Hypoadrenocorticism (Addison’s Disease)

Hypoadrenocorticism, or Addison's disease, is uncommon in the dog and even rarer in the cat (around 40cases described) and is characterised by an insufficient production of mineralcorticoids and/or of glucocorticoids by the cortical substance of the adrenal glands. Hypoadrenocorticism has also been called “the great imitator” since, from the symptomatological viewpoint, it mimics other diseases and is therefore a challenge for clinician. Symptoms usually appear when at least 85-90% of the cortical tissue of the adrenal glands is impaired and they can appear subtly and progressively or quickly and suddenly. Although the symptomatological picture is extensive and non-specific, the diagnostic protocol is easily carried out and the treatment, if correctly performed, makes it possible to ensure the patient a completely favourable prognosis.

AETIOLOGY

Hypoadrenocorticism derives from a spontaneous or iatrogenic alteration of the hypothalamic-pituitary–adrenal axis. Based on the location of the problem the forms present may be primary (adrenal), secondary (pituitary) or tertiary (hypothalamic).

The diagram in Figure 1 summarises the aetiological classification of the disease, also indicating, for each condition, which corticosteroid component is impaired: both mineralcorticoids and glucocorticoids (Mineralcorticoid- and glucocorticoid-deficient hypoadrenocorticism or “MGDH”) or only glucocorticoids (Glucocorticoid-deficient hypoadrenocorticism or “GDH”).

The hereditary, autosomal recessive nature of the disease has been described in some canine breeds, such as the Portuguese Water Dog, Poodle and Nova Scotia Duck Tolling Retriever.

Occasionally, hypoadrenocorticism may be associated with one or more endocrine gland disorders, such as hypothyroidism, diabetes mellitus, hypoparathyroidism or azoospermia. In these cases reference is made about “autoimmune polyglandular syndrome”.

Spontaneous hypoadrenocorticism

• “Classic” primary spontaneous hypoadrenocorticism.This is the most frequent form and is the result of atrophy or, more commonly, of an immune-mediated destruction of the three layers of the adrenal cortex, with consequent inadequate secretion of mineralcorticoids and glucocorticoids (MGDH). Rarer causes are: fungal infiltrations (histoplasmosis, blastomycosis, coccidioidomycosis, cryptococcosis), lymphomatous infiltrations in cats, neoplasias (primary and metastatic), amyloidosis, traumas or coagulopathies.
• “Atypical” primary spontaneous hypoadrenocorticism.Approximately 10% of the cases of hypoadrenocorticism fall within this category. It is characterised by the absence of electrolytic alterations and presumably is the result of damage exclusively to the portion of the adrenal cortex that secretes glucocorticoids (GDH).
• Spontaneous secondary hypoadrenocorticism.Rarer than primary hypoadrenocorticism (4-24%), it is caused by the inability of the pituitary gland to secrete ACTH, whose deficiency involves atrophy of the fascicular and reticular zones; the result is a glucocorticoid deficiency but preserved mineralcorticoid production (GDH). Causes of damage to the pituitary gland can include: neoplasias, inflammation and head trauma.
• Spontaneous tertiary hypoadrenocorticism.Triggered by changes in the hypothalamus and consequent CRH deficiency, it is rare in both humans and in dogs.

Iatrogenic hypoadrenocorticism

• Iatrogenic primary hypoadrenocorticism.This is caused by drugs, used during hypercortisolism, which can damage the adrenal cortex:
  • Mitotane: mainly causes necrosis of the fascicular and reticular zones, but may also involve the glomerulus zone; the disease may thus appear only with a glucocorticoid deficiency (GDH) or with a glucocorticoid and mineralcorticoid deficiency (MGDH).
  • Trilostane: occasionally this may cause necrosis of the adrenal cortex, leading to a mineralcorticoid and glucocorticoid deficiency (MGDH); however, a glucocorticoid deficiency (GDH) alone has also been described.
• Iatrogenic secondary hypoadrenocorticism.The iatrogenic secondary form usually occurs following the sudden discontinuation of a glucocorticoid treatment. The administration of exogenous corticosteroids involves, through a negative “feedback” system, a suppression of the endogenous production of ACTH and consequent atrophy of the fascicular and reticular zones of the adrenal glands (GDH). Hypophysectomy for the treatment of pituitary adenomas is another example of iatrogenic secondary hypoadrenocorticism.

SIGNALMENT

Hypoadrenocorticism may affect subjects of all ages, but it is more common in young animals (average 4-5 years). In dogs it occurs more often in females than in males (69%). Hypoadrenocorticism can appear in any breed, but some have a higher incidence (Table 1). No breed or gender predisposition is reported in the feline species.

Table 1. Canine breeds most affected by hypoadrenocorticism.

CLINICAL HISTORY AND PHYSICAL EXAMINATION

In 25-43% of the cases clinical signs are episodic and irregular, while in other patients the symptoms show a progressive trend. The number and severity of the clinical signs, as well as the speed of progression of the endocrine disorder, vary from subject to subject. In fact, at the physical examination, the patient may present from moderately dehydrated but alert, to severely dehydrated, in shock, with increased capillary refill time and a weak pulse. It should be underlined that the various forms of hypoadrenocorticism are not easily distinguishable through the clinical signs. The most common symptoms are listed in Table 2.

Table 2. Clinical signs of hypoadrenocorticism in the dog and cat with relative frequency of presentation expressed in percentage.

LABORATORY FINDINGS

Complete blood count

• Anaemia: a mild normochromic, normocytic, nonregenerativeanaemiais found in 21-25%of subjects.
• Absence of a “stress leukogram”:in a debilitated patient, the absence of a stress leukogram (lymphopenia, eosinopaenia) allows to suspect the presence of hypoadrenocorticism, especially in the atypical form in which the absence of electrolytic alterations makes it more difficult to suspect the disease. Eosinophilia is found in 10-20% of cases and lymphocytosis in 10-13% of patients.

Biochemical profile

• Hyperkalaemia:it occurs in around 95% of patients with the classic form. This finding is not observed during secondary or atypical hypoadrenocorticism.
• Hyponatraemia:aldosterone deficiency causes hyponatraemia in 86% of patients with primary hypoadrenocorticism. The same alteration appears in 34% of subjects with the secondary form, following gastrointestinal losses and lack of appetite.
• Hypochloraemia:commonly found, it is due to renal and gastrointestinal losses.
• Na:K ratio (normal 27:1-40:1): 95%of dogs with primary hypoadrenocorticismhave a ratio <27:1.A ratio below 15:1is strongly suggestive ofhypoadrenocorticism.

Hyperkalaemia, hyponatraemia, hypochloraemia and a decrease in the Na:K ratio are the classic alterations during hypoadrenocorticism, however, they should not be considered pathognomonic for this disease since they may also be present during other pathological conditions (Table 3). In addition, the absence of these findings should not lead to exclude hypoadrenocorticism from the list of differential diagnoses since the “atypical” form and the secondary form are not characterised by these electrolytic alterations.

Table 3. Differential diagnoses of hyperkalaemia and/or hyponatraemia.

• Pre-renal azotaemia: caused by the decrease in renal perfusion and in the degree of glomerular filtration (GFR). This finding is detected in the majority (66-95%) of subjects with primary hypoadrenocorticism.
• Hyperphosphataemia: present in 66-85% of subjects with primary hypoadrenocorticism.
• Urine specific gravity (SG): in spite of the pre-renal azotaemia, the increase in urine SG is not usually present and in the majority of cases (68-88%) a urine SG <1.030 is observed.
• Metabolic acidosis: occurs in around 50% of subjects with hypoadrenocorticism.
• Hypercalcaemia: usually asymptomatic, the increase in total calcium appears in 30% of dogs with hypoadrenocorticism. Hypercalcaemia is generally resolved with fluid therapy [12] and corticosteroid supplementation.
• Hypoglycaemia: found in 22% of subjects with primary hypoadrenocorticism and in 43% of those with the secondary form.·Hypoalbuminaemia:from moderate to severe, it is reported in 17-39% of subjects with hypoadrenocorticism.
• Increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST): in 30-50% of subjects.
• Hypocholesterolaemia: found in 17.5% of subjects with hypoadrenocorticism.

DIAGNOSTIC IMAGING

Chest x-ray
Hypovolaemia may cause microcardia (Fig. 2), reduced dimensions of the caudal vena cava or decrease in the size of the pulmonary vessels. Megaesophagus  may sometimes be detected.

Abdominal ultrasound
Through abdominal ultrasound it is possible to highlight a decrease in the length and thickness of the adrenal glands, however, their dimensions in subjects with hypoadrenocorticism may sometimes be similar to those of a healthy animal.

BLOOD PRESSURE

Hypotension is frequently found in subjects with hypoadrenocorticism.

ELECTROCARDIOGRAM (ECG)

The detection of bradycardia should lead to the suspicion of the presence of a cardiac conduction disturbance triggered by hyperkalaemia. However, the heart rate can be normal when the potassium concentrations are not high enough to cause it to decrease and/or when it is increased by the sympathetic action triggered by hypovolaemic shock; thus the ECG of a patient with hypoadrenocorticism may be normal or show serious alterations, including:

• bradycardia  
• tachyarrhythmia
• conduction disturbances
• sinoventricular rhythm
• ventricular fibrillation
• asystole

DEFINITIVE DIAGNOSIS

ACTH stimulation test
This is a simple and easy-to-perform test. It should be carried out before starting treatment with corticosteroids; however, the administration of dexamethasone before the test does not change the results.

It is the gold standard for the diagnosis of hypoadrenocorticism since the test verifies the ability of the adrenal glands to produce cortisol following maximum stimulation. The test is performed by measuring the basal blood cortisol level before the intravenous or intramuscular administration of synthetic ACTH (250 µg in dogs and 125 µg in cats) and measuring the cortisol level a second time one hour after administration.

Table 4. Blood cortisol concentrations before and after administration of ACTH in healthy subjects and in subjects with hypoadrenocorticism.

Basal cortisolaemia
The measurement of basal cortisol alone is not sufficient to make a diagnosis of hypoadrenocorticism, however recent studies show that a basal cortisolaemia below 1.0 μg/dl (27.59nmol/L) has 100%sensitivity and 98.2%specificity for detecting subjects with the disease. Basal cortisolaemias < 2 μg/dl (55.2 nmol/L) have 100% sensitivity but a lower specificity (78.2%). It is unlikely that a subject with hypoadrenocorticism will have a basal cortisolaemia >2 μg/dl (55.2 nmol/L). Consequently, the evaluation of basal cortisolaemia is useful for excluding hypoadrenocorticism; nevertheless the ACTH stimulation test is necessary to confirm the disease.

Endogenous ACTH
By measuring endogenous ACTH it is possible to distinguish a primary from a secondary hypoadrenocorticism: subjects with the primary form have high endogenous ACTH (>100 pg/ml) while those with secondary hypoadrenocorticism, on the other hand, have endogenous ACTH below the reference values (<20 pg/ml). The greatest limit to this determination resides in the fact that ACTH is extremely labile. EDTA blood has to be centrifuged rapidly after sampling (ideally with refrigerated centrifuge), frozen and sent frozen to the laboratory that will measure it.

TREATMENT DURING AN ADDISON CRISIS

An Addison crisis is a true medical emergency since the patient usually presents in a state of severe hypovolaemia, dehydration, hypotension and with electrolyte and acid-base imbalances. Treatment must therefore be started immediately with the following interventions:

• restore blood volume and the state of hydration;
• resolve the electrolyte imbalances (especially hyperkalaemia and hyponatraemia);
• restore the acid-base balance;
• supplement corticosteroids.

Restoring blood volume
Blood volume and perfusion must be restored quickly through the intravenous infusion of fluids. In the case of shock the speed of infusion in dogs should be 60-90 ml/Kg for the first 1-2 hours and then the dosage should be adjusted based on the needs of the individual patient. It is appropriate to infuse saline solution (NaCl 0.9%) since it makes it possible to restore the natremia, to reduce the kalaemia and to improve the acid-base state. When NaCl 0.9% is not available, other types of crystalloids may be used (lactated or acetated Ringer's solution); the small amount of potassium contained does not seem to harm the patient undergoing an Addison crisis. Fluid therapy should be continued for at least 48 hours, monitoring the patient frequently.

Hypoglycaemia
Hypoglycaemia, when symptomatic, should be treated with an initial bolus of 0.5-1 ml/Kg of 50% glucose solution, administered intravenously in 15-20 minutes: this solution should be diluted to prevent phlebitises. If the hypoglycaemia is not symptomatic, it is sufficient to add some glucose solution to the fluid therapy to obtain a 2.5%-5% solution of glucose depending on the severity of the hypoglycaemia.

Hyperkalaemia
The first intervention consists in carrying out a suitable fluid therapy that allows a decrease in the kalaemia owing to the dilution effect, to the improvement in renal perfusion, to the potassium “shift” from the extracellular to the intracellular space and thanks to the improvement in the metabolic acidosis. In the most severe cases, often associated with bradyarrhythmias, an additional therapeutic intervention becomes appropriate:

• The simplest treatment for lowering kalaemia consists in the intravenous administration of 0.2 IU/Kg of regular insulin, followed by a bolus of glucose (4 ml of 50% glucose solution for each unit of insulin administered) and by the addition of glucose to the fluids (5%). The insulin transports the potassium inside the cells and thus lowers the kalaemia. After the administration of insulin, glycaemia should be monitored every 30-60 minutes.
• Another method for lowering kalaemia, to be used only if the patient can be closely monitored with blood-gas analysis, consists in the slow administration of 1-2 mEq/Kg of sodium bicarbonate intravenously. The effect appears after about one hour and lasts several hours. This procedure can be dangerous due to the risk of development of a difficult to correct metabolic alkalosis.
• The administration of 10% calcium gluconate (0.5-1 mL/Kg up to 10 mL/dog through intravenous infusion in 10-15 minutes) may be useful in critical subjects. This intervention does not lower the kalaemia but merely limits the cardiac conduction disturbances that a severe hyperkalaemia can trigger. By virtue of the well-known side effects during infusion, it is essential to monitor the ECG.

Hyponatraemia
During the recovery of the electrolyte balance, the natremia should not increase by more than 10-12 mmol/L per day. Indeed, a rapid increase may cause damage to the central nervous system (pontine myelinolysis). The clinical signs connected with this complication arise several days after correction of the natraemia and consist in: lethargy, weakness, lockjaw, decreased response to threat, ataxia that progresses to hypermetria and spastic tetraparesis. Thus, in cases of severe and protracted hyponatraemia, it might be appropriate to administer fluid therapy based on NaCl 0.45%.

Metabolic acidosis
Many patients undergoing an Addison crisis have a mild-moderate metabolic acidosis that is usually resolved with fluid therapy. When a severe acid-base imbalance persists (pH<7.1 or HCO3<12 mmol/L) in spite of the fluid therapy, sodium bicarbonate can be administered, calculating the patient’s HCO₃ deficit with the following formula:

bicarbonate deficit (mmol/L) = 0.3 x body weight in Kg x (24 – patient’s HCO₃)

It is necessary to administer ¼ or ½ of the calculated deficit intravenously in 2-4 hours and then repeat the blood-gas analysis. The goal of the administration of bicarbonates should not be to resolve the metabolic acidosis completely but to bring the patient’s bicarbonate level above 12 mmol/L and the pH above 7.2.

Glucocorticoid supplementation
Glucocorticoid supplementation is of essential importance when treating an Addison crisis and it should be carried out in conjunction with fluid therapy. Ideally the ACTH stimulation test should be carried out before administering corticosteroids since, except for dexamethasone, they can alter the test results.

Table 5. Glucocorticoids for potential use during an Addison crisis and their respective dosages.

Mineralcorticoid supplementation
Some authors maintain that intensive fluid therapy and glucocorticoid supplementation are sufficient to stabilise the patient, while others recommend starting mineralcorticoid supplementation during the crisis.

Table 6. Mineralcorticoids for potential use during an Addison crisis and their respective dosages.

Other adjunctive therapies
Many patients undergoing an Addison crisis experience vomiting and/or nausea, thus it may be useful to administer antiemetics and gastroprotectors when these symptoms do not disappear with the beginning of the treatment described above. A blood transfusion may be indicated when the anaemia is very severe. A broad-spectrum antibiotic therapy can also be started since a bacterial translocation from the damaged intestine is possible, with consequent sepsis.

The Addison crisis is usually resolved in a few hours with suitable fluid therapy and glucocorticoid supplementation.

The therapies, especially the glucocorticoids, should be administered parenterally until vomiting stops, after which they may be administered orally. Before discharge it is important to make sure that the subject is stable for at least 24 hours after the fluid therapy is discontinued.

MAINTENANCE THERAPY

Patients with classic primary hypoadrenocorticism require lifelong glucocorticoid and mineralcorticoid supplementation. Subjects with atypical primary hypoadrenocorticism will require lifelong glucocorticoid supplementation only; the mineralcorticoids may instead be discontinued after a certain period of time. Animals with secondary hypoadrenocorticism require lifelong glucocorticoid supplementation but not for mineralcorticoids.

Glucocorticoid supplementation

Table 7. Glucocorticoids used in maintenance therapy.

Mineralcorticoid supplementation

Table 8. Mineralcorticoids used in maintenance therapy.

Salt supplementation
When, in spite of treatment, the patient remains hyponatraemic, common salt may be added to the diet (0.1 g/Kg/day).

MONITORING AND PROGNOSIS

The goal of treatment should be to eliminate the clinical signs and to have a patient in a good state of health and with haematobiochemical parameters within the normal range. Once a suitable dosage of corticosteroids has been attained, the controls can be carried out every 3-4 months. The control consists of gathering the medical history, a careful clinical examination and execution of haematobiochemical tests (at least electrolytes).

Every time the patient shows the onset of clinical signs he/she must be re-evaluated quickly. The presence of electrolytic alterations suggests an adjustment of the mineralcorticoid level, while the onset of vomiting, diarrhoea, lack of appetite or lethargy indicates that the glucocorticoid component should be increased.

Subjects with hypoadrenocorticism, if treated correctly, have an absolutely favourable prognosis and can lead a totally normal life.

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