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Hypoadrenal Gland Disease print email

By Robert M. Hardy

Source: Textbook of Veterinary Internal Medicine, 4th edition, Chapter 19, pp. 1579-1591.

 


 

 

Hypoadrenocorticism can be one of the most diagnostically and therapeutically challenging, confusing, and frustrating dis­eases that a companion animal practitioner must face.  The first human cases were described in 1855 by Thomas Addison, and this disease is often identified in the literature as "Addison's" disease.  At about the same time, animal experiments verified that removal of the adrenal glands leads rapidly to death.  It was not until the 1930s that crude aqueous ex­tracts of adrenal glands were shown to prevent death in adrenalectomized cats.  It was still several  more years before sources of glucocorticoids and mineralocorticoids became com­mercially available, so that af­fected humans could now survive this previously fatal disease.

Hypoadrenocorticism is an uncommon endocrine disorder in dogs and rare in cats.  The first canine case was reported in 1953, and the first reported case in a cat in 1983.  The prevalence in dogs at one large  veterinary hospital is said to be less than 1/1000.  Since its initial recognition, several case series of dogs with Hypoadrenocorticism have been published.  Only one series of 10 cats with this disorder has appeared.

 

ETIOLOGY

Hypoadrenocorticism in dogs and cats is most often as­sociated with diseases of the adrenal gland that result in combined deficiencies of glucocorticoids and mineralocor­ticoids (primary Hypoadrenocorticism).  Less com­monly, disruption of the hypothalamic-pituitary-adrenal axis occurs.  this leads to deficient tropic hormone secre­tion of either corticotropin- releasing hormone (CRH) or adrenocorticotropic hormone (ACTH).  Lack of pituitary stimulation of the adrenal cor­tex results in bilateral adrenal cortical atrophy and is clas­sified as secondary Hypoadrenocorticism.  Secondary Hypoadrenocorticism is only as­sociated with signs of glucocorticoid deficiency.

 

PRIMARY HYPOADRENOCORTICISM

Primary Hypoadrenocorticism, which is most often classified as idiopathic, is usually characterized his­topathologically as bilateral adrenal atrophy with fibrosis.  In some cases, significant in­filtration of the adrenal cortex by lymphocytes and plasma cells has been seen, suggesting an immune-mediated basis for the disease.  Two recent reports have identified through indirect immunofluorescence the presence of antiadrenal antibodies in the serum of two of three dogs with primary adrenal insufficiency.  The third dog had an infiltrate of lymphocytes and plasma cells in its adrenal cortex at necropsy.  One of these dogs was also severely hypothyroid and had antithyroid antibodies detected in its serum as well.  Up to 50 per cent of humans with Hypoadrenocorticism are though to have an immune-mediated basis for their disease, and multiple endocrine organs are often in­volved simultaneously.  In a survey of 45 dogs from the University of California, six were found to have at least one additional endocrinopathy.  Four were hypothyroid, one had diabetes mellitus, and one had partial gonadal failure.

Other less common causes for spontaneous primary adrenal failure include infections (coccidioidomycosis, blas­tomycosis, or tuberculosis), hemorrhagic infarctions, metas­tatic neoplasia, trauma, and amyloidosis.

Genetic influences may play a role in some breeds of dogs.  The only well-documented cases of familial Hypoadrenocorticism have occurred in standard poodles located on the East coast of the United States.  Labrador retrievers and Por­tuguese water spaniels are also said to have familial tendencies for this disease.

Iatrogenic primary Hypoadrenocorticism may follow the administration of the adrenocorticolytic drug o,p'-DDD (mitotane), in the treatment of dogs for hyperadrnocorticism (Cushing's disease).  Relative cortisol deficiency is common after treatment for this disease and is usually transient.  However, combined mineralocor­ticoid and glucocorticoid deficiency occurs in ap­proximately 5 per cent of treated dogs.  Dogs suffering severe adrenal cortical destruc­tion following o,p'-DDD therapy almost always have a permanent requirement for mineralocor­ticoid and glucocorticoid sup­plementation.

Two other therapeutic agents that may interfere with adrenal cortical function are ketoconazole and megestrol acetate.  Both only interfere with the synthesis of glucocor­ticoids.  Ketoconazole impairs the normal response of the adrenal cortex to ACTH but leaves basal concentrations un­changed.  Adrenal reserve, as measured by ACTH stimulation testing, returns to normal within 3 weeks of discontinua­tion of ketoconazole administra­tion.

Megestrol acetate has profound adrenal suppressive ef­fects in cats.  When given to normal cats at 5 mg/day for 16 days, ACTH response was severely impaired.  Only three of seven cats had regained normal adrenal reserve capacity one month after the drug discontinued.  None of the cats showed signs of cor­tisol deficiency, however.

 

SECONDARY HYPOADRENOCORTICISM

Secondary Hypoadrenocorticism may be naturally occurring or iatrogenic.  Naturally occur­ring secondary Hypoadrenocorticism is due to a lack of nor­mal adrenal stimulation via CRH or ACTH and implies primary hypothalamic or pituitary failure.  Most of these cases are the result of inflammation, tumors, trauma, or congenital defects of the hypothalamus or pituitary gland.

Iatrogenic secondary Hypoadrenocorticism is the most common cause for adrenal corti­cal nonresponsiveness in veteri­nary practice.  it occurs fol­lowing the administration of ex­ogenous glucocorticoids.  Ex­ogenous glucocorticoids suppress normal pituitary ACTH production and this leads to bilateral adrenal atrophy.  Secondary adrenal atrophy may develop after the administration of vir­tually any glucocorticoid used by veterinarians, including oral, injectable, and topical.  Even otic and ophthalmic preparations can induce ACTH nonresponsiveness rapidly.  For­tunately, the majority of dogs and cats receiving exogenous glucocorticoids do not develop signs of glucocorticoid deficiency when their medication is discontinued.

Although any glucocorticoid may inhibit ACTH release, long- acting depot preparations cause the most severe adrenal atrophy and result in long periods of adrenal hypofunction.  Dexamethasone- containing preparations are 50 to 150 times as potent as endogenous cortisol in suppressing ACTH production.

Adrenal nonresponsiveness may occur within a few days fol­lowing daily or repositaol glucocorticoid administration.  Most dogs and cats have normal ACTH stimulation results within 2 weeks of steroid withdrawal.  However, those who receive potent preparations or receive glucocorticoids for months or years may have prolonged periods before ACTH stimulation results normalize (weeks to months).

 

PATHOPHYSIOLOGY

The adrenal glands are es­sential for life.  they secrete a number of hormones that are required for normal functioning of an animal as well as for sur­vival in stressful situations (cortisol, epinephrine, norepinephrine).  The outer zona glomerulosa of the cortex is primarily involved with the synthesis and secretion of the mineralocorticoid, aldosterone.  The middle zona fasciculata syn­thesizes and secretes glucocorticoids, of which cortisol is the most important in mammals.  The inner zona reticularis of the adrenal cortex secretes primarily adrenal sex steroids.  The androgens and estrogens secreted by the zona reticularis are of unknown clinical sig­nificance in animals.  The adrenal medulla secretes the catecholamines, epinephrine and norepinephrine, which are not affected in Hypoadrenocorticism.

There is significant adrenal cortical functional reserve in animal and man.  It is es­timated that approximately 90 per cent of adrenal function must be compromised before clinical signs become evident.  Approximately 10 per cent of animals with Hypoadrenocorticism have waxing/waning clinical courses, with signs only becom­ing evident following stressful situations (e.g., disease, trauma, surgery, kenneling).  This probably reflects slight residual adrenal reserve that maintains them at rest in a non­stressful environment.  As their glandular reserve progressively declines, they may develop an adrenal crisis with no obvious precipitating event.

 

MINERALOCORTICOIDS IN HEALTH AND DISEASE

Mineralocorticoids serve primarily to maintain sodium, chloride, and water balance.  The primary adrenal mineralocor­ticoid, aldosterone, promotes renal reabsorption of sodium and chloride and their accompanying water in exchange for potassium and hydrogen ions.  This effect is mediated primarily by the kidneys.

aldosterone release is con­trolled by three mechanisms working concurrently.  The primary control is via the reninangiotensin- aldosterone system.  Minor modifications in aldosterone secretion occur in response to hyperkalemia and also following an increase in plasma ACTH concentrations.  Renin is stored in the cells of the juxtaglomerular apparatus of the kidney and is released in response to changes in extracel­lular volume.  Anything that leads to hypotension or contrac­tion in extracellular fluid volume will stimulate renin release (e.g., hemorrhage, dehydration, diuretic use, salt restriction).  Renin acts on an­giotensinogin in the circulation to release angiotensin I, an alpha-2 globulin.  Angiostensin I is hydorlyzed by an angiostensin-converting enzyme in the lung to angiotensinII, a potent vasoconstrictor and the primary stiulus for aldosterone release.  Angiotensin II has a direct effect on vasuclar smooth muscle, raising blood pressure.  Aldosterone promotes active sodium, chloride, and water reabsorption, which expands the extracellular fluid (ECF) volume.  Once blood pressure and ECF volume normalize, further renin release is inhibited.

An inability to release al­dosterone has a number of ad­verse effects on the animal.  the failure to conserve sodium and chloride leads to their loss as well as water depletion.  The resulting hyponatremia and hypochloremia are typical of primary hypoadrenocorticism.  A continuing loss of sodium, chloride and water causes a progressive decline in ECF volume, which results in dehydration, hyptension, an prerenal azotemia.  In associa­tion with hypotension and dehydration, pituitary ADH release may be increased, promoting renal water reabsorp­tion and thus further aggravat­ing the hypnatremia.  Untreated human patients have an impaired ability to excrete a free water load and are prone to water in­toxication.  Decreased tissue perfusion, prerenal azotemia, and failure to eliminate hydor­gen ions in exchange for potas­sium - all lead to varying de­grees of metabolic acidosis.

Polydipsia, polyuria, and low urine specific gravity in the face of clinical dehydration and azotemia are frequent abnor­malities in both dogs and cats with hypoadrenocorticism.  These findings probably reflect an on­going solute diuresis of sodium chloride, and water secondary to hypoaldosteronism.  Profound hypnaturemia also impairs the renal concentrating capacity through medullary solue washout, decreasing the maximal renal concentrating ability.  Sodium and chloride account for ap­proximately 50 per cent of the normal renal medullary solute gradient.

It has been proposed that severe hyponatremia may impair normal renal concentrating ability by interfering with ADH release.  The primary stimulus fo rADH release is an increase in serum osmolality.  since sodium and chloride account for the majority of ECF osmolality, severe decreases in these ions may impair normal osmotic stimuli for DAF release, promot­ing a dilute urine in the face of dehydration.

Failure to excrete potas­sium in exchange for sodium leads to hyperdalemia, on of the classic electrolyte abnor­malities of adrenal insuf­ficiency.  Hyperkalemia not only is due to hypoaldosteronism bu is worsened by the decreased renal perfusion (*impairs excre­tion) and accompanying metabolic acidosis (promotes shift of potassium from intracellular to extracellular space).  hperkalemia leads to decreased neuro-muscular excitability and impaired myocardial contrac­tility.  This may result in signs of muscular weakness, bradycardia and hypotension.  As serum potassium concentrations approach 8 to 10 mEq/L, severe bradycardia and atrial arrest are seen.  Ultimately, ventricular fibrillation or car­diac stand still results in death of the patient.

 

GLUCOCORTICOIDS IN HEALTH AND DISEASE

Glucocorticoids are synthsized primarily in the zona fasciculata of the adrenal cor­tex and have effects on nearly every tissue in the body.  Their synthesis and secretion are un­der a relatively simple negative feedback mechanism between the hypthalamic-piuitary axis and the adrenal gland.  when serum cortisol concentrations decline, hypthalamic CRH increases, thus stimulating increased production and release of pituitary ACTH.  ACTH circulates to the adrenal cortex and increases production and release of cortisol.  In­creasing levels of cortisol in­hibit CRH and ACTH release, which inhibits adrenal glucocor­ticoid production.

In primary hypoadrenocor­ticism, the lack of negative feedback by cortisol on the pituitary gland leads to chroni­cally elevated concentrations of ACTH.  In secondary hyoadrenocorticism, whether iatrogenic or naturally occur­ring, chronic lack of stimula­tion of the adrenal cortex by ACTH leads to severe adrnal cor­tical atrophy, nad endogenous ACTH concentrations are low.  Thus, endogenous plasma ACTH concentrations are the best diagnostic test for differen­tiating primary from secondary hypoadrenocorticism.

In normal animals, glucocorticoids promote a general sense of well-being and stimulate appetite.  They main­tain fasting blood glucose values by promoting gluconeogenesis and hepatic glycogenesis, by impairing up­take of glucose by peripheral tissues, and by augmenting lipolysis.  Glucocorticoids promote renal water elimination by increasing the GFR and in­hibiting ADH effects on the kid­ney.  They help to maintain nor­mal serum calcium concentrations by augmenting renal excretion of calcium.  they have anit- inflammatory and immunosuppres­sive effects on white blood cells while stimulating erythrocytosis.  they protect organisms against shock, and maintain blood pressure by in­creasing vascular reactivity to catecholamines, preventing capillary dilatation, and im­pairing protein extravasation from capillaries.

 

CLINICAL FINDINGS

SIGNALMENT

 

Hypoadrenocorticism is primarily a disease of middle-aged female dogs.  Most surveys indicate that from 70 to 85 per cent of affected dogs are female.  The age of presentation ranges from 2 months to 9 years, with a mean of about 4 to 4.5 years of age.  The majority of dogs are diagnosed while under 7 years of age.  Although there is no increased risk based on breed or size, some evidence for familial tendencies exists in standard poodles, Labrador retrievers, and Portuguese water spaniels.

 

HISTORY

 

The clinical signs ex­hibited by dogs with hypoadrenocorticism usually reflect combined mineralocor­ticoid and glucocorticoid deficiencies.  Hypoadrenocor­ticism is typically a disease associated with vague, nonlocal­ized clinical signs such as depression, lethargy, weakness, anorexia, and weight loss (Table 119-1).  IN others, signs more typical of gastrointestinal (GI) diseases (vomiting, diarrhea) or renal diseases (polydipsia and polyuria) are seen.  Additional abnormalities reported less of­ten include shaking or tremors and a sensitive abdomen.  The duration of clinical illness is generally about 2 weeks before presentation to a veterinarian.  although it is commonly con­sidered a disease that has a waxing and waning course as animals get into and recover from stressful situations, this observation is actually made by only 10 per cent of owners.  Some animals will have received, and generally responded well to, supportive care for these signs in the recent past (fluids and glucocorticoids).  Because signs of adrenal insufficiency mimic many other common diseases, the definitive diagnosis may be missed as animals are treated for these more commonly recog­nized disorders.  They may ac­tually present in what is per­ceived to be an "acute" adrenal crisis, when in actuality it is the end stage of progressively deteriorating adrenal gland dis­ease.

 

PHYSICAL EXAMINATION FINDINGS

 

Physical examination find­ings are generally unrewarding in terms of leading to a specific diagnosis owing to the nonspecific nature of abnor­malities induced by mineralocor­ticoid and glucocorticoid deficiencies.  Depression, weak­ness, and dehydration are the most commonly identifed physical examination findings.  Dogs in an adrenal crisis may be in shock, with only vague signs of illness noted previously.  Ap­proximately one-third of these dogs have bradycardia and/or weak pulses.  although bradycar­dia is not pathognomonic for hypoadrenocorticism, its occur­rence in a dehydrated, hypoten­sive animal with GI signns should arouse a strong suspicion that hypoadrenocorticism exists.  Only occasionally will abdominal pain, hypothermia, or amaciation be found.

 

LABORATORY DIAGNOSIS

 

The definitive diagnosis of hypoadrenocorticism requires a thorough history, a careful physical examination, and com­plete laboratory screening.  In animals suspected of having hypoadrenocorticism, a CBC, serum chemistry profile (including an electrolyte panel), and a urinalysis will be helpful in supporting the diag­nosis.  However, a definitive diagnosis is only established through an assessment of adrenal reserve capacity (ACTH stimula­tion test).

 

Hemogram Alterations

 

Alterations in the hemogram are much discussed but only oc­casionally of value in the diag­nostic process.  the changes seen are all secondary to glucocorticoid deficiency.  a mild normocytic, normochromic anemia is common in dogs.  It may be masked initailly by dehydration, only becoming evi­dent following volume expansion.  The packed cell volume then is usually in the 25 to 35 per cent range.

Ill animals with noninfec­tious diseases typically have a stress leukogram.  This is characterized by a mature neutrophilia, eosinopenia, lym­phopenia, and monocytosis.  The dog or cat with hypodrenocor­ticism, lacking adequate cor­tisol reserve, would not be ex­pected to develop this pattern in spite o being seriously "stressed".  This would produce a hemogram characterized by a normal WBC count, with an eosinophilia and a lym­phocytosis.  In actuality, a "non-stressed" hemogram is un­common in dogs with hypoadrenocorticism.  Eosinophilia and lymphocytosis occur in only 10 to 15 per cent of affected dogs.  However, the presence of a normal white count and normal numbers of eosinophils or lymphocytes in an ill animal is not normal, and hypoadrenocorticism should be considered.

 

Electrolyte Abnormalities

Sodium an dPotassium Abnor­malities. The patient with hypoadrenocorticism may have ab­normalities in all the commonly reported electrolytes (sodium, potassium, chloride, calcium, phosphorus).  typically, a presumptive diagnosis of hypoadrenocorticism is made based on the presence of hyponatremia, hypochloremia, hy­perkalemia, and a sodium/potassium ratio less than 27:1 (Table 119-2).  Normal sodium/potassium ratios range from 27:1 to 40:1, with a mean of 30:1.  Most dogs with adrenal insufficiency have ratios less than 20:1.  The presence of hy­perkalemia and an abnormal sodium/potassium ratio-regardless of cause-warrants therapy to prevent life-threatening cardiac arrhythmias from developing.  The most com­mon diseases associated with hy­perkalemia other than hypadrenocorticism are acute oliguric or anuric renal failure avere gastrointestinal disor­ders.  All of these diseases benefit from judicious fluid ad­ministration while test to dis­criminate between them are per­formed.

Unfortunately, neither the presence of normal electrolytes nor a normal sodium/potassium ration can completely rule out a diagnosis of hypoadrenocor­ticism.  Approximately 10 per cent of dogs with this disease have a normal sodium and/or a normal potassium levels.  Clini­cal signs of so-called "atypical hypoadrenocorticism" are due primarily to cortisol deficiency and may be caused by either primary or secondary hypoadrenocorticism.  Some dogs with primary hypoadrenocorticism initially have signs at­tributable only to severe cor­tisol deficiency, while mineralocorticoid secretion is adequate to maintain serum electrolytes in the normal range.  Over time, electrolyte abnormalitites will develop the expected pattern.  If naturally occurring or iatrogenic secon­dary hypoadrenocorticism is present, mineralocorticoid release is normal and electrolyte abnormalities never develop (Table 119-3).  These latter cases required assessment of both ACTH stimulation and en­dogenous ACTH concentration for definitive diagnosis.

An abnormal sodium/potassium ratio is not pathognomonic for hypoadrenocor­ticism.  Any disease associated with severe sodium depletion can cause the ratio to become sub­normal, whereas diseases as­sociated with hyperkalemia also produce ratios of <27:1 and may be misdiagnosed as hypoadrenocorticism (Table 119-4).  It is important to dif­ferentiate nonadrenal from adrenal causes for hyperkalemia, because therapy for primary hypoadrenocorticism is needed permanently.

The most often recognized causes for non-adrenal-associated hyperkalemia include acute oliguric/anuric renal failure, chronic oliguric renal failure (less commonly), uroab­domen secondary to a reptured urinary bladder or ureter, postrenal uremia associated with urethral obstruction, severe gastrointestinal diseases, and metabolic acidosis (Table 119-4).  GI diseases that may present with biochemical data resembling hypoadrenocorticism inclue infectious diarrheas (salmonellosis, trichuriasis, ancylostomiasis, parvovirus, distemper), perforated GI ul­cers, gastric dilatation and volvulus, and severe malabsorp­tion.

Less commonly, hyperkalemia may be associated with the use of therapeutic agents (potassium-sparing diuretics, non-steroidal anti- inflammatory drugs, angiotensin-converting enzyme inhibitors, and potassium-containing fluids).  These causes should be readily identifiable.

Another less commonly recognized cause for both hyper­kalemia and hyponatremia is seen in dogs with both chylous and nonchylous pleural effusions.  The exact mechanism is unknown.  Renal potassium excretion is im­paired in spite of elevated serum aldosterone concentration in these animals.

Massive release of potas­sium to the extracellular space can occur in severe crush in­juries, in association with aor­tic thrombosis in cats, or fol­lowing rhabdomyolysis secondary to heat stroke or heavy ex­cercies.  It also occurs in as­sociation with severe hemolysis (rare) or in massive infections.

Pseudohyperkalemia has been seen in the Akita breed as a unique genetic abnormality.  Their RBC's contain larger potassium concentrations than those of most dogs, and potas­sium concentrations increase after serum is left in contact with RBCs for 4 hours or more following collection.  Pseudo­hyperkalemia may also occur in animals with severe leukocytosis (total WBC = >100,000/mm3) or in cases of severe thrombocytosis (platelets = 100,000/mm3).  The potassium elevates in the serum as blood is clotting and is an in vitro phenomenon.

Hyponatremia can occur in many diseases other than hypoadrenocorticism (see Table 119-4).  Severe hyponatremic states often result in a sodium/potassium ratio of less than 27:1, and hypoadrenocor­ticism must be considered in the differential diagnosis.  Dis­eases associated with hyponatremia include GI losses secondary to vomiting, hemor­rhagic gastroenteritis, and par­voviral enteritis, nephrotic syndrome and other edematous states, postobstructive diuresis, congestive heart failure, myxedema, diabetes mel­litus, primary polydipsia, and inappropirate secretion of ADH.  All of these diseases are dif­ferentiated from hypoadrenocor­ticism by their response to therapy and results of ACTH stimulation testing.  Their clinical signs and other biochemical data overlap a great deal with those of primary hypoadrenocorticism and often cannot be differentiated on the basis of these data alone.

Calcium Abnormalities. Ap­proximately one-third of dogs with hypadrenocorticism are hy­percalcemic when they are hyper­kalemic.  In a review of 16 dogs whose hypercalcemia was as­sociated with primary hypoadrenocorticism, the range of calcium concentrations was found to be from 12.0 to 14.9 mg/dl.  The magnitude of the hy­percalcemia correlated with the severity of their dehydration and other electrolyte abnor­malities.  Other causes for hy­percalcemia must be considered as well and include pseudohyper­parathyroidism, primary hyper­parathyroidism, hypervitaminosis-D, acute and chronic renal failure, and in­toxication with rodenticides containing vitamin D.

The hypercalcemia further complicates the process of es­tablishing a diagnosis since hy­percalcemia is seen much more often in patients with malignant disease, such as lymphosarcoma.  Hypercalcemia induces polydip­sia, polyuria, and varying de­grees of renal failure-findings that also characterize hypoadrenocorticism.

 

Renal Function

Elevations in blood urea nitrogen (BUN) and creatinine and a reduction in renal con­centrating ability are common in dogs with hypoadrenocorticism (see Tables 119-2 and 119-3).  The mean BUN concentration in two large surveys was 83 mg/dl, with a range of 12 to 223.  The BUN concentrations, coupled with  a urine specific gravity that is often less than 1.030, and some­times in the isosthenuric range in a dehydrated animal, may lead to the erroneous conclusion that primary renal failure exists.  However, serum creatinine values are typically less elevated than the BUN concentrations, support­ing the existence of a prerenal component.  Values for creatinine typically range from 0.9 to 3.8 mg/dl (mean=2.2 mg/dl).

The elevations in BUN and crenine relfect the severe volume contraction, hypotension, and dehydration that are as­sociated with hypadrenocor­ticism.  The decreased urine specific gravity is related to the hypnatremia, meullary solute washout, and solute diuresis seen in this disease.  The BUN and creatinine usually return to normal in 24 to 48 hours if ap­propriate fluid therapy is ad­ministered, even in cases with BUN concentrations over 200 mg/dl.  Renal concentrating ability returns to normal in nearly all cases following ap­propriate medical management.

If hypotension is severe, renal ischemia may develop.  The ischemia may induce a primary renal injury.  Thus, a primary renal injury can be superimposed on a prerenal component, con­founding both management and diagnosis.

 

Acid-Base Status

Mild to moderate degrees of metabolic acidosis exist in many dogs with hypadrenocorticism.  The acidosis is secondary to decreased renal H+ excretion in the mineralocorticoid-deficient animal.  Decreased renal perfu­sion and hypotension may also contribute to the acidosis.  Fortunately, the majority of animals do not require specific therapy for the acidosis.  Ade­quate fluid resuscitation and mineralocorticoid replacement correct the abnormality in most cases.

 

Blood Glucose

Hypoglycemia (blood glucose = 70 mg/dl) is an uncommon laboratory finding in animals with hypoadrenocorticism in spite of the important role that cortisol plays in maintaining fasting blood glucose concentra­tions (see Table 119-2).  Hypoglycemia is reported in from 8 to 37 per cent of dogs with this disease.  It may be severe enough to cause weakness, tremors, and even convulsions.  Occasionally, hyperglycemia is seen as well.

 

Serum Albumin

A number of dogs with primary hypoadrenocorticism have mild hypoalbuminemia.  The serum concentration is usually 2.0 gm/dl (normal >2.7 gm/dl).  In these cases, no other cause for the hypoalbuminemia can be iden­tified, and it reverses with treatment for the hypoadrenocor­ticism.  Hypoalbuminemia was noted in one of six dogs with hypadrenocorticism in one review.  The exact mechanism remains speculative at this time, although it is known that glucocorticoids influence hepatic albumin synthesis, and a deficiency in cortisol may im­pair hepatic albumin production.

 

RADIOGRAPHIC FINDINGS

Survey radiographs are of­ten obtained on dogs in an adrenoal crisis as part of the routine data base required in the evaluation of a critically ill dog.  Thoracic radiographs may idenify the presence of microcardia due to the profound hypovolemia present in some patients.  The cardiac silhouette appears small rela­tive to the thoracic volume of the animal.  The descending aorta appears flattened and of decreased diameter.  The caudal vena cava also appears small.  These findings are not diagnos­tic for hypadrenocorticism.  They reflect the presence of shock and the severity of ECF volume contraction seen in these animals.

One additional radiographic observation that may be made is that of megaesophagus.  Several reports have identified this ab­normality in recent years.  Some dogs have been asymptomatic (no regurgitation history), whereas others were evaluated primarily for signs of regurgitation.  One animal had primary hypoadrenocorticism that was only associated with cortisol deciency.  Replacment glucocor­ticoid therapy was associated with resolution of the megaesophagus.

 

ELECTROCARDIOGRAPHIC ABNORMALITIES

The hyperkalemia associated with mineralocorticoid deficiency can have profound ef­fects on myocardial contrac­tility and the EKG.  An EKG is an easy, inexpensive and rapid tool for assessing changes in serum potassium (K4) concentra­tion in patients with hyper­kalemia.  When a bradycardia is identified on physical examina­tion, and EKG is an efficeint means of deternining the presence of hyperkalemia.  This is particularly true once clinicians become familiar with the electrocardiographic changes typical for this electrolyte ab­normality.  Therapy can then be instituted during the wait for laboratory values to be returned.  An EKG is also an ef­ficient aid to monitoring the initial therapeutic response of the patient.

EKG changes tend to paral­lel the severity of the serum potassium concentration.  However, since hyponatremia, hy­percalcemia, hypoxia, and metab­olic acidosis can also affect myocardial performance, the severeity of EKG changes for a given potassium concentration varies from patient to patient.  The primary effects of hyper­kalemia are on electrical con­duction through the myocardium and strength of contractions.  Mild hyperkalemia (serum K+ = 5.5 to 6.5 mEq/L) is generally associated with a tall, "peaked" T wave.  As the K+ concentration increases from 6.5 to 8.5 mEq/L, there is widening and flattening of the QRS complex, prolongation of the PR interval, decrease in P wave amplitude, and increase in duration of the P wave.  At potassium concentrations of >8.5 mEq/L, atrial standstill, ab­sence of P waves, and deviations of the ST segment from the base line are expected.  At serum potassium concentrations of 11 to 14 mEq/L, ventricular asys­tole or ventricular fibrillation is common.

The frequency of ocurrence of EKG abnormalities was quan­tified in a large group of dogs with primary hypoadrenocor­ticism.  Tall peaked T waves (>0.5 mV) in lead II occurred in 22 per cent of dogs.  A decreased amplitude of the R wave (<0.5 mV) in lead II was observed in 22 per cent, and P waves were absent in 50 per cent of cases.  The serum potassium concentration associated with an absence of P waves ranged from 8.6 to 11.3 mEq/L.

 

ADRENAL FUNCTION TESTING

Although results of a CBS, biochemical profile, urinalysis, and EKG may all be supportive of the diagnosis of hypoadrenocor­ticism, the definitive diagnosis requires an assessment of the integrity of the hypothalamic-pituitary-adrenal axis.  This may be done in a number of ways, including basal plasma cortisol concentrations, 24-hour urinary 7-hydorxy-corticosteroid con­centrations, ACTH stimulation testing, endogenous ACTH con­centrations, and plasma aldos­terone concentrations.

 

ACTH Stimulation Testing

Basal plasma cortisol con­centrations are of little diag­nostic value and should not be used as the sole criterion for establishing the diagnosis.  Normal dogs can have basal cor­tisol values of zero, and dogs with hypoadrenocorticism oc­casionally have resting values within the low normal range.  Assessing adrenal reserve capacity is the only way to diagnose this disease.

Performing an ACTH stimula­tion test is currently the best method for confirming the diag­nosis of hypoadrenocorticism in dogs and cats.  The test is run as soon as the diagnosis is suspected, regardless of the time of day.  It is important to observe sample- handling instruc­tions from the laboratory that will perform the hormone assays.  Cortisol samples are usually stable in serum or plasma for as long as 5 days at room tempera­ture.  If the diagnosis is suspected and it is necessary to administer some sort of glucocorticoid before the test is completed, the recommended drug is dexamethasone, as it does not interfere with glucocorticoid assay.  Most other synthetic glucocorticoids will be measured by the radioim­munoassay (RIA) techniques and confound the diagnostic process.  It is generally of no increased risk to the patient with hypoadrenocorticism if only fluids (saline) are administered whle plasma cortisol values are awaited, to be follwoed by ap­propriate glucocorticoids as soon as the second sample is colledted (in 1 or 2 hours).

The test is performed in the following manner.  Either animal- origin ACTH gel (Cortigel 40, Savage Labs, Melville, NY 11747) or synthetic ACTH, tetracosactrin (Cortrosyn, Or­ganon Pharmaceuticals, West Orange, NJ 07052), may be used.  The gel preparation is given at a dosage of 1 U/lb (2.2 U/kg) IM in both dogs and cats, and plasma samples are collected at 0 and 2 hours following ad­ministration in dogs and at 0, 60 and 120 minutes in cats.  Awueous synthetic ACTH is given at 0.25 mg/dog or 0.125 mg/cat IM and plasma samples are col­lected at 0 and 1 hour postin­jection in dogs, and 0, 30, and 60 minutes postinjection in cats.

Results of ACTH stimulation testing in dogs and cats with hypoadrenocorticism typically have resting levels in the low normal range that fail to in­crease following ACTH.  Post-stimulation values are often similar to or below resting values.  Some animals will have a slight increase in post-stimulation values, but in all reported cases in dogs, values have been below the minimum nor­mal post-stimulation value (Table 119-5).  Post-stimulation cortisol values are consistently less than 50 ng/ml (5.0 ug/dl) in dogs with hypoadrenocor­ticism.

 

Endogenous ACTH Concentrations

The results of ACTH stimulation testing will not differentiate primary from secondary hypoadrenocorticism.  This requires measurement of en­dogenous plasma ACTH concentra­tions.  Sample handling is critical for this hormone as it is much more labile than cor­tisol.  It is imperative that the laboratory processing the sample provide handling instruc­tions.  Samples generally must be drawn and centrifuged im­mediately and stored frozen in plastic tubes.

Plasma endogenous ACTH con­centrations are primarily of value in animals in which just glucocorticoid deficiency exists (ACTH stimulation test is non­responsive, but electrolytes are normal).  Some dogs with primary hypoadrenocorticism only have signs of glucocorticoid deficiency (i.e. lethargy, depression, anorexia, vomiting, diarrhea, and weakness).  Their sodium, potassium, and chloride values are normal.  Endogenous ACTH values should be high in dogs with primary hypoadrenocor­ticism, since no negative feeback from cortisol occurs.  The presence of high endogenous ACTH concentrations confirms that the pituitary is function­ing and that the primary lesion is located in the adrenal gland.  These dogs should have serum electrolytes monitored every 3 to 4 months, as progressive destruction of adrenal tissue is to be anticipated.   They would be expected to eventually develop minearlocorticoid deficiency and need replacement therapy.  Progressive destruc­tion of adrenal function does not always occur, however.  In one reported case, a dog with pure glucocorticoid-deficient primary hypoadrenocorticism failed to develop electrolyte abnormalities even after several years of monitoring.  It is being well managed with glucocorticoid replacement therapy alone.

The range of endogenous ACTH concentrations from 18 dogs with primary hypadrenocorticism was reported as 554 to 4950 pg/ml.  Normal values are from 20 to 100 pg/ml.  If both electrolytes and ACTH stimula­tion testing are abnormal, primary hypoadrenocorticism is confirmed, and endogenous ACTH concentrations become of academic interest.

Animals with pituitary failure causing their adrenal insufficiency should have low or undetectable endogenous ACTH concentrations, which leads to bilateral adrenal atrophy.  This is true in both naturally occur­ring and iatrogenic secondary hypoadrenoncorticism in which endogenous ACTH concentrations were measured.  Both dogs had values less than 20 pg/ml.  These animals need only cortisol replacement therapy to control signs of their disease.

 

Plasma Aldosterone Assay

Measurement of plasma al­dosterone concentrations may be of diagnostic value, but the as­say is available commercially from few sources.  It may be of interest to demonstrate normal results in dogs suspected to have secondary hypoadrenocor­ticism.  It could also be of value in the rare situation in which an animal has hyperkalemia and hyponatremia, an abnormal sodium/potassium ratio, but nor­mal ACTH stimulation results.  Such an animal may have primary hypoadrenocorticism, but cor­tisol reserve is still normal.

Aldosterone release is measured as part of an ACTH stimulation test protocol.  Limited numbers of dogs with primary hypoadrenocorticism have been tested, but all had low to non- detectable basal aldosterone concentrations and no repsonse following ACTH administration.  Normal serum aldosterone values are reported to be 20.3 + 7 ng/dl before and 39.7 + 9.4 ng/dl one hour after 0.25 IU/lb (0.5 IU/kg) synthetic ACTH (Cosyntrosyn) was given IV, and 5 to 345 pg/ml before and 71 to 758 pg/ml 2 hours after 1 U/lb (2.2 U/kg) IM ACTH gel was ad­ministered.

Modified Thorn Test

A modified Thorn test has been proposed as a rapid method for supporting or refuting the diagnosis of hypoadrenocorticism during initial diagnostic evaluation of patients suspected of having this disease.  The test is performed at the same time as ACTH stimulation testing is done for cortisol assays.  This test is not recommended.

 

THERAPY OF HYPOADRENOCORTICISM

ACUTE ADRENAL CRISIS MANAGEMENT

Patients with the clinical, biochemical and electrolyte ab­normalities compatible with acute hypoadrenocorticism should be treated as if they have the disease until they respond ap­propriately or the diagnosis is refuted.  To delay therapy pend­ing cortisol assays may lead to death of the patient.  Patients with nonadrenal causes for their hyperkalemia will not be harmed by therapy.  The primary goals of therapy are to correct hyp­volemia and hyptension, to rees­tablish vascular responsiveness, to replace glucocorticoid deficits, and to correct electrolyte abnormalities, hypoglycemia, and acidosis (Table 119-6).

 

Management of Shock, Hyptension, an Hypovolemia

Death from hypadrenocor­ticism is usually secondary to vascular collapse and shock, not from profound hyperkalemia.  Therefore, immediate intravenous fluid therapy is life-saving.  Fluids not only increase the intravascular volume, raise blood pressure, and improve renal perfusion but also dilute out the extracellular potassium, reducing the risk of developping fatal cardiac arrhythmias.

Normal saline (0.9 per cent sodium chloride) is the fluid of choice.  The primary electrolyte deficits are sodium and chloride, and the ideal fluid should be potassium-free.  An intravenous line is established, and baseline samples are col­lected for a CBC, chemistry profile, resting cortisol, and a urine analysis.  Saline is ini­tially administered at 20 to 40 ml/lb (40 to 80 mg/kg) during the first hour.  Total fluid re­quirements and rates of ad­ministration are determined by the degree of dehydration, main­tenance needs, and ongoing losses, and they are adjusted accordingly.  If the patient is found to be hypoglycemic, 50 per cent dextrose is added to the saline to make a 5 per cent solution (100 ml of 50 per cent dextrose per liter).  Potassium-containing fluids such as lactated Ringer's solution are relatively contraindicated (K+ = 4 mEq/L).  However, the serum potassium of the patient is usually much higher than the concentration in lactated Ringer's solution (LRS), and the volume expansion provided by LRS will dilute out the hyper­kalemia.  Administration of LRS is certainly preferable to giving no fluids at all.  The patient's urine output needs to be monitored to be sure adequate  urine production occurs once re­placement fluids are begun.

Glucocorticoid replacement therapy can be delayed until a post- ACTH plasma cortisol sample is obtained (1 hour for syn­thetic ACTH and 2 hours for ACTH gel).  Rapid volume expansion provides therapy for nearly all the acutely fatal complications associated with hypoadrenocor­ticism.  If a steroid is given during the time ACTH stimuloa­tion testing, it should be dexamethasone (see below for dosages).  This glucocorticoid is not measured by most RIA techniques for cortisol.

The ideal glucocorticoid to utilize in an acute hypoadrenal crisis would be hydrocortisone hemisuccinate or hydrocortisone phosphate (see Table 119-8).  These glucocorticoids possess both glucocorticoid and mineralocorticoid activity and are given at a dose of 1 to 2 mg/lb (2 to 4 mg/kg) IV ini­tially, and repeated every 8 hours.  Prednisolone sodium suc­cinate can be used as an alter­native rapid-acting glucocor­ticoid and is given at a dosage of 2 to 10 mg/lb (4 to 20 mg/kg) IV over 2 to 4 minutes.  This dosage is repeated in 2 to 6 hours, depending on how well the patient is responding.  Pred­nisolone sodium succinate also possesses some mineralocorticoid activity.  Dexamethasone sodium phosphate may also be used as replacement glucocorticoid therapy during intial treatment at dosages of 0.25 to 1.0 mg/lb (0.5 to 2 mg/kg) initially.  This dosage is reduced, once shock is reversed, to 0.02 to 0.05 mg/lb (0.04 to 0.1 mg/kg) twice daily and is added to the patients intravenous fluids.

 

 

Mineralocorticoid Replacement

Correction of sodium, chloride, and water deficits is accomplished by saline ad­ministration.  Hyperkalemia is also improved by volume expan­sion and improved renal perfu­sion alone.  There is no longer any rapid-acting parenteral mineralocorticoid preparation available.  Dexoxycorticosterone acetate has been taken off the market.  Hydrocortisone hemisuc­cinate or phosphate will provide adequate mineralocorticoid ac­tivity along with saline infu­sions to stabilize the hyper­kalemia until oral daily mineralocorticoid or injectable monthly mineralocorticoids (desoxycorticosterone pivalate, Percorten-V) can be given.  After initial shock dosages of hydrocortisone are administered, the dosage can be progressively reduced to 0.2 to 0.5 mg/lb (0.4 to 1.0 mg/kg) every 6 hours intravenously.  This may be fur­ther reduced on day 2 to 0.05 to 0.1 mg/lb (0.1 to 0.2 mg/kg) every 6 hours.  By day 3 the drug may be given at the same dosage with the frequency reduced to every 12 hours.  Sup­plemental mineralocorticoid therapy will usually be needed when the dosage of hydrocor­tisone reaches this mainteance level.

 

Management of Life-Threatening Hyperkalemia

In some animals the hyper­kalemia is so severe that alter­natives to volume expansion and mineralocorticoid replacement alone must be considered.  These alternative strategies for con­trolling hyperkalemia are rarely, if ever, needed.  In ad­dition to rapid volume expansion with 0.9 per cent saline, intravenous glucose, glucose plus regular insulin, sodium bicarbonate therapy, and intravenous 10 per cent calcium bicarbonate therapy may be con­sidered.

Intravenous glucose is use­ful in managing hyperkalemia be­cause as glucose enters cells, potassium follows, lowering its extracellular concentration.  glucose may be given as a 10 per cent solution at a dosage of 2 to 5 ml/lb (4 to 10 ml/kg), which may be added to the saline and given over 30 to 60 minutes.  Insulin is also known to promote the movement of extracellular potassium into cells.  Regular insulin can be given either SQ or IV at a dosage of 0.03 to 0.06 U/lb (0.06 to 0.12 U/kg) to promote rapid potassium uptake by cells.  For each unit of in­sulin given, 20 ml of 10 per cent dextrose are given to the patient to prevent hypoglycemia.

Alkalosis also promotes the transcellular movement of ex­tracellular potassium into cells, reducing its cardiotoxic effects.  Bicarbonate may be given at 0.25 to 0.5 mEq/lb (0.5 to 1.0 mEq/kg) as a slow IV bolus administration.  Again, this should not be necessary in most hypadrenal patients.

Finally, calcium gluconate is known to protect against the effects of hyperkalemia on the myocardium.  It can be given IV as a 10 per cent solution at 0.2 to 0.5 mg/lg (0.4 to 1.0 mg/kg) over a 10- to 20-minute period.  Administration of calcium gluconate may provide time for other slower-acting therapies to be effective.  Patients receiv­ing intravenous calcium gluconate must have continuous EKG monitoring.  If any new ar­rhythmias are noted, the infu­sion should be stopped.

 

Acidosis Management

The metabolic acidosis seen in patients with hypoadrenocor­ticism is usually mild and rarely needs to be treated specifially.  Volume expansion, increased tissue perfusion, and improved renal function usually lead to correction of preexist­ing metabolic acidosis.  If the total CO2 concentration (TCO2) is less than 12 mEq/L, judicious sodium bicarbonate therapy may be indicated.  The base deficit is calculated as body weight (kg) x 0.5 x base deficit (mEq/L).  In the absence of blood gas analysis for deter­mination of the base deficit, it can be estimated as:  base deficit = 22 - TCO2.  One-fourth of the calculated bicarbonate deficit is given to the patient in the first 6 to 8 hours of therapy.  It would be rare for nay more alkalinization therapy to be needed.  Sodium bicar­bonate therapy has an additional benefit in that it will help to promote the intracellular move­ment of potassium from the ex­tracellular space, reducing its adverse physiologic effects.

Most patients improve sig­nificantly within hours after the administration of ap­propriate fluid, electrolyte, and glucocorticoid replacement therapy.  Within 24 to 48 hours, most have stopped vomiting and diarrhea has ceased.  Gradual reintroduction of oral food, water and medications can now be safely done.  A rapid reversal of severe renal compromise, hy­percalcemia, and hyperkalemia lends further support for the diagnosis if results of ACTH stimulation testing are still pending.  Most other causes for these biochemical abnormalities will not respond this rapidly to the therapy described above.

In rare cases, renal func­tion may not return rapidly to normal.  In such animals it is liekly that the shock associated with hypoadrenocorticism induced severe reanl ischemia or that some preexisting primary renal disease was aggravated by hypovolemia and hyptension.  In this situation, a rapid return to normal BUN or creatinine is not expected.  These patients require much more judicious fluid administration, especially if they become oliguric.

 

MAINTENANCE THERAPY OF HYPOADRENOCORTICISM

Once patients stabilize following initial aggressive fluid, electrolyte, glucocor­ticoid, and acidosis therapy, maintenance therapy can be started (Table 119-7).  In most animals with primary hypoadrenocorticism, both glucocorticoid and mineralocor­ticoid replacment therapy will be needed for life.  In the rare animal with only glucocorticoid deficiency, no mineralocor­ticoids will be needed.  Low dosages of glucocorticoids will control signs of their disease.

Oral glucocorticoid replac­ment therapy is continued for 3 to 4 weeks in most animals after the crisis is over.  Prednisone or prednisolone may be given initially at 0.25 to 0.5 mg/lb/day (0.5 to 1 mg/kg) in divided doses every 12 hours.  This dosage is gradually tapered off (decrease by 50 per cent per week) until the drug is discon­tinued entirely.  The majority of dogs do well on replacement mineralocorticoid alone after the first few weeks of therapy if fludrocortisone acetate is used (Florinef).  If dogs show signs of cortisol deficiency (anorexia, lethargy, depression), low dosages of prednisone or prednisolone can be started again.  Daily main­tenance needs for prenisone or prednisolone are approximately 0.1 mg/lb/day (0.22 mg/kg) in most dogs.  All owners should be given a prescription for some sort of glucocorticoid to use in times of stress, regardless of whether the patient needs them daily.

Long-term mineralocorticoid replacement therapy can be provided by a number of means including oral fludrocortisone acetate, injectable desoxycor­ticosterone pivalate (DOCP), or surgically implanted DOCP pel­lets.  The durg used most com­monly is fludrocortisone acetate (Florinef).  Fludrocortisone is a potent oral mineralocorticoid that is useful as daily replace­ment therapy.  It is available in 0.1-mg tablets, and its mineralocorticoid potency is equivalent to that of natural aldosterone.  It also has sig­nificant glucocorticoid ac­tivity.  On a milligram basis, it is ten times as potent as cortisol.  Thus, it provides for both the glucocorticoid and mineralocorticoid needs of most patients once the cortisol needs during an adrenal crisis are managed.  It is administered at approximately 0.1 mg/10 lb body weight (0.1 mg/5 kg) in divided doses every 12 hours.  Dosages are adjusted based on normaliza­tion of serum sodium and potas­sium concentrations.  Electrolytes should be monitored every 4 to 7 days during the first week or two and then every 3 to 4 months during the first year of therapy.  Dogs generally develop increased need for fludrocortisone during the ini­tial 6 to 18 months of therapy.  After that time, most have stable mineralocorticoid dosages.  This increasing drug needmay be due to progression of adrenal inflammatory disease that was ongoing at the time of inital diagnosis.

Maintaining the serum potassium concentration in the high- normal range is the goal of therapy.  The drug's cost and side effects (polyuria, incon­tinence) are limiting factors in the treatment of some dogs with hypoadrenocorticism.  Par­ticularly in giant breeds, the cost of daily fludrocortisone can be several dollars a day.  By maintaining the serum potas­sium in the high- normal range, one can be sure the minimual amount necessary is being given, which helps to control long-term drug costs for the owner and is not associated with any in­creased clinical risk of relapse for the dog.

In some animals on large fludrocortisone dosages, polyuria can be profound and in­tolerable for owners, probably owing to the glucocorticoid ac­tivity inherent in this product.  It has been suggested that this may be controlled by the use of oral hyrocortisone as replace­ment therapy for both glucocor­ticoids and mineralocorticoids.  Hydrocortisone may be given at 0.0612 mg/lb (0.125 mg/kg), with two-thirds given in the morning, when steroid needs are greatest, and one-third given 12 hours later.  In some dogs, supplemen­tal fludrocortisone will still be needed, but at reduced dosages (0.05 to 0.2 mg/day).

In occasional animals, hyponatremia will persist in spite of normal serum potassium concentrations.  In such cases, the addition of table salt to the diet should normalize the sodium concentrations without an increase in fludrocortisone dosages (a more costly alternative).

An alternative to daily oral fludrocortisone therapy is the use of injectable desoxycor­ticosterone pivalate (DOCP).  DOCP is a long-acting ester of desoxycorticosterone in a microcrystalline suspension.  Several recent reports have dis­cussed its use as a replacement for daily fludrocortisone tablets.  It was available com­mercially as Percorten pivalate until 1987, when commercial production was discontinued.  Since that time it has only been available from the manufacturer upon individual request.  The drug, Percorten-V, has gone through initial clinical trials and is awaiting approval by the FDA for use in dogs.  The manufacturer anticipates ap­proval of the drug for general use by veterinarians sometime in 1994 or 1995.  At this time, it can only be obtained from the manufacturer by individual re­quest.  (Write CIBA Animal Health at P.O. Box 18300, Greensboro, NC  27419-1180 for information about obtaining DOCP for selected animals.  Current costs are $62.00 per 100-mg vial[25 mg/ml].)

DOCP is useful for dogs that develop significant polydipsia and polyuria when receiving Florinef; for those that require large dosages, and thus incur high costs for con­trol of their disease; or for animals in which fludrocortisone appears ineffective even in large doseages.  DOCP is ini­tially given at 1 mg/lb (2.2 mg/kg) IM once every 25 days.  Serum should be collected after 14 days and again at 25 days for the first 2 to 3 months of therapy to determine whether dosage adjustments are needed.  Occasionally, there are in­dividual dosage variations with DOCP, and frequent monitoring, at least during the first few months of therapy, is of value.  The goal is to maintain the dog on the smallest dosage needed to achieve normal serum electrolyte concentrtions and to prevent clinical signs of disease.  If the sodium and potassium are normal at day 25 (the day of injection), the dosage may be decreased by 0.1 mg/lb (0.2 mg/kg) at each subsequent dosing interval until the lowest dosage that maintains normal electrolytes is obtained.  As an alternative, the doing interval may be increased to 30 days and and electrolyte panel evaluated at the end of the new 30-day inter-injection interval.

In some dogs the duration of action is less than 25 days.  If electrolytes are normal at 14 days, but not at day 25, the dosing interval should be shortened.  Shorten the inter-injection interval to 21 days first.  Rare animals need DOCP as often as every 14 days.

Current data suggest that approximately 15 per cent of dogs will require 0.5 mg/lb (1.1 mg/kg) every 25 days, and 30 per cent will require between 0.5 and 1.0 mg/lb (1.0 and 2.2 mg/kg).  Over 50 per cent are well maintained on 1.0 mg/lb (2.2 mg/kg) every 25 days.  Few require more than 1.0 mg/lb/injection (2.2 mg/kg).

Because DOCP has little or no glucocorticoid activity, sup­plemental glucocorticoid therapy should be combined with DOCP, at least initially.  Interestingly, approximately 50 per cent of dogs do well with no supplemen­tal glucocorticoids when main­tained on DOCP alone.  Ini­tially, dogs are given ap­proximately 0.1 mg/lb/day (0.22 mg/kg) of prednisone or pred­nisolone.  This dosage may be gradually reduced and eliminated after several weeks if the dog has no clinical signs of disease (anorexia, lethargy, depression) in the absence of glucocorticoid supplementation.  Some dogs do well when glucocorticoids are given only once every 2 to 3 days.  Owners should have a supply of glucocorticoids avail­able to give during stressful situations even if they are not needed on a daily basis.  Glucocorticoid demands during stress are two to ten times those needed for maintenance.

Side effects associated with DOCP have been infrequent.  Polydipsia and polyuria are oc­casionally seen.  This most of­ten results from combining glucocorticoids with the DOCP and responds to lowering the glucocorticoid dosage.  In rare animals, lowering of the DOCP dosage results in elimination of these signs.  One animal was reported to have a less favorable response to DOCP than Florinef, and one dog had an acute adrenal crisis in spite of having received the drug, and was considered a drug failure.  Mild hypoalbuminemia has been noted in occasional dogs receiv­ing DOCP (serum albumin 2.0 to 2.5 gm/dl).

The owner's main disad­vantages in the use of DOCP are the need to return monthly for an injection and the costs of repeated examinations and laboratory work.  Owners can be taught to give the injections at home and are seen only every 3 to 4 months once the patient is stable, to ensure that electrolytes are well main­tained.  Recent data also sug­gest that subcutaneous injec­tions are as effective as IM in­jections, simplifying at-home management for owners.

The last method for mineralocorticoid replacement is that of DOCP pellets.  DOCP pel­lets contain 125 mg of DOCP and are surgically implanted sub­cutaneously.  They release ap­proximately 0.5 mg of desoxycor­ticosterone acetate per im­planted pellet per day and have a duration of action of ap­proximately 10 months.  The are costly, require more technical manipulations (surgery), and are the least reliable of the three methods available.  They are not recommended for use at this time.

 

Therapy of Secondary Hypoadrenocorticism

Animals with spontaneous or iatrogenic secondary hypoadrenocorticism need only glucocorticoids to reverse their clinical signs.  Dosages are similar to those recommended previously, starting at 0.25 to 0.5 mg/lb/day (0.5 to 1 mg/kg) and tapering to the lowest needed to control clinical signs of disease.  Periodic reevalua­tion of serum electrolytes is indicated in animals thought to have naturally occurring secon­dary hypoadrenocorticism (pituitary disease) because some animals may actually have primary disease and have been misdiagnosed initially.  They develop electrolyte abnor­malities only late in their dis­ease course.  This is par­ticularly true if endogenous ACTH concentrations are not available for analysis.  In cases of iatrogenic hypoadrenocorticism, glucocor­ticoid dosages are gradually reduced to alternate-day therapy at low dosages until eventually no supplemental therapy is needed.

 

PROGNOSIS

The long-term prognosis for animals with hypoadrenocor­ticism, once an adrenal crisis is controlled, is excellent.  With appropriate glucocorticoid and or minerlocorticoid replace­ment, dogs and cats should be expected to live a normal life.  Good communication between the veterinarian and the owner is critical for success, however.  The importance of life-long therapy and the need for peri­odic physical examinations and biochemical evaluations must be emphasized to owners.  In addi­tion, owners need to know that their pet may deteriorate in high-stress situations if glucocorticoids are not in­creased.  They also need to be educated about how to recognize signs of glucocorticoid defiency.

 

TABLE 119-1.  HISTORICAL OWNER COMPLAINTS FOR DOGS WITH HYPOADRENOCORTICISM*

% OF

SIGN                                        OCCURRENCE

Anorexia                                           77

Vomiting                                           68

Lethargy/depression                           64

Weakness                                         38

Weight loss                                       23

Diarrhea                                            22

Shaking/shivering                               21

Polyuria (with or                                15

without polydipsia)

Waxing-waning course                       10

of illness

Sensitive abdomen                            9

 

*Frequency of the various signs of canine hypoadrenocorticism as noted by the owners of these dogs.  Results are a compilation of 100 personal and reported cases.             From Feldman EC and Nelson RW:  Canine and Feline Endocrinology and Reproduction.  Philadelphia, WB Saunders, 1987, p. 199.

 

TABLE 119-2.SELECTED LABORATORY VALUES IN DOGS WITH PRIMARY HYOADRENOCORTICISM

FACTOR                         NORMAL VALUE           TESTED         MEAN              (%)                    (%)                RANGE

Serum sodium                    136-150 mEq/L              36               129               22(60)                   0( 0)            106-146

Serum potassium                3.5-50. mEq/L               36               7.2                 0( 0)                    33(92)           4.7-10.8

Sodium/potassium ratio           >27:1                       36               19                  35(97)                  0( 0)           11.2-29.1

BUN (pre-Rx)                       9-25 mg/dl                  36                84                  0( 0)                   33(92)           12-223

BUN (after 24 hr Rx)            9-25 mg/dl                    9                25                  0( 0)                    4(44)             11- 47

Serum calcium                   8.8-11.0 mg/dl               13              11.5                 0( 0)                    8(62)            9.3-14.4

Serum glucose                  70-110 mg/dl                  24              81.5                8(33)                   4(17)              20-130

Serum bicarbonate             18-24 mM/L                   16               14                13(81)                    0( 0)                9-19

Urine specific gravity                 -                            25              1.024                 -                          -                1.008-1.062

 

From Feldman EC:  Adrenal gland disease.  In Ettinger SJ (ed): Textbook of Veterinary Internal Medicine. 3rd ed. Philadelphia, WB Saunders, 1989, p. 1761.

 

 

 

TABLE 119-3.  SELECTED LABORATORY VALUES IN DOGS WITH PITUITARY FAILURE TO SECRETE ACTH AND SECONDARY ADRENOCORTICISM INSUFFICIENCY

NUMBER           NUMBER

NUMBER                      DECREASED    INCREASED

FACTOR                       NORMAL VALUE          TESTED         MEAN               (%)                    (%)           RANGE

Serum sodium                 136-150 mEq/L                3                142                   0                        0           136-146

Serum potassium              3.5-5.0 mEq/L                3                4.3                    0                        0            4.0-4.5

Sodium/potassium ratio        >27:1                         3                 29                    0                        0             28-31

BUN                                9-25 mg/dl                    3                30.5                  0                         0             25-35

Serum glucose                70-110 mg/dl                  3                  68                 2(67)                  2(66)         41-105

Urine specifi gravity                 -                             3               1.044                 -                         0          1.028-1.052

 

From Feldman EC:  Adrenal gland disease. In Ettinger SJ (ed):  Textbook of Veterinary Internal Medicine. 3rd ed. Philadelphia, WB Saunders, 1989, p 1762.

 

TABLE 119-4.  DIFFERENTIAL DIAGNOSIS FOR SIGNIFICANT HYPERKALEMIA AND/OR HYPNATREMIA IN DOGS AND CATS*

 

I.  Hypoadrenocorticism

II.  Renal or urinary tract disease

A.  Acute primary renal failure

B.  Chronic severe oliguric or anuric failure (rare)

C.  Urethral obstruction

D.  Uroabdomen (ruptured ureter, bladder, or urethra)

E.  Postobstructive diuresis

F.  Nephrotic syndrome

III.  Severe liver failure

A.  Cirrhosis

B.  Neoplasia

IV.  Severe gastrointestinal diseases

A.  Parasitic infestations

1.  Trichuriasis

2.  Ascariasis

3.  Ancylostomiasis

B.  Salmonellosis

C.  Viral enteritis

1.  Parvovirus

2.  Distemper

D.  Gastric dilatation/volvulus

E.  Gastrointestinal perforation

F.  Severe malabsorption

G.  Idiopathic hemorrhagic enteritis

V.  Severe metabolic or respiratory acidosis

VI.  Congestive heart failure

VII.  Massive release of potassium to the extracellular fluid

A.  Crush injuries

B.  Aortic thrombosis

C.  Rhabdomyolysis

1.  Heat stroke

2.  Exertional

D.  Massive infections

E.  Massive hemolysis (rare)

VIII.  Pseudohyperkalemia

A.  The Akita breed

B.  Severe leukocytosis (>100,000 mm3)

C.  Severe thrombocytosis (>1,000,000 mm3)

IX.  Diabetes mellitus

X.  Primary polydipsia

XI.  Inappropriate ADH secretion

XXI.  Drug-Induced

A.  Potassium-sparing diuretics

B.  Nonsteroidal anti-inflammatory agents

C.  Angiotensin-converting enzyme inhibitors

D.  Potassium-containing fluids

__________________________________________________________________

*Most of these diagnoses/conditions are rarely associated with abnormal electrolyte abnormalities.

Modified from Feldman EC:  Adrenal gland disease.  In Et­tinger, SJ (ed):  Textbook of Veterinary Internal Medicine.  3rd ed.  Philadelphia, WB Saunders, 1989, p 1764.

 

TABLE 119-5.  PLASMA RIA CORTISOL CONCENTRATIONS BEFORE AND AFTER SYNTHETIC ACTH STIMULATION AND BASAL ENDOGENOUS PLASMA ACTH CON­CENTRATIONS IN DOGS WITH SPONTANEOUS ADRENOCORTICAL INSUFFICIENCY*

PLASMA-CORTISOL CONCENTRATION (ug/dl) PLASMA ACTH

CONCENTRATION

Dog Number                       Before Stimulation                                 After 60 min       (pg/ml)

 

1                                              0.2                                                           0.1                                                 681

2                                              0.5                                                           0.4                                               3740

3                                              1.3                                                           2.4                                                 572

4                                              0.7                                                           3.7                                               1633

5                                              0.4                                                           0.4                                                 736

6                                              0.4                                                           0.4                                                 607

7                                              0.2                                                           0.9                                                 983

8                                              0.1                                                           0.2                                                 760

9                                              0.1                                                           0.1                                              2840

10                                              0.2                                                           0.3                                                 554

11                                              0.5                                                           0.4                                               1290

12                                              1.6                                                           0.7                                               1793

13                                              0.2                                                           0.2                                               4950

14                                               0.6                                                           1.3                                               2300

15                                               0.1                                                           0.1                                               1680

16                                               0.3                                                           0.2                                               1720

17                                               0.5                                                          1.8                                               1040

18                                                0.5                                                           0.4                                                 967

19                                                1.3                                                           5.5                                                 <20

20                                                0.9                                                           0.3                                                 <20

 

Normal range                                0-8.1                                                      4.9-15.3                                             20-100

Normal mean                                 3.3                                                           12.3                                                 46

 

*Dogs 1-18 had primary adrenal failure.  Dogs 19 and 20 had secon­dary adrenal failure.

From Feldman EC and Nelson RW:  Canine and Feline Endocrinology and Reproduction.  Philadelphia, WB Saunders, 1987, p 209.

 

 

 

TABLE 119-6.  THERAPEUTIC MANAGEMENT OF AN ACUTE ADRENAL CRISIS

 

1.  Collect blood for CBC, chemistry profile, urinalysis, resting

cortisol

2.  Intravenous 0.9 per cent saline IV (20-40 ml/lb) initially

3.  ACTH stimulation test

A.  1 U/lb ACTH gel IM-sample-at 0 and 2 hours in dogs, 0, 1,

and 2 hours for cats

B.  0.25 mg synthetic ACTH IM in dogs; 0.125 mg IM in cats-

sample at 0 and 1 hours in dogs; 0, 20 and 60 minutes in

cats

4.  Glucocorticoid replacement

A.  Hydrocortisone hemisuccinate or phosphate, 1-2 mg/lb IV slowly or

B.  Prenisolone sodium succinate, 2-10 mg/lb IV or

C.  Dexamethasone sodium phosphate, 0.25 to 1.0 mg/lb IV

5.  Add 100 ml of 50 per cent dextrose to each liter of saline if hypoglycemic

6.  Mineralocorticoid replacement

A.  Hydorcortisone sodium succinate or phosphate as above

or

B.  Desoxycorticosterone pivalate, 1 mg/lb IM or SQ every 25 days

or

C.  Fludrocortisone acetate, 0.1 mg/10 lb/day once hydrated and not vomiting or having diarrhea

7.  Sodium bicarbonate-replacement needs calculated as follows:

Body weight (kg) x 0.5 x base deficit.  Give 1/4 of this amount IV over the first 6 hours of therapy.  Administer only if TCO2 is <12 mEq/L

8.  Monitor:

A.  ECB

B.  Serum electrolytes

C.  BUN, creatinine, and urine output

D.  Blood glucose, if low initially

TABLE 119-7.  MAINTENANCE THERAPY OF HYPOADRENOCORTICISM

 

1.  Oral glucocorticoids continued for 3 to 4 weeks

A.  Prednisone or prednisolone, 0.2 to 0.5 mg/lb/day in di-vided doses every 12 hours

B.  Taper by 50 per cent/week until stopped or dog shows signs of cortisol deficiency.  Use least amoutn necessary.

2.  Mineralocorticoid replacement

A.  Fludrocortisone acetate, 0.1 mg/10 lb/day in divided doses every 12 hours

B.  Hydrocortisone hemisuccinate, 0.612 mg/lb, 2/3 AM and 1/3 PM;  Fludrocortisone may be needed in reduced dosages (0.05 to 0.2 mg/day)

or

C. Desoxycorticosterone pivalate, 1 mg/lb every 25 days, IM or SQ

D.  Supplemental salt may be added to the food if hyponatremia persists but potassium is normal

3.  Recheck

A.  Electrolytes

B.  BUN and creatinine

C.  Physical examination

 

 

TABLE 119-8.  DRUG INDEX

GENERIC                                TRADE                          DOSAGE               ROUTE                   FREQUENCY                                   DESCRIPTION

 

ACTH gel                                Cortigel                        1 unit/lb                       IM             Sample at 0, 2 hr (dogs)                  Assess adrenal reserve function

Sample at 0, 1, 2 hr (cats)

Tetracosactrin                         Cortrosyn                    0.25 mg/dog                  IM                     Sample at 0, 1 hr (dogs)          Assess adrenal reserve function

0.125 mg/cat                            IM                     Sample at 0, 0.5, 1 hr (cats)

Hydrocortisone                     Solu Cortef                        1-2 mg/lb                   IV                      Every 8 hours                         Acute crisis therapy

hemisuccinate                      A-hydrocort                    0.0612 mg/lb                Oral                    2/3 AM, 1/3 PM                       Maintenance mineralocorticoid

phosphate                            Hydrocortone                   1-2 mg/lb                    IV                      Every 8 hours                         Acute crisis therapy

Prednisolone sodium             Solu-delta cortef               2-10 mg/lg                    IV                      Every 2 to 6 hours                  Acute crisis therapy

succinate

Dexamethasone sodium             Azium                       0.25 to 1 mg/lb               IV                      Every 12 hours                       Acute crisis therapy

phosphate

Desoxycorticosteron               Percorten-V                     1 mg/kg                  IM/SQ                    Every 25 days                         Maintenance mineralocorticoid

pivalate

Fludrocortisone                       Florinef                         0.05 mg/5 lb               Oral                      Every 12 hours                       Maintenance mineralocorticoid

 

 

 

 

 

 

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