid therapy alone corrects hyperkalemia; however, if evidence of cardiotoxic effects of hyperkalemia (severe bradycardia or arrhythmias) is present, specific treatment for hyperkalemia is warranted.
      — Calcium gluconate (2-10 mL/dog IV over 10-15 minutes) ($) can be administered to act as a cardioprotectant; the patient must be monitored with continuous electrocardiography throughout the administration.
      — Specific treatment of hyperkalemia can be accomplished with the administration of regular insulin (0.2-0.5 U/kg IV), ($) followed by glucose infusion (2 g dextrose diluted to 25% using 0.9% sodium chloride IV per unit of insulin, followed by a continuous-rate infusion of 1.25% to 2.5% dextrose in isotonic replacement crystalloid) ($); the glucose must be closely monitored with hourly serial rechecks for the first 4-6 hours, then every 2 hours, as necessary.
      — The use of bicarbonate to treat hyperkalemia and acidosis has been recommended in the past. However, it is very rarely necessary and may lead to severe complications (such as paradoxical cerebral acidosis).
    • Glucocorticoid therapy should be instituted in conjunction with fluid therapy. $
      — Dexamethasone solution or dexamethasone sodium phosphate should be used because neither interferes with the ACTH stimulation test.
      — Dexamethasone should be administered at a dose of 0.2-0.3 mg/kg IV; the dose can be repeated in 6-8 hours. There is no reason to use a higher dose.
      — Once the patient is able to begin taking oral medications, dexamethasone can be discontinued and prednisone begun at a dosage of 0.5-1 mg/kg/d after the ACTH stimulation test has been completed. Patients require two to 10 times the physiologic dose of prednisone during acute illness.
      — After the patient is discharged from the hospital, glucocorticoid doses can be gradually adjusted to minimize clinical signs of hypoadrenocorticism and adverse effects of the glucocorticoid.
    • Additional symptomatic treatment can be initiated as necessary.
      — Dogs displaying GI signs (hematemesis or melena) should be treated with GI protectants (H2 blockers and sucralfate) as needed ($). Administration of prophylactic antibiotics to these patients to treat bacterial translocation from the GI tract is controversial.
      — Packed red blood cell or whole blood transfusion ($-$$) may be necessary to treat anemia that develops secondary to GI blood loss.
    • Dogs should be monitored for response to therapy.
      — Vital parameters should be monitored regularly.
      — Electrolytes should be rechecked every 1-2 hours until the patient is hemodynamically stable and hyperkalemia is out of the life-threatening range; electrolyte levels can then be measured every 6-12 hours, depending on the patient's condition.
      — Sodium should not be increased by >0.5 mEq/h.
      — Continuous electrocardiography should be monitored until resolution of arrhythmias.

    Supportive Treatment

    • IV fluid therapy with balanced isotonic crystalloid fluids such as LRS or Normosol-R, with or without hetastarch.
    • Glucocorticoid therapy.
      — Initial administration of dexamethasone (0.2-0.3 mg/kg IV).
      — As the patient improves, dexamethasone can be replaced with oral prednisone/prednisolone at a dosage of 0.5-1 mg/kg/d during hospitalization (dosage can be tapered after discharge). Alternatively, injectable hydrocortisone (0.2-0.5 mg/kg/d) can be given instead of dexamethasone, as hydrocortisone also has some mineralocorticoid properties.

    Maintenance Therapy

    • Most patients with primary hypoadrenocorticism require mineralocorticoid supplementation and glucocorticoid therapy.
      — Patients with atypical hypoadrenocorticism require glucocorticoid therapy only.

    Mineralocorticoid Therapy

    • Desoxycorticosterone pivalate (DOCP; $) is a long-acting mineralocorticoid.
      — DOCP should be administered at 2.2 mg/kg every 25 days (the interval may be increased or decreased depending on response).
      — SC administration is appropriate for most dogs; occasionally, dogs may require IM administration because of inconsistent absorption.
      — Electrolytes should be reevaluated at 14 and 25 days postinjection.
      — At the 14-day recheck:
      • If potassium is above the reference range and sodium is below the reference range, the dose should be increased 10% to 25% at the next administration.
      • If potassium is below the reference range and sodium is above the reference range, the dose should be decreased.
      • If potassium and sodium are within the reference ranges, continue with the current dosage.
      — At the 25-day recheck:
      • If potassium is above the reference range and/or sodium is below the reference range, the interval between doses should be decreased by 1-2 days.
      • If potassium is below the reference range and/or sodium is above the reference range, the interval between doses should be increased by 1-2 days.
      • If potassium and sodium are within the reference ranges, continue with the current dosing interval.
      — The interval between doses of DOCP is typically 25 days but may vary from 21 to 30 days.
    • Fludrocortisone acetate ($) has also been used for mineralocorticoid supplementation.
      — Fludrocortisone acetate should be administered at a dosage of 0.02 mg/kg/d PO divided bid.
      — Serial electrolytes should be measured weekly after the crisis and the dose gradually increased 0.05-0.1 mg/kg as needed to equalize electrolyte values.
      — Electrolytes should be monitored every 3-4 months after the values have normalized.
      — During the first year of treatment, the dose is typically incrementally increased but then stabilizes.
      — If a patient remains mildly hyponatremic on fludrocortisone acetate, its food may be salted (0.1 mg/kg/d).
      — Fludrocortisone acetate has some glucocorticoid activity as well as mineralocorticoid activity; therefore, additional glucocorticoid therapy may not be necessary in all patients.

    Glucocorticoid Therapy

    • Prednisone ($) should be administered at a physiologic dosage (0.22 mg/kg/d PO initially and tapered to effect).
      — It is extremely important to note that patients require two to 10 times the physiologic dose of prednisone during acute illness and stressful situations, including routine veterinary visits (such as for DOCP administration).

    Patient Monitoring

    • Serial monitoring of electrolytes (every 3-6 months, depending on patient condition).

    Home Management

    • Patients should be closely monitored during stressful events or acute illness and their dose of prednisone increased by two to 10 times the physiologic dose.
    • Owners should be informed of the signs of addisonian crisis:
      — Depression.
      — Weakness.
      — Anorexia.
      — Vomiting.
      — Diarrhea.

    Milestones/Recovery Time Frames

    • This is a lifelong disease process and, therefore, requires lifelong administration of glucocorticoids and/or mineralocorticoids. Owners should be informed of this at diagnosis in case lifelong administration of medications is cost prohibitive.

    Treatment Contraindications

    • Mineralocorticoids should be used cautiously in patients with cardiac disease. Fludrocortisone is generally used in these patients because the dose can be adjusted more readily.

    Prognosis

    Favorable Criteria

    • Improvement with initial treatment and continued supportive care.
    • Stabilization of electrolyte values with administration of DOCP or fludrocortisone acetate.
    • Excellent prognosis when maintenance therapy and owner education are combined.

    Unfavorable Criteria

    • Financial limitations.
      — Approximate treatment cost for a 25-kg dog for 25 days with DOCP (2.2 mg/kg/d): $100 (year total: $1460).
      — Approximate treatment cost for a 25-kg dog for 25 days with fludrocortisone acetate (0.02 mg/kg/d): $155 (year total: $2260).
    • Delayed treatment.
    • Poor response to therapy (uncommon without concurrent disease).
    • Repeated addisonian crises.
      — Most frequently occur when owners skip or extend time between doses of DOCP due to expense.
      — May also occur in presence of concurrent disease.

    Adler JA, Drobatz KJ, Hess RS. Abnormalities of serum electrolyte concentrations in dogs with hypoadrenocorticism. J Vet Intern Med 2007;21:1168-1173.

    Herrtage ME. Hypoadrenocorticism. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. Philadelphia: Elsevier Saunders; 2005:1612-1622.

    Kintzer PP, Peterson ME. Hypoadrenocorticism. In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy XIV. Philadelphia: Saunders; 2008:231-235.

    Lathan P, Moore GE, Zambon S, Scott-Moncrieff JC. Use of a low-dose ACTH stimulation test for diagnosis of hypoadrenocorticism in dogs. J Vet Intern Med 2008;22:1070-1073.

    Lathan P, Tyler JW. Canine hypoadrenocorticism: diagnosis and treatment. Compend Contin Educ Pract Vet 2005;27(2):121-132.

    Lathan P, Tyler JW. Canine hypoadrenocorticism: pathogenesis and clinical features. Compend Contin Educ Pract Vet 2005;27(2):110-120.

    Thompson AL, Scott-Moncrieff JC, Anderson JD. Comparison of classic hypoadrenocorticism with glucocorticoid-deficient hypoadrenocorticism in dogs: 46 cases (1985-2005). JAVMA 2007;230:1190-1194.

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