Contributors: David Bruyette, Ian Ramsey, Emma Roberts

 Species: Canine   |   Classification: Diseases

Introduction Pathogenesis Diagnosis Treatment Outcomes Further Reading

Introduction

  • Uncommon (reported prevalence 0.06-0.28%).
  • Cause: insufficient mineralocorticoid and/or glucocorticoid production.
  • Signs: inappetence, lethargy/depression, vomiting/diarrhea, weakness, shivering, polyuria, polydipsia, collapse.
  • Diagnosis: aldosterone and/or cortisol suppression on an ACTH stimulation test.
  • Treatment: hormonal supplementation (mineralocorticoids and glucocorticoids).
  • Prognosis: excellent once controlled.
Print off the owner factsheet on Addison's disease (hypoadrenocorticism) Addison's disease (hypoadrenocorticism) to give to your client.

Presenting Signs

  • Inappetence/anorexia.
  • Lethargy/depression.
  • Vomiting (may contain fresh blood (hematemesis)).
  • Weakness.
  • Diarrhea (may contain fresh (hemorrhage) or digested blood (melena).
  • Weight loss.
  • Shivering/muscle stiffness.
  • Polyuria/polydipsia.
  • Acute collapse.
  • Regurgitation.
  • Seizures (secondary to hypoglycemia Hypoglycemia).

Acute Presentation

  • Hypovolemic shock (prolonged capillary refill times, weak peripheral pulses +/- tachycardia), weakness and collapse (NB some dogs can be bradycardic despite being in hypovolemic shock due to hyperkalemia).

Age Predisposition

  • Young to middle-aged (average age at diagnosis 4-5 years).
  • Younger age of onset in the Nova Scotia Duck Tolling Retriever Retriever: Nova Scotia Duck Tolling (median age at diagnosis 2.6 years).

Breed Predisposition

Pathogenesis

Etiology

  • Destruction (spontaneous hypoadrenocorticism) of adrenal cortex leads to impaired secretion of mineralocorticoids and glucocorticoids.
  • Immune-mediated destruction is thought to be the most common cause though usually not diagnosed.
  • Other possible causes:
    • Idiopathic.
    • Necrosis.
    • Hemorrhagic infarction.
    • Metastatic neoplasia.
    • Amyloidosis Amyloidosis.
    • Granulomatous destruction, eg blastomycosis Blastomycosis, histoplasmosis Histoplasmosis, cryptococcosis Cryptococcosis.
    • Drug induced, eg mitotane, ketoconazole, trilostane (idiosyncratic).
  • Secondary hypoadrenocorticism also reported both spontaneous and iatrogenic (rapid withdrawal of chronic corticosteroid treatment).
  • Hypoadrenocorticism may form part of a polyglandular autoimmune syndrome in some dogs, which can also include hypothyroidism, hypoparathyroidism and diabetes mellitus.

Predisposing Factors

General

  • Breed.
  • Drug therapy, eg mitotane, or withdrawal of drug therapy, eg prednisolone.

Pathophysiology

Aldosterone deficiency

  • Leads to a reduced ability to conserve sodium and chloride and excrete potassium and hydrogen ions.
  • Sodium loss may be further increased by vomiting/diarrhea and reduced intake, ie anorexia.
  • Loss of sodium and chloride leads to loss of water concurrently and volume depletion, reduced cardiac output and decreased glomerular filtration rate.
  • Reduced perfusion to the gastrointestinal tract can potentially lead to gastrointestinal ulceration, and acute pancreatitis.
  • Reduced renal perfusion → increased hyperkalemia → reduced myocardial and muscle excitability → bradycardia and weakness.

Glucocorticoid deficiency

  • Reduced glucogenesis + fat metabolism may → hypoglycemia.
  • Reduced cortisol to the CNS may lead to lethargy and depression.
  • Cortisol also required for intestinal integrity and reduction contributes to vomiting, diarrhea and inappetence.
  • Cortisol stimulates appetite and red blood cell production, therefore deficiency can result in inappetence and anemia.
  • In 1° adrenal insufficiency → increased ACTH secretion from pituitary → impaired tolerance to stress.

Atypical hypoadrenocorticism

  • Cases of hypoadrenocorticism in which only glucocorticoid deficiency is present. Previously classified as atypical when the typical electrolyte changes were not present, ie hyperkalemia and/or hyponatremia, however recent work has shown that cases of typical hypoadrenocorticism do not always have electrolyte abnormalities.
  • These cases tend to be older at the time of diagnosis and have a longer duration of clinical signs when compared to cases of typical hypoadrenocorticism.
  • More likely to be anemic, hypoalbuminemic and hypocholesterolemic than typical hypoadrenocorticism cases.
  • Diagnosis in these cases is particularly difficult and clinical signs can include lethargy, severe gastrointestinal disease (often hemorrhage), weight loss and regurgitation secondary to megaesophagus.
  • Diagnosis is based on evidence on lack of cortisol but not aldosterone stimulation on an ACTH stimulation test.
  • These cases may progress over time to become deficient in mineralocorticoids as well, however, in some cases animals have been monitored for several years with no development of electrolyte abnormalities.

Secondary hypoadrenocorticism

  • Caused by lack of production of ACTH by the pituitary gland. This can be idiopathic or due to lesions in the hypothalamus or pituitary caused by head trauma, neoplasia or inflammation.
  • This can also occur due to rapid withdrawal of chronic corticosteroid treatment (iatrogenic).
  • Results in lack of glucocorticoid production only.

Timecourse

  • May have an insidious onset over months to years with waxing and waning clinical signs.
  • Often present in acute crisis with circulatory collapse.

Diagnosis

Client History

  • Collapse Collapse.
  • Lethargy/depression.
  • Anorexia.
  • Vomiting (which may include hematemesis) and diarrhea (which may be hemorrhagic or melenic).
  • Weight loss.
  • Weakness (usually episodic).
  • Waxing and waning illness.
  • Shaking/muscle tremors.
  • Polyuria, polydipsia.
  • Abdominal pain.
  • Regurgitation.

Clinical Signs

Acute adrenocortical crisis

  • Rapidly progressive, life-threatening:
    • Hypovolemic shock (weak pulses, prolonged capillary refill time).
    • Bradycardia or tachycardia.
    • Collapse.
    • Depression.
    • Hypothermia.

Chronic

  • Depression/lethargy.
  • Weakness.
  • Dehydration.
  • Weight loss.
  • Bradycardia, weak femoral pulse.
  • Restlessness/shaking/shivering.
  • Abdominal pain.
  • Gastrointestinal hemorrhage.

Diagnostic Investigation

Hematology

  • Hemoconcentration in crisis secondary to dehydration/hypovolemia (increased PCV, increased [plasma protein]).
  • Chronic form: a non-regenerative anemia Anemia: non-regenerative may be seen but can be masked by hemoconcentration if dehydrated.
  • Severe anemia can be seen due to gastrointestinal hemorrhage.
  • Occasionally lymphocytosis and/or eosinophilia Hematology: eosinophil can be seen.
    Lack of stress leukogram in a sick dog → increased suspicion of hypoadrenocorticism in sick animal.

Biochemistry

Urinalysis

  • SG Urinalysis: specific gravity: less than 1.030 (57.6%) (due to impaired concentrating mechanism resulting from hyponatremia) can be seen in the presence of azotemia in hypoadrenocorticism.

Radiography

  • See also thoracic radiography Radiography: thorax.
  • Microcardia, reduced diameter of the caudal vena cava and cranial lobar pulmonary artery and a small liver: due to dehydration and hypovolemia.
  • On very rare occasions a megaesophagus may be seen due to severe muscle weakness.

Electrocardiography

  • See also ECG ECG: overview.
  • Impaired conduction [potassium].
  • ECG changes include sinus bradycardia, a reduction and eventual loss of the P wave, an increase in T wave amplitude, a widening of the QRS interval and a decrease in the QRS amplitude, ventricular fibrillation and asystole.
  • Experimentally:
    • >5.5 mmol/L - increased T wave amplitude.
    • >6.5 mmol/L - decreased amplitude of R wave, prolongation of QRS and PR interval and ST segment depression.
    • >7.0 mmol/L - P wave amplitude decreased, increased P wave duration, prolongation of QT interval.
    • >8.5 mmol/L - atrial standstill, asystole, ventricular fibrillation, ventricular flutter.
  • However, ECG changes correlate poorly with the potassium concentrations due to increased calcium concentrations and/or the presence of acidosis. The absence of a bradycardia does not exclude hypoadrenocorticism. 

Ultrasonography

  • May demonstrate a reduction in adrenal gland size but this finding is not consistent and should not be relied on for the diagnosis of hypoadrenocorticism.

Basal cortisol

  • Basal cortisol Blood biochemistry: cortisol is an effective screening test for hypoadrenocorticism with a value <55 nmol/L shown to have a 100% sensitivity for diagnosing hypoadrenocorticism, however the specificity is poor at 63.3% and so an ACTH stimulation test ACTH stimulation test should be performed to confirm the diagnosis.
  • Other causes of the animal's clinical signs should be considered if the basal cortisol is >55 nmol/L.

ACTH assay

  • Endogenous ACTH concentrations are high in primary hypoadrenocorticism because no negative feedback from cortisol occurs.
  • It can be used to differentiate cases of atypical primary hypoadrenocorticism (where it will be high) from cases of secondary hypoadrenocorticism (where it will be low/undetectable).

Aldosterone to renin (ARR) or cortisol to ACTH ratio (CAR)

  • Calculation of the ratios eliminates the overlap that occurs between [cortisol] and [ACTH] in healthy and hypoadrenocorticoid dogs.
  • Although an early study showed the CAR ration could be used to diagnose hypoadrenocorticism in dogs, a more recent and larger study has shown that overlap of this ratio can occur between dogs with hypoadrenocorticism and dogs with diseases mimicking hypoadrenocorticism in a small number of cases. Therefore due to this overlap, although a CAR > 0.01 was found to have a sensitivity of 100% and a specificity of 99% for the diagnosis of hypoadrenocorticism, an ACTH stimulation test ACTH stimulation test should still be considered in these cases due to the small possibility of a mis-diagnosis occurring.
  • Special care is needed in collecting samples for the ACT assay as the level of this hormone rapidly decreases post-sampling due to hemolysis/proteolysis.
  • The ARR ratio has yet to be assessed in a study that includes dogs with hypoadrenocorticism as well as dogs with diseases mimicking hypoadrenocorticism, therefore its reliability cannot be commented on. Renin assays are also technically difficult to run and not currently widely available.  

Definitive diagnosis of hypoadrenocorticism

  • ACTH stimulation test (definitive) ACTH stimulation test.
  • Plasma [cortisol] low/undetectable initially and no/minimal response to ACTH.
  • Aldosterone release can also be measured via ACTH stimulation test.
  • Hypoadrenocorticism confirmed if post-ACTH cortisol concentrations are less than 55 nmol/L (<2 µg/dl). Most cases have pre- and post-ACTH cortisol <27 nmol/L (<1 µg/dl).

Differential Diagnosis

  • Artifactual hyperkalemia:
    • Akita → may have high [potassium] in RBCs, hemolysis of sample.
    • EDTA contamination of heparinized sample leads to false elevation of potassium level.
    • Extreme thrombocytosis can cause artifactual hyperkalemia.
  • Lipemia can cause artifactual hyponatremia.

Other causes of Na: K ratio <27:1 and/or hyperkalemia and/or hyponatremia can include:

  • Gastrointestinal disease (including Salmonella and Trichuris vulpis).
  • Liver and/or pancreatic disease.
  • Renal and urinary tract disorders, eg acute renal failure Kidney: acute kidney injury (AKI), urethral obstruction.
  • Cardiorespiratory disease including congestive heart failure.
  • Repeated drainage of chylous and non-chylous pleural effusions Pleural: effusion.
  • Pregnancy.

Treatment

Standard Treatment

Acute crisis

  • Rapid infusion of 0.9% saline if in hypovolemia shock using shock rates and then reduce fluid rate depending on clinical response as required.
    • Lactated Ringer's solution or Normosol-R can also be used.
Perform ACTH stimulation test before administering glucocorticoids.If steroids administered before ACTH stimulation test then false positive diagnoses may occur. The longer lasting the preparation and the higher the dose the longer this effect may persist.
  • If the dog is hemodynamically unstable and rapid administration of glucocorticoids is needed prior to the ACTH stimulation test, then dexamethasone should be used.
  • Intravenous glucocorticoids:
    • Hydrocortisone sodium succinate (2-4 mg/kg IV IM q4-6 h or 0.5-0.625 mg/kg/hr CRI) Hydrocortisone.
    • Prednisolone sodium succinate (1-2 mg/kg IV IM q12 h) Prednisolone.
    • Dexamethasone sodium phosphate (0.1-0.2 mg/kg) Dexamethasone then 0.05-0.1 mg/kg q12 h until oral glucocorticoids can be given.
  • Intravenous glucose (with saline) if hypoglycemic.
  • Continue IV fluids until electrolytes stabilized and animal eating again.
  • Monitor serum electrolytes, blood glucose, acid-base status, blood pressure, urine output and ECG (if hyperkalemic).
  • Specific treatment of hyperkalemia Hyperkalemia with insulin/glucose infusions or calcium gluconate may be needed dependent on the individual case.

Chronic

Either Fludrocortisone acetate (starting dose //www.vetlexicon.com0.01-0.02 mg/kg/day PO) either once/day or divided twice daily Fludrocortisone.
Or Desoxycorticosterone pivalate DOCP (UK) (or DOCP (US)) (mineralocorticoid) SC (2.2 mg/kg q25-28 days) and glucocorticoid replacement with Prednisolone (starting dose //www.vetlexicon.com0.2 mg/kg/day) Prednisolone. The prednisolone dose should be tapered gradually according to clinical signs/side effects, to the lowest effective dose. Some texts report that every other day may be possible in some cases.

  • Some clinicians advocate adding table salt added to food to correct mild hyponatremia for dogs receiving fludrocortisone, however, there is no evidence to support or refute this suggestion and it should not be required if the animal is eating a commercial balanced diet.
  • Additional prednisolone may be required during times of stress Prednisolone.
  • Water ad lib.

Monitoring

  • Usually show rapid response to therapy (within 1-2 hours).
  • Hypotension resolving.
  • ECG changes resolving.
  • [Sodium] and [potassium] concentrations normalizing.
  • Acidosis resolving.
  • Azotemia resolving.
    Rehydration may unmask severe anemia so monitor PCV Hematology: packed cell volume.

Subsequent Management

Treatment

  • Lifelong therapy.
  • Regular monitoring of Na: K ratio (usually once every 3-6 months).
  • Increased dose of glucocorticoids during periods of stress, eg illness, surgery or kenneling.
  • Recent research has also proposed measurement of plasma renin activity as a monitoring tool for mineralocorticoid supplementation.
  • Those dogs with atypical hypoadrenocorticism should be monitored for the possible development of mineralocorticoid deficiency developing in the future.

Outcomes

Prognosis

  • Excellent once adrenal crisis is controlled.

Expected Response to Treatment

Reasons for Treatment Failure

  • Incorrect diagnosis.
  • Initial therapy and monitoring not sufficiently aggressive.
  • Not supplying glucocorticoid replacement Prednisolone with mineralocorticoid therapy DOCP when using DOCP.
  • Insufficient supplementation of mineralocorticoids and/or glucocorticoids.
  • Concurrent disease, ie hypothyroidism Hypothyroidism.
  • Owner not realizing importance of:
    • Lifelong therapy.
    • Regular monitoring.
    • Need to increase glucocorticoid dose during stress.

Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
  • Gunn E, Shiel R E, & Mooney C E (2016) Hydrocortisone in the management of acute hypoadrenocorticism in dogs: a retrospective series of 30 cases. JSAP, 57 (5), 227-233 PubMed.
  • Roberts E, Boden L A & Ramsey I K (2016) Factors that affect stabilisation times of canine spontaneous hypoadrenocorticism. Vet Rec 179 (4), 98 PubMed.
  • Boretti F S, Meyer F, Burkhardt W A, Riond B, Hofmann-Lehmann R, Reusch C E & Sieber-Ruckstuhl N S (2015) Evaluation of the cortisol-to-ACTH ratio in dogs with hypoadrenocorticism, dogs with diseases minicking hypoadrenocorticism and in healthy dogs. JVIM 29 (5), 1335-1341 PubMed.
  • Baumstark M E, Nussberger J, Boretti F S, Baumstark M W, Riond B, Reusch C E & Sieber-Ruckstuhl N S (2014) Use of plasma renin activity to monitor mineralcorticoid treatment in dos with primary hypoadrenocorticism: desoxycorticosterone versus fludrocortisone. JVIM 28 (5), 1471-1478 PubMed.
  • Baumstark M E, Sieber-Ruckstuhl N S, Muller C, Wenger M, Boretti F S & Reusch C E (2014) Evaluation of aldosterone concentrations in dogs with hypoadrenocorticism. JVIM 28 (1), 154-159 PubMed.
  • Bovens C, Tennant K, Reeve J & Murphy K F (2014) Basal serum cortisol concentration as a screening test for hypoadrenocorticism in dogs. JVIM 28 (5), 1541-1545 PubMed.
  • Lathan P, Scott-Moncrieff J C & Wills R W (2014) Use of the Cortisol-to-ACTH Ratio for Diagnosis of Primary Hypoadrenocorticism in Dogs. JVIM 28 (5), 1546-1550 PubMed.
  • Zeugswetter F K & Schwendenwein I (2014) Diagnostic efficacy of the leukogram and the chemiluminometric ACTH measurement to diagnose canine hypoadrenocorticism. Tierärztliche Praxis. Ausgabe K, Kleintiere/Heimtiere, 42 (4), 223-230 PubMed.
  • Wenger M, Mueller, C, Kook, P H & Reusch C E (2010) Ultrasonographic evaluation of adrenal glands in dogs with primary hypoadrenocorticism or mimicking diseases. Vet Rec 167 (6), 207-210 PubMed.
  • Neilsen L, Bell R, Zoia A, Mellor D, Neiger R & Ramsey I (2008) Low ratios of sodium to potassium in the serum of 238 dogs. Vet Rec 162 (14), 431-435 PubMed.
  • Tag T L & Day T K (2008) Electrocardiographic assessment of hyperkalemia in dogs and cats. Journal of Veterinary Emergency and Critical Care 18 (1), 61-67 VetMedResource.
  • Adler J A, Drobtaz K J & Hess R S (2007) Abnormalities of serum electrolyte concentrations in dogs with hypoadrenocorticism. JVIM 21 (6), 1168-1173 PubMed.
  • Hughes A M, Nelson R W, Famula T R, & Bannasch D L (2007) Clinical features and heritability of hypoadrenocorticism in Nova Scotia Duck Tolling Retrievers: 25 cases (1994-2006). JAVMA 231 (3), 407-412 PubMed.
  • Thompson A L, Scott-Moncrieff J C & Anderson J D (2007) Comparison of classic hypoadrenocorticism with glucocorticoid-deficient hypoadrenocorticism in dogs: 46 cases (1985-2005). JAVMA 230 (8), 1190-1194 PubMed.
  • Javadi S, Galac S, Boer P, Robben J H, Teske E & Kooistra H S (2006) Aldosterone-to-renin and cortisol-to-adrenocorticotropic hormone ratios in healthy dogs and dogs with primary hypoadrenocorticism. J Vet Intern Med 20 (3), 556-561 PubMed.
  • Oberbauer A M, Bell J S, Belanger J M, & Famula T R (2006) Genetic evaluation of Addison’s disease in the Portuguese Water Dog. BMC Veterinary Research, 2, 15 PubMed.
  • Famula T R, Belanger J M & Oberbauer A M (2003) Heritability and complex segregation analysis of hypoadrenocorticism in the standard poodle. JSAP 44 (4), 8-12 PubMed.
  • Oberbauer A M, Benemann K S, Belanger J M, Wagner D R, Ward J H, & Famula T R (2002) Inheritance of hypoadrenocorticism in Bearded Collies. Am J Vet Res 63 (5), 643-647 PubMed.
  • Schaer M, Halling K B, Collins K E & Grant D C (2001) Combined hyponatremia and hyperkalemia mimicking acute hypoadrenocorticism in three pregnant dogs. JAVMA 218 (6), 897-900 PubMed.
  • Melián C, Stefanacci J, Peterson M E, & Kintzer P P (1999) Radiographic findings in dogs with naturally-occurring primary hypoadrenocorticism. JAAHA 35 (3), 208-212 PubMed.
  • Syme H M & Scott-Moncrieff J C (1998) Chronic hypoglycemia in a hunting dog due to secondary hypoadrenocorticism. JSAP 39 (7), 348-351 PubMed.
  • Kintzer P P & Peterson M E (1997) Treatment and long-term follow-up of 205 dogs with hypoadrenocorticism. JVIM 11 (2), 43-49 PubMed.
  • Lifton S J, King L G & Zerbe C A (1996) Glucocorticoid deficient hypoadrenocorticism in dogs - 18 cases (1986-1995). JAVMA 209 (12), 2076-2081 PubMed.
  • Peterson M E, Kintzer P P & Kass P H (1996) Pretreatment clinical and laboratory findings in dogs with hypoadrenocorticism - 225 cases (1979-1993). JAVMA 208 (1), 85-91 PubMed.
  • Sadek D S & Schaer M (1996) Atypical Addison's disease in the dog - a retrospective survey of 14 cases. JAAHA 32 (2), 159-163 PubMed.
  • Schaer M & Chen C L (1983) A clinical survey of 48 dogs with adrenocortical hypofunction. JAAHA 19 (4), 443-452 VetMedResource.

Other sources of information

  • Scott-Moncrieff J C (2015) Hypoadrenocorticism. In: Canine and Feline Endocrinology. 4th edn. Eds Feldman E C, Nelson R W, Reusch C E & Scott-Moncrieff J C. St Louis, Missouri: Elsevier Saunders. pp 485-514
  • Scott-Moncrieff J C (2010) Hypoadrenocorticism. In: Textbook of Veterinary Internal Medicine, 7th edn. Eds Ettinger S J & Feldman E C. St Louis, Missouri: Elsevier Saunders. pp 1847-1857
  • Feldman E C & Nelson R W (2004) Hypoadrenocorticism Addisons Disease. In: Canine and Feline Endocrinology and Reproduction. 3rd edn. St Louis, Missouri, Saunders Elsevier, pp 394-439.
  • Ramsey I (2003) Diagnosis and treatment of canine hypoadrenocorticism. In Practice 25, 18-25.
  • Feldman E C & Peterson M E (1984) Hypoadrenocorticism. Vet Clin N Am 14, pp 751.

Other Sources of Information