IMMUNE-MEDIATED (AUTOIMMUNE) DISEASE.

Idiopathic adrenal insufficiency is the most common diagnostic “label” for dogs with adrenocortical failure, because the cause of the disease is usually not obvious. However, the disease is most common in young to middle-age female dogs, and many of the features of the disease resemble those in humans. The most common cause of human hypoadrenocorticism is immune-mediated destruction of the adrenal cortices (Table 8-1), which affects four times as many women as men (Findling and Tyrell, 1991). In the active phase of the disease, histologic examination of the adrenals reveals widespread but variable infiltrates consisting of lymphocytes, plasma cells, and macrophages. In advanced stages, the cortex is replaced by fibrous tissue (Findling et al, 1997).

TABLE 8-1 CAUSES OF PRIMARY AND SECONDARY ADRENAL INSUFFICIENCY IN HUMANS

* Type I autoimmune polyglandular syndrome consists mainly of adrenal insufficiency, hypoparathyroidism, and mucocutaneous candidiasis. Type II autoimmune polyglandular syndrome consists mainly of adrenal insuffi-ciency, autoimmune thyroid disease, and insulin-dependent diabetes mellitus.

† Diabetes insipidus is often present.

From Oelkers (1996); used with permission.

It is likely that most dogs and cats with naturally occurring hypoadrenocorticism also have immune-mediated destruction of the adrenal cortices (Schaer et al, 1986; Reusch, 2000). Idiopathic atrophy of all the layers of the adrenal cortex continues to be the most frequently observed histologic lesion in dogs with hypoadrenocorticism. Necropsy of recently afflicted dogs is not common, which decreases the possibility of visualizing an active inflammatory process. Most dogs afflicted with hypoadrenocorticism either die without necropsy or are diagnosed and treated. Dogs and cats treated for any length of time have no immune-mediated infiltrates and are left with atrophied/fibrotic glands. The pituitary gland is normal in primary immune-mediated adrenocortical atrophy (Boujon et al, 1994).

Humans who would formerly have been considered to have idiopathic adrenal insufficiency can now be evaluated for the presence of antiadrenocortical antibodies. In this way, immune-mediated destruction of human adrenal cortices can be confirmed with readily available laboratory testing. Similar tests have not yet been applied and reported from a large series of dogs with the syndrome, although antiadrenal antibody testing is occasionally mentioned (Kooistra et al, 1995).

MULTIPLE IMMUNE-MEDIATED DISORDERS

OTHER CAUSES OF PRIMARY HYPOADRENOCORTICISM.

Uncommon (rare?) causes of canine adrenocortical insufficiency include destruction of the adrenal cortices by granulomatous diseases such as histoplasmosis and blastomycosis; hemorrhagic infarctions (secondary to trauma, warfarin-type toxicity, or other coagulopathies), metastases of cancer to the adrenal glands; amyloidosis of the adrenal cortices; trauma (accidents); and iatrogenic causes (surgical removal of the adrenals, rapid withdrawal of a dog from chronic glucocorticoid therapy, or overdose with the adrenocorticolytic drug o,p′-DDD, which is used in the treatment of hyperadrenocorticism). Interestingly, in humans with hypoadrenocorticism secondary to hemorrhage or metastases to the glands, bilateral adrenal enlargement (sometimes massive enlargement) is often detected with ultrasonography or computed tomography (Tyrrell et al, 1991).

NATURALLY OCCURRING DISEASE.

In addition to disease processes specifically affecting the adrenal glands, reduced secretion of ACTH by the pituitary gland results in decreased synthesis and secretion of adrenocortical hormones, especially glucocorticoids (see Fig. 8-1). Reduced secretion of corticotropin-releasing hormone (CRH) by the hypothalamus may also result in secondary adrenocortical failure. Destructive lesions in the pituitary or hypothalamus that would result in ACTH or CRH insufficiency (or both) are usually caused by neoplasia; inflammation and trauma are less common causes (Velardo et al, 1992; Thodou et al, 1995) (see Table 8-1). Among humans with secondary disease, especially those with space-occupying lesions, few have only adrenal insufficiency. Other hormonal systems are usually involved, and neurologic or ophthalmologic symptoms may accompany, precede, or follow adrenal insufficiency (Vance, 1994).

IATROGENIC CAUSES

PHYSIOLOGIC ACTIONS.

Mineralocorticoids function to control sodium, potassium, and water homeostasis. They promote sodium, chloride, and water resorption, as well as potassium excretion in epithelial tissues, including the intestinal mucosa, salivary glands, sweat glands, and kidneys. The primary site of aldosterone effect is the renal tubule, where aldosterone promotes proximal convoluted renal tubular resorption of sodium and chloride and distal convoluted tubular resorption of sodium by exchange with potassium (Nelson, 1980).

RENIN-ANGIOTENSIN SYSTEM.

Secretion of aldosterone is under primary control of the renin-angiotensin system. This system is closely associated with the renal juxtaglomerular apparatus, which consists of the juxtaglomerular cells surrounding the afferent arterioles of the renal cortical glomeruli and a group of special staining cells, the macula densa, situated in the distal convoluted tubule. The juxtaglomerular cells are specialized myoepithelial cells cuffing the afferent arterioles that act as miniature pressure transducers. They monitor renal perfusion by perceiving pressure changes as distortions of the existing stretch on the arteriolar walls. Volume depletion caused by events such as hemorrhage, diuretic administration, or salt restriction are perceived by the juxtaglomerular cells as decreased stretch. These cells respond to this stimulus by synthesizing and secreting renin.

Renin, in turn, acts on a plasma α₂-globulin produced by the liver, releasing the decapeptide angiotensin I. Converting enzyme in the lung splits off two amino acids from angiotensin I, producing angiotensin II, which is a potent vasoconstrictor and a primary stimulant for aldosterone secretion. Increased plasma aldosterone concentrations enhance sodium retention, thereby expanding the extracellular fluid volume, increasing renal perfusion, and suppressing the initiating signal for release (Fig. 8-3) (Ganong, 1981; White, 1994).

FIGURE 8-3 A, Regulation of intravascular volume and plasma potassium concentration by the renin-angiotensin-aldosterone system. A decrease in intravascular volume increases the secretion of renin by the juxtaglomerular apparatus, leading to increased conversion of angiotensinogen to angiotensin I and then to angiotensin II. Angiotensin II acts on the adrenal zona glomerulosa to increase the activity of aldosterone synthetase and therefore the secretion of aldosterone. Hyperkalemia also increases the activity of aldosterone synthase. Aldosterone acts on renal distal tubules to increase the resorption of sodium (Na excretion of potassium [K]). ACE denotes angiotensin-converting enzyme, and the arrows pointing up or down before a word or symbol indicate an increase or decrease, respectively. B, Pathways of adrenal steroid biosynthesis. The pathways of biosynthesis of aldosterone and cortisol from cholesterol are shown. The chemical structures of these substances appear at the bottom and top of the figure, respectively. Aldosterone exists in two conformations (18-aldehyde and hemiacetal) that are freely interconvertible; the hemiacetal predominates under physiologic conditions. The enzymes responsible for each biosynthetic step are shown at the left; the last three enzymatic conversions required for aldosterone biosynthesis are mediated by a single enzyme, aldosterone synthetase (CYP11B2). The conversions that take place in the zona glomerulosa and the zona fasciculata are indicated.

(From White PC: N Engl J Med 331:250, 1994.)

NORMAL EFFECT OF PLASMA POTASSIUM CONCENTRATION

Aldosterone secretion can be regulated independent of the renin-angiotensin system as a function of the plasma potassium concentration. When a solution of potassium ions is injected into adrenal arteries, the adrenal venous aldosterone concentration immediately increases. Thus potassium appears to have a direct stimulatory effect on adrenocortical production of aldosterone, presumably through a transmembrane effect. This potassium-mediated aldosterone control system operates parallel to the renin-angiotensin system and is of comparable potency, although the importance of this process in vivo is probably not as significant as that associated with renal perfusion.

NORMAL EFFECT OF ACTH.

The release of aldosterone can be stimulated by ACTH, but ACTH is not the dominant force in stimulation of secretion of mineralocorticoids by the zona glomerulosa. Apparently, ACTH is not important in most physiologic conditions, but rather exerts a “permissive” influence over aldosterone secretion (Tyrrell et al, 1991).

PHYSIOPATHOLOGY OF MINERALOCORTICOID DEFICIENCY

BACKGROUND: PHYSIOLOGIC ACTIONS.

Glucocorticoid secretion is controlled by the hypothalamic-pituitary axis via a simple negative feedback loop. CRH is synthesized and secreted by the hypothalamus, and it then stimulates the secretion of ACTH by the pituitary gland. ACTH stimulates the synthesis and secretion of adrenal glucocorticoids. As plasma concentrations of glucocorticoids increase, they exert negative feedback on the secretion of CRH and ACTH (see Fig. 8-1) (Ganong, 1981). A major physiologic factor that influences the secretion of ACTH is cortisol metabolism, which reduces negative feedback and releases CRH. A second major factor in ACTH release results from stress (Nelson, 1980). Diurnal fluctuation of ACTH secretion, considered a well-documented phenomenon in humans, is not well documented in dogs.

Glucocorticoids (cortisol) affect almost every tissue in the body. Cortisol has a vital supportive role in the maintenance of vascular tone, endothelial integrity, vascular permeability, and the distribution of total body water in the vascular compartment (Lamberts et al, 1997). Cortisol potentiates the vasoconstrictor actions of catecholamines and controls the secretion of corticotropin (ACTH), CRH, and vasopressin (ADH) by negative feedback inhibition. Cortisol is vital to the metabolism of carbohydrates and protein, at least in part by stimulating gluconeogenesis and glycogenesis by liver and muscle. It suppresses peripheral cellular uptake and utilization of plasma glucose. It has some control over the immune system by suppressing inflammatory responses and lymphoid tissue. Cortisol stimulates erythrocytosis, maintains normal blood pressure, and counteracts the effects of stress (Oelkers, 1996). Pain, fever, and hypovolemia all result in a sustained increase in the secretion of ACTH and cortisol. During surgical procedures, for example, serum ACTH and cortisol concentrations rise quickly, slowly returning to basal values within 24 to 48 hours. Patients receiving steroid treatment for chronic autoimmune or inflammatory disease need less additional corticosteroid during severe illness and perioperatively than those receiving replacement therapy for adrenal insufficiency (Lamberts et al, 1997).

PHYSIOPATHOLOGY OF SIGNS ATTRIBUTED TO INSUFFICIENT CORTISOL SECRETION

PATHOGENESIS.

Development of the clinical syndrome associated with adrenocortical insufficiency is believed to require at least 90% destruction of adrenal cortices. Naturally occurring, immune-mediated destruction of the adrenal cortices is usually a gradual process, initially resulting in a “partial deficiency syndrome” characterized by inadequate adrenal reserve, with symptoms manifest only during times of stress (see Table 8-1). Stress may be associated with surgery, trauma, infection, or even psychologic distress, such as when dogs are placed in boarding kennels. However, basal hormone secretion in the unstressed state may be adequate to maintain near-normal plasma electrolyte concentrations and minimal clinical signs. For these dogs, the diagnosis can be confirmed only with tests that assess adrenocortical reserve. As destruction of the adrenal cortices continues, hormone secretion becomes inadequate even under nonstressful conditions, and a true metabolic crisis without any obvious inciting event can result.

TIMING OF EFFECT ON ZONES OF THE ADRENAL CORTEX.

In dogs with primary adrenal insufficiency, each of the three adrenocortical zones seems to become damaged at about the same rate. In other words, aldosterone deficiency (with its associated clinical signs and electrolyte abnormalities) and glucocorticoid deficiency (with its associated clinical signs) occur in tandem. Therefore the ACTH stimulation test (assaying plasma cortisol concentrations) is used to directly assess the capacity for cortisol synthesis and indirectly assess the capacity for aldosterone synthesis. It is extremely rare (but possible) for the zona glomerulosa (aldosterone secretion) to be significantly more or less damaged than the zona fasciculata and zona reticularis (cortisol secretion) (Lobetti, 1998). In contrast, insufficient cortisol response to exogenous ACTH administration in a dog with normal serum electrolyte concentrations could be explained by chronic glucocorticoid administration (common) or pituitary failure to secrete ACTH (rare).

TOTAL WHITE BLOOD CELL (WBC) COUNTS.

Total WBC counts in hypoadrenal dogs vary from low normal to mildly increased. Most of these dogs have normal total WBC counts. No consistent WBC differential count was obvious in our series of dogs. An increase in the WBC count may reflect a granulocytic response to concurrent bacterial infection (see Table 8-6).

EOSINOPHILS.

The presence of an absolute eosinophilia in hypoadrenal dogs is not commonly reported in the veterinary literature. Some veterinarians have suggested that eosinophilia is common, but most have observed eosinophilia to be an inconsistent feature of the disease. Eosinophils were absent on CBCs obtained on admission in 14% of 506 dogs, whereas only 10% of these dogs had an absolute eosinophilia. The remaining dogs had eosinophil counts that were within the reference range, both on relative and absolute tabulations.

The presence of a normal absolute eosinophil count in an ill dog may be significant because a stress pattern with no or few eosinophils is expected in such dogs if they have normal adrenocortical function. The finding of a normal eosinophil count in a stressed or ill dog should be viewed with a suspicion for hypoadrenocorticism. It must be remembered that a relative or absolute eosinophilia may also occur with many other diseases and, when present, eosinophilia can be used in developing a differential diagnosis that may lead to an explanation or cause for the illness (Table 8-7) (Rothenberg, 1998). The presence or absence of eosinophils should be considered a nonspecific and insensitive means of deciding the likelihood that any animal may or may not have hypoadrenocorticism.

TABLE 8-7 POTENTIAL CAUSES OF EOSINOPHILIA IN DOGS AND CATS

LYMPHOCYTES.

Animals with normal adrenal function respond to stress in part by secreting cortisol. Glucocorticoids decrease lymphocyte numbers in the circulation. Therefore ill and untreated hypoadrenal dogs should have a relative or absolute lymphocytosis. However, as with eosinophils, lymphocyte numbers or percentages have not provided consistent, sensitive, or specific alterations that can be considered classic for hypoadrenocorticism (see Table 8-6). This parameter could be used as a “clue” to adrenocortical health. Hypoadrenocorticism should be suspected when normal or increased lymphocyte counts are present in an ill dog. Thirteen percent of our 506 hypoadrenal dogs had lymphocytosis, and 80% had normal absolute counts.

MODIFIED THORN TEST.

Before assays were readily available to easily measure plasma cortisol concentrations, indirect tests of adrenocortical function were used. Included were tests that assessed changes in WBC numbers and/or percentages of certain WBCs present in the circulation after an injection of ACTH. A “modified Thorn test” (named after Dr. G. W. Thorn, who described such a protocol in 1948) has been reviewed. The recommendation for dogs was to obtain blood samples before and 4 hours after ACTH administration. Dogs with normal adrenocortical function demonstrate an increase in the neutrophil: lymphocyte ratio of at least 30%, and eosinophils decrease by at least 50% from pre-ACTH values (Chastain et al, 1989). This test was recommended as simple and readily available for determining the need for plasma cortisol measurements. We do not use this test.

PATHOPHYSIOLOGY OF SERUM ELECTROLYTE ALTERATIONS.

The classic electrolyte alterations in Addison’s disease are hyponatremia, hypochloremia, and hyperkalemia. These abnormalities are due primarily to aldosterone deficiency causing failure of the kidneys to conserve sodium or to excrete potassium. Hyponatremia is primarily caused by renal sodium wasting. Sodium lost via the kidneys is accompanied by water, resulting in both hyponatremia and dehydration should fluid intake not compensate for urinary losses. To some extent this dehydration may mask sodium depletion (mild or severe). Deficiency in adrenocortical hormones allows greater amounts of sodium to pass into the intracellular compartment as intracellular potassium concentrations decrease. Hyperkalemia results from both a shift of potassium from intracellular to extracellular compartments and from a decrease in renal excretion. The former condition results from a loss of cortisol effects on the sodium-potassium pump, which normally maintains a gradient across cellular membranes (Nelson, 1980).

Hypoaldosteronism and acidosis enhance the shift of potassium from intracellular to extracellular compartments. Decreased potassium exchange for sodium in the distal renal tubule leads to decreased urinary potassium excretion and increased sodium excretion. The shift in electrolytes between body compartments may be partly corrected by the administration of cortisol, but aldosterone or another mineralocorticoid is necessary to prevent renal loss of sodium and retention of potassium (Tyrrell et al, 1991).

SODIUM.

Serum sodium concentrations have varied from normal to as low as 106 mEq/L at the time of diagnosis of Addison’s disease in dogs (Table 8-8). Of 483 dogs with primary hypoadrenocorticism, 417 (86%) had serum sodium concentrations less than 142 mEq/L at the time of diagnosis. In addition, eight of the 23 dogs with apparent ACTH deficiency (secondary adrenocortical deficiency) were hyponatremic at the time of diagnosis. In 60 hypoadrenal dogs described in a separate study, the mean serum sodium concentration at the time of diagnosis was 128 mEq/L (Lynn et al, 1993), a value similar to the mean value for the 506 dogs.

TABLE 8-8 SELECTED SERUM BIOCHEMISTRY VALUES FROM 506 DOGS WITH HYPOADRENOCORTICISM

POTASSIUM.

Serum potassium concentrations in dogs at the time hypoadrenocorticism is diagnosed vary from normal to extremely increased levels that induce clinically obvious cardiac rhythm disturbances (see Table 8-8). Of the 483 hypoadrenal dogs in this review, 460 (95%) had serum potassium concentrations greater than 5.5 mEq/L at the time of diagnosis. In 60 of our more recently diagnosed hypoadrenal dogs, the mean serum potassium concentration was 7.2 mEq/L, and in the 506 dogs it was 7.0 mEq/L. None of the 23 dogs with apparent ACTH deficiency had hyperkalemia.

SODIUM: POTASSIUM RATIO: VALUE AND LIMITATIONS.

The sodium to potassium ratio has frequently been used as a diagnostic tool to aid in gaining a suspicion or in specific identification of dogs with adrenal insufficiency. The normal ratio varies between 27:1 and 40:1. Values are often below 27:1 and may be below 20:1 in dogs with primary hypoadrenocorticism. Determination of serum electrolyte concentrations from dogs suspected of having adrenal insufficiency is of paramount importance. The finding of the classic electrolyte abnormalities, or of hyperkalemia without a decrease in the serum sodium concentration or vice versa (decreases in serum sodium without an increase in the serum potassium concentration) should prompt immediate therapy. The assumption that the clinician may be treating Addison’s disease is warranted and may be lifesaving.

If the provisional diagnosis of hypoadrenocorticism made on the basis of serum electrolyte concentrations is incorrect, emergency therapy is rarely harmful. Aggressive management of hypoadrenocorticism is not significantly different from that for life-threatening renal or gastrointestinal diseases. However, the limitations of a diagnosis based solely on serum electrolyte determinations must be realized. Reliance on serum electrolyte concentrations as the sole criterion for diagnosing adrenal insufficiency can be misleading if three factors are not kept in mind (see next three sections): first and most important is the slow, progressive nature of the development of primary adrenal insufficiency in many dogs; second, dogs with pituitary failure continue to secrete aldosterone; and third, hyperkalemia and hyponatremia are not pathognomonic for adrenal insufficiency (Figs. 8-4 and 8-5).

FIGURE 8-4 Algorithm for the differential diagnosis of hyperkalemia and for determining its cause.

FIGURE 8-5 Algorithm for the differential diagnosis of hyponatremia and for determining its cause.

SERUM ELECTROLYTE ASSESSMENT IS NOT ALWAYS DEFINITIVE

Pituitary ACTH Deficiency (Secondary Adrenocortical Failure).

For the most part, electrolyte alterations are attributed to inadequate secretion of mineralocorticoids. Therefore an animal that has pituitary deficiency of ACTH may have a clinical syndrome that reflects only glucocorticoid deficiency. The gastrointestinal, mental, and metabolic changes typical of hypocortisolemia may become obvious to the owner and veterinarian, whereas those changes ascribed to hypoaldosteronism are absent.

Volume depletion, dehydration, and serum potassium abnormalities are usually absent because aldosterone is only minimally affected by ACTH. Hypotension is usually not present except in acute presentations. Hyponatremia was documented in 8 of 23 dogs in the series included here, and it may have been the result of water retention, anorexia, and vomiting and/or diarrhea. Inability to excrete a water load is not typically accompanied by hyperkalemia. Prominent clinical features are weakness, lethargy, anorexia, and occasionally vomiting. Joint, muscle, and/or abdominal pain may be apparent. Hypoglycemia is occasionally the presenting feature (Table 8-9). Acute decompensation and shock may occur.

TABLE 8-9 SELECTED SERUM BIOCHEMISTRY VALUES IN 23 DOGS WITH NATURALLY OCCURRING SECONDARY HYPOADRENOCORTICISM

ACTH deficiency may occur as a result of a primary pituitary problem (trauma, infection, cancer) or secondary to long-term corticosteroid medication that is acutely discontinued (see Fig. 8-1). Clinically, these dogs may be indistinguishable from dogs with primary adrenal insufficiency or those with renal or gastrointestinal problems. Only a thorough medical history can alert the veterinarian to the possibility of secondary adrenal insufficiency.