. .,.

ADRENAL DISORDERS 0195-5616/97 $0.00 + .20

PRIMARY AND
SECONDARY CANINE
HYPOADRENOCORTICISM
Peter P. Kintzer, DVM, and Mark E. Peterson, DVM

Naturally occurring canine primary hypoadrenocorticism, or Addi-

son's disease, results from atrophy or destruction of the adrenal cortices,
whereas secondary hypoadrenocorticism is due to deficient pituitary
adrenocorticotropic hormone (ACTH) production:'· 7• 17 Primary hypoad-
renocorticism usually results in inadequate glucocorticoid and mineralo-
corticoid secretion and is usually attributed to an immune-mediated
process. 111 Occasionally, some dogs with primary hypoadrenocorticism
have normal serum electrolyte levels or so-called atypical hypoadreno-
corticism.16 This may be the result of a gradual loss of adrenocortical
tissue with which glucocorticoid secretion becomes subnormal before
mineralocorticoid secretion is substantially affected. On the other hand,
multiple blood samples may be necessary to demonstrate abnormal
electrolyte levels in some dogs, especially when recent previous thera-
peutic intervention has occurred. In secondary adrenal insufficiency,
deficient pituitary ACTH secretion results in inadequate glucocorticoid
production, whereas mineralocorticoid secretion is usually preserved
because ACTH has little trophic effect on mineralocorticoid production.

CLINICAL PRESENTATION

Hypoadrenocorticism is an uncommon endocrinopathy typically

occurring in young to middle-aged female dogs.2• 3• 7• 9• 18• 21 We have

From the Boston Road Animal Hospital, Springfield (PPK); and the Department of Medi-
cine, Tufts University School of Veterinary Medicine, North Grafton (PPK), Massachu-
setts; and the Division of Endocrinology, The Animal Medical Center, New York,
New York (MEP)

VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE

VOLUME 27 • NUMBER 2 • MARCH 1997 349
350 KINTZER & PETERSON .....

recently reported the pretreatment clinical and laboratory findings in a

large cohort of dogs with naturally occurring hypoadrenocorticism. 14
Common historical and clinical findings seen in dogs with hypoadreno-
corticism are listed in Table 1. No set of clinical signs is pathognomonic
for hypoadrenocorticism, and the typical signs are present in a wide
variety of more common disorders. The severity and duration of these
clinical findings varies greatly between dogs. The majority of affected
animals show chronic progressive problems present for a variable period
of time (up to 1 year), whereas those dogs in an acute adrenal crisis
constitute a true medical emergency. Even in these cases, a thorough
history often elicits findings consistent with hypoadrenocorticism that
precede the onset of acute adrenocortical insufficiency by days to
months. An important diagnostic clue is a waxing/waning course of
illness that is exacerbated by stress and that responds to nonspecific
treatment and supportive care (parenteral fluid administration and cage
rest). Given that the historical and clinical findings associated with
canine hypoadrenocorticism are vague, nonspecific, often intermittent,
and similar to those seen in a variety of more common disorders, a high
index of suspicion is necessary for prompt recognition and diagnosis of
the disease.

CLINICOPATHOLOGIC FINDINGS

Common clinicopathologic abnormalities in dogs with hypoadreno-

corticism are listed in Table 2. 2• 7• 14 The classic abnormalities are hyperka-

Table 1. HISTORICAL AND CLINICAL ABNORMALITIES IN CANINE

HYPOADRENOCORTICISM
Sign Approximate Percentage of Cases
Lethargy/depression 95
Anorexia 90
Vomiting 75
Weakness 75
Weight loss 50
Dehydration 45
Diarrhea 40
Waxing/waning course 40
Collapse 35
Previous response to therapy 35
Hypothermia 35
Slow CRT 30
Shaking 27
Polyuria/polydipsia 25
Melena 20
Weak pulse 20
Bradycardia (< 60 bpm) 18
Painful abdomen 8
Hair loss 5

CRT ; capillary refill time: bpm ~ beats per minute.

. •"'" PRIMARY AND SECONDARY CANINE HYPOADRENOCORTICISM 351

Table 2. CLINICOPATHOLOGIC ABNORMALITIES IN CANINE

HYPOADAENOCOATICISM
Finding Approximate Percentage of Cases
Hyperkalemia 95
Hyponatremla 80
Na/K ratio < 27 95
Hypochloremia 40
Hypercalcemla 30
Azotemia 85
Decreased Tcea 40
Elevated ALT/AST 30
Hyperbilirubinemia 20
Hypoglycemia 17
Anemia 25
Eosinophilia 20
Lymphocytosis 10
Urine specific gravity < 1.030 60

Teo, = total carbon dioxide; ALT = alanine aminotransferase; AST = aspartate aminotransferase.

lemia, hyponatremia, azotemia, mild to moderate metabolic acidosis,

and absence of a stress leukogram. In addition, hypercakemia may be
seen in up to 30% of cases. 12 Electrolyte disturbances cannot be relied
on for the definitive diagnosis of hypoadrenocorticism, however. Hyper-
kalemia may occur in a variety of other diseases, particularly renal
failure, gastrointestinal disorders, and acidosis. Azotemia is typically
prerenal in origin and resolves with adequate fluid replacement. In the
unusual instance that creatinine and blood urea nitrogen (BUN) do not
quickly return to normal, inadequate fluid therapy or ischemic renal
damage may be present. Serum biochemical evaluation in cases of sec-
ondary adrenocortical insufficiency is usually unremarkable, although
hyponatremia and azotemia may be seen. Hematologic evaluation may
reveal a mild to moderate nonregenerative normocytic normochromic
anemia and the absence of a stress leukogram. Urinalysis frequently
reveals a decreased urine specific gravity, especially when the specific
gravity is considered in the context of prerenal azotemia. In our experi-
ence, over 50% of dogs have an impaired ability to concentrate urine
(specific gravity < 1.030) in the presence of an elevated BUN and
creatinine. 1~ This decreased renal concentrating ability has been attrib-
uted to medullary washout and decreased medullary blood flow. 20

ELECTROCARDIOGRAPHIC FINDINGS

An electrocardiogram should be performed in all dogs with brady-

cardia and those with significant hyperkalemia (> 6.5 mEq/L). Arrhyth-
mias associated with hypoadrenocorticism can have life-threatening
consequences for dogs with hypoadrenocorticism. The classic electrocar-
diographic findings seen with hyperkalemia, including QRS prolonga-
352 KINTZER & PETERSON

tion, decreased R wave amplitude, increased T wave amplitude, PR

interval prolongation, and absence of P waves often correlate poorly
with serum potassium levels in dogs with hypoadrenocorticism. This is
a result of the interaction of other concurrent electrolyte abnormalities,
metabolic acidosis, and decreased tissue perfusion with the cardiac
conduction system.5• 6 Electrocardiographic abnormalities are found in
over 50% of cases in which an electrocardiogram is performed. 14 Sino-
atrial standstill is by far the most common arrhythmia and ventricular
premature contractions and atrial fibrillation are occasionally found.
Heart block ranging from first degree heart block to atrioventricular
dissociation is present in approximately 12% of cases in which an electro-
cardiogram is performed. 14

RADIOGRAPHIC FINDINGS
Radiographs are usually taken when a dog is in acute adrenal crisis
or when it shows significant clinical signs associated with hypoadreno-
corticism. Abnormal findings may include microcardia, a narrowed vena
cava or descending aorta, and hypoperfused lung fields, which result
from volume depletion and decreased tissue perfusion. A transient meg-
aesophagus that resolves with treatment of the adrenocortical insuffi-
ciency has been reported in very rare instances. 1• 14

DIAGNOSIS
Definitive diagnosis of hypoadrenocorticism requires demonstration
of inadequate adrenal reserve characterized by a low resting serum
cortisol concentration coupled with a subnormal or negligible response
to exogenous adrenocorticotropic hormone (ACTH) administration. The
ACTH-response test can be performed using either ACTH gel (if avail-
able) or synthetic ACTH. When using ACTH gel, serum cortisol levels
are determined before and 2 hours after injection of 20 U intramuscu-
larly. If synthetic ACTH is used, samples are drawn before and 1 hour
after administration of 250 µ.g (1 vial) intramuscularly or intravenously.
Recent work has shown, however, that a dosage of 5 to 10 µg/kg
of synthetic ACTH (Cosyntropin [Organon, West Orange, NJI) given
intravenously yields comparable results, allowing multiple use of a
vial. 15 ACTH gel repository corticotropin injection (distributed by Aus-
tin, Division of Vetoquinol Canada, Joliette, Canada) seems to be effica-
cious in dogs, but is not readily available in the United States. In the
experience of these authors, some preparations of ACTHAR gel (80
units/mL [Rhone-Poulenc-Rorer, Collegetown, PA]) may lack biological
activity in dogs.
The ACTH response test can be done immediately or after several
hours of stabilization with parenteral fluid and glucocorticoid adminis-
tration. Dexamethasone sodium phosphate does not interfere with corti-
sol determination and should be used in the initial treatment of acute
adrenocortical insufficiency. Prednisone, prednisolone, hydrocortisone,
and cortisone all cross-react with serum cortisol assays and should be
 PRIMARY AND SECONDARY CANINE HYPOADRENOCORTICISM 353

withheld until completion of ACTH-response testing. Therefore, in those

dogs that have received prednisone, prednisolone, hydrocortisone, or
cortisone, glucocorticoid therapy is changed to dexamethasone for at
least 24 hours before an ACTH-response test can be performed. In dogs
with hypovolemia or significant dehydration, delaying ACTH-response
testing until after initial fluid replacement may be advisable. In such
cases, decreased tissue perfusion may impede absorption of an intramus-
cular ACTH injection (particularly if ACTH gel is used) resulting in
inaccurate and misleading data.
Electrolyte abnormalities (hyperkalemia and hyponatremia) coupled
with a subnormal cortisol response to ACTH indicate primary hypoadre-
nocorticism. Keep in mind, however, that some dogs with secondary
hypoadrenocorticism have hyponatremia. A plasma ACTH level should
be used to differentiate primary from secondary adrenal insufficiency in
dogs with normal electrolyte levels. Plasma ACTH concentrations are
elevated in dogs with primary hypoadrenocorticism as a consequence
of the loss of negative feedback of cortisol on the pituitary, whereas
plasma ACTH concentrations are undetectable to low in dogs with
secondary hypoadrenocorticism. Plasma samples for ACTH levels
should ideally be drawn before corticosteroid administration and must
be appropriately handled to ensure accurate results.

TREATMENT
Treatment of canine hypoadrenocorticism requires the provision of
appropriate mineralocorticoid and/or glucocorticoid replacement. Initial
dosage, route of administration, and urgency of treatment depend on
the clinical presentation. We recently reported the results of treatment
of two large cohorts of dogs with naturally occurring hypoadreno-
corticism.8• •~

Acute Adrenocortlcal Insufficiency

Acute adrenocortical insufficiency (Addisonian crisis) is a life-
threatening emergency requiring immediate intervention. If the history
and presentation are compatible with acute hypoadrenocorticism, appro-
priate therapy should be instituted without delay and the definitive
diagnostic workup begun while the initial treatment is in progress.
Blood for determination of complete blood count, electrolyte levels, and
serum chemistry as well as urine for urinalysis must be collected before
initiating therapy, however. Of primary importance is the rapid adminis-
tration of large volumes of intravenous fluids, preferably 0.9% NaCl. In
our experience, the use of lactated Ringer's solution in the initial therapy
of adrenal crisis is not inappropriate; the small amount of potassium in
lactated Ringer's does not appear to be detrimental and any harm is far
outweighed by the benefit of rapid correction of hypovolemia. 6• 13
Fluid therapy is initiated at a rate of 60 to 80 mL/kg/h for 1 to 2
hours to ensure prompt correction of hypovolemia; the infusion rate is
then decreased. Such rapid fluid administration is also a dependable
354 KINTZER & PETERSON '
means of quickly decreasing the serum potassium concentration as a
result of a dilutional effect as well as improved renal perfusion with
concomitant increased potassium excretion. Urine output should be
monitored to assess the adequacy of urine production and to help guide
fluid therapy. Fluids are tapered to a maintenance rate and are eventu-
ally discontinued over a few to several days based on the patient's
clinical status, response to therapy, urine output, and laboratory parame-
ters.
Also of great importance in the treatment of acute adrenocortical
insufficiency is the intravenous administration of a glucocorticoid. A
rapid-acting formulation such as dexamethasone sodium phosphate (2
to 4 mg/kg) or prednisolone sodium succinate (15 to 20 mg/kg) is
preferred (dexamethasone sodium phosphate must be used if an ACTH-
response test is in progress). The initial dose of rapidly acting glucocorti-
coid can be repeated in 2 to 6 hours if necessary. Glucocorticoid supple-
mentation is gradually tapered to a maintenance dosage of prednisone
or prednisolone (0.2 mg/kg daily) as the patient's condition improves.
Supplementation is administered parenterally until vomiting has ceased.
A rapidly acting parenteral mineralocorticoid formulation is no
longer available for use in the treatment of acute adrenocortical insuffi-
ciency; however, rapid correction of hypovolemia and the amelioration
of shock and restoration of vascular integrity with glucocorticoids are
sufficient to stabilize the patient. Nevertheless, oral mineralocorticoid
supplementation with fludrocortisone acetate (Florinef) can be instituted
immediately; even an animal that is vomiting may absorb some of
the drug.
Other clinicopathologic derangements may require attention. In
most cases, metabolic acidosis is corrected by fluid and glucocorticoid
therapy; administration of sodium bicarbonate is rarely necessary. Se-
vere acidosis (pH < 7.2), however, should be treated. The total dose of
bicarbonate is calculated using the following formula: Deficit in
mEq = (body weight in kg) (0.5) (base deficit). Twenty-five percent of
the calculated deficit is given in the intravenous fluids over the initial 6
to 8 hours, at which time the acid-base status is reevaluated. For a dog
to require additional sodium bicarbonate administration is unusual.
Hypoglycemia, if present, should be addressed. If the animal is not
dehydrated, glucose can be added to the intravenous fluids at a concen-
tration of 2.5%. Symptomatic hypoglycemia should be treated with a
slow intravenous bolus of 0.5 to 1 mL/kg of 50% dextrose.
Cardiac conduction abnormalities associated with severe hyperka-
lemia can progress to ventricular fibrillation or asystole. Rapid fluid
infusion results in a significant lowering of serum potassium concentra-
tion and dramatic electrocardiographic improvement within 30 to 60
minutes in most cases. Should severe hyperkalemia persist despite such
fluid administration (this is rare), or if death from hyperkalemic myocar-
dial toxicity is imminent, intravenous insulin and glucose can be given.
Regular insulin is given at a dosage of 0.5 U/kg. Two to 3 g of glucose
per unit of insulin is administered, half as an intravenous bolus and half
in the intravenous fluids over the next 6 to 8 hours. Such patients must
. .,. PRL\tARY AND SECONDARY CANINE HYPOADRENOCORTICJSM 355

be closely monitored for signs of hypoglycemia, because dogs with

adrenocortical insufficiency are very sensitive to the hypoglycemic action
of insulin. Intravenous glucocorticoid supplementation (as described
above), if given before the administration of insulin, helps minimize
the occurrence of severe hypoglycemia. Continuous electrocardiographic
monitoring is indicated until the electrocardiogram has returned to nor-
mal.

Chronic Adrenocortical Insufficiency

Most dogs with hypoadrenocorticism show clinical signs and labo-

ratory abnormalities of varying severity and duration. Although these
dogs do not require the aggressive therapeutic intervention discussed
above, fluid therapy and parenteral glucocorticoid replacement may be
necessary if azotemia, dehydration, or vomiting is present, and should
be continued until these abnormalities have resolved and oral therapy
can be initiated. Similarly, in dogs recovering from an adrenal crisis,
maintenance therapy is instituted once the dog is stable and oral medi-
cation can be tolerated. Maintenance therapy of canine hypoadreno-
corticism consists of lifelong mineralocorticoid and/or glucocorticoid
supplementation. Either fludrocortisone acetate (Florinef) or desoxycorti-
costerone pivilate (DOCP) can be administered for chronic mineralocorti-
coid replacement.
Fludrocortisone is instituted at an initial dosage of 0.01 to 0.02 mg/
kg daily and the daily dosage is adjusted by 0.05- to 0.1-mg increments
as needed based on serial serum electrolyte determinations. After initia-
tion of therapy, serum electrolyte levels should be monitored weekly
until stabilized within the normal range. Once this is achieved, serum
electrolyte concentrations and BUN or creatinine should be reevaluated
monthly for the first 3 to 6 months and every 3 to 6 months thereafter.
In many dogs in which fludrocortisone is used as a long-term mineralo-
corticoid replacement, the daily dose required to control the disorder
increases incrementally over the treatment period. This is usually most
evident during the first 6 to 24 months of therapy and can be attributed
to continuing destruction or atrophy of any remaining adrenocortical
tissue. In most dogs, the final fludrocortisone dosage needed is 0.02 to
0.03 mg/kg daily; very few can be controlled on a dosage of 10 µg/
kg per day or less. Overall, considerable individual variation in the
fludrocortisone dosage required for normalization and continued control
of serum electrolyte concentrations can be expected. Adverse effects
(usually polydipsia and polyuria), development of a relative resistance
to the effects of fludrocortisone, or financial considerations (especially
when treating large or giant-breed dogs) may, in some cases, necessitate
a change to DOCP therapy as described below.
Typically DOCP should be initiated at a dosage of 2.2 mg/kg given
intramuscularly or subcutaneously at approximately 1-month intervals.M·
w. 11 After the first two to three injections of DOCP, serum electrolyte
356 KINTZER & PETERSON

levels should ideally be determined at 2, 3, and 4 weeks postinjection to

determine the duration of action. Once serum electrolyte concentrations
have stabilized, levels should be determined just before each injection
and the dosage of DOCP adjusted if necessary. The duration of action
of DOCP varies between dogs. Although most dogs require the drug at
3- to 4-week intervals, a few need injections every 2 weeks. Alternatively,
to maintain a monthly injection schedule, one can incrementally increase
the dosage of DOCP given while monitoring serum electrolyte concen-
trations. Although many dogs could be controlled on a maintenance
DOCP regimen somewhat lower than 2.2 mg/kg per dose, a dose of 2.2
mg/kg can still be recommended. 8 Almost all dogs with hypoadrenocor-
ticism will be well controlled using a maintenance DOCP dose of 2.2
mg/kg per injection. This approach obviates the need for the practitioner
to incrementally increase the maintenance dose of DOCP over the first
6 to 12 months of therapy, which is necessary for many dogs in which
DOCP is initiated at a lower dose. Obviously, client anxiety and frustra-
tion are also minimized with this protocol. Furthermore, no adverse
effects such as hypertension or sodium retention have been noted with
the use of a standard dose of 2.2 mg/kg per injection. Nevertheless, one
can attempt to lower the monthly maintenance dosage of DOCP if so
desired to determine a minimally effective dose, particularly if cost is a
factor."· 1•1
Daily glucocorticoid replacement (0.2 mg/kg) appears to be neces-
sary in only about one half of dogs being treated for primary hypoadre-
nocorticism, because of the glucocorticoid activity of fludrocortisone or
DOCP. In general, all dogs are initially treated with both mineralocorti-
coid and glucocorticoid (prednisone or prednisolone). The glucocorticoid
can then be tapered to alternate days and then discontinued to see if
mineralocorticoid replacement alone is sufficient for maintenance ther-
apy. Nevertheless, additional glucocorticoid supplementation (2 to 10
times basal levels) is necessary during periods of stress such as illness,
trauma, or surgery; therefore, the client should always have some on
hand.
Dogs with documented secondary adrenal insufficiency require only
glucocorticoid replacement. A daily dosage of 0.2 mg/kg of prednisone
or prednisolone is usually sufficient, except during periods of stress as
mentioned above. If a primary pituitary ACTH deficiency has not been
confirmed by the demonstration of undetectable to low plasma ACTH
concentrations, however, one must continue to monitor serum electrolyte
concentrations on a regular basis. Many dogs with atypical primary
hypoadrenocorticism, originally showing normal electrolyte levels and
believed to have secondary hypoadrenocorticism, subsequently develop
the classic electrolyte abnormalities of hypoadrenocorticism and require
mineralocorticoid replacement.

References
I. Uartges JW, Nielson DL: Reversible megaesophagus associated with atypical primary
hypoadrenocorticism in a dog. J Am Vet Med Assoc 201:889-991, 1992
. ,. ... PRIMARY AND SECONDARY CANINE HYPOADRENOCORTICISM 357

2. Feldman EC, Peterson ME: Hypoadrenocorticism. Vet Clin North Am Small Anlm
Pract 14:751-766, 1984
3. Hadlow WJ: Adrenal cortical atrophy in the dog: Report of three caSt.>s. Am J Pathol
29:353-357, 1953
4. Hardy RM: Hypoadrenal gland disease. /11 Ettinger SJ, Feldman EC (eds): Textbook of
Veterinary Internal Medicine, ed 4. Philadelphia, WB Saunders, 1995, pp 1579-1593
5. Hariman RJ, Chen CM: Effects of hyperkalaemia on sinus nodal function in dogs:
Sino-ventricular conduction. Cardiovasc Res 17:509-517, 1983
6. Hartog M, Joplin GF: Effects of cortisol deficiency on the electrocardiogram. Br Med J
2:275-277, 1968
7. Kintzer PP, Peterson ME: Hypoadrenocorticism in dogs. Ill Bonagura JD (ed): Kirk's
Current Veterinary Therapy, t.'CI 12. Philadelphia, WB Saunders, 1995, pp 425-429
8. Kintzer PP, Peterson ME: Treatment of canine hypoadrenocorticism: 205 caSt.'S (1979-
1994). J Vet Intern Med, in press, 1997
9. Lorenz MD: Hypoadrenocorticism: Diagnosis and treatment. Comp Conlin Ed Pract
Vet 1:634-638, 1979
10. LyM RC, Feldman EC: Treatment of canine hypoadrenocorticism with microcrystalline
desoxycorticosterone pivalate. Br Vet J 147:478--483, 1991
11. LyM RC, Feldman EC, Nelson RW: Efficacy of microcrystalline desoxycorticosterone
pivalate for treatment of hypoadrenocorticism in dogs: DOCP Clinical Study Group. J
Am Vet Med Assoc 202:392-396, 1993
12. Peterson ME, Feinman JM: Hypercalcemia associated with hypoadrenocorticism in
sixteen dogs. J Am Vet Med Assoc 181:802-804, 1982
13. Melian C, Peterson ME: Diagnosis and treatment of naturally occurring hypoadreno-
corticism in 42 dogs. J Small Anim Pract 37:268-275, 1996
14. Peterson ME, Kintzer PP: Pretreatment clinical and laboratory findings in dogs with
hypoadrenocorticism: 225 cases (1979-1993). JAMA 208:85-91, 1996
15. Peterson MP, Wallace MS, et al: Dose-response relationship between plasma concentra-
tions of ACTH and cortisol after administration of incremental doses of cosyntropin for
ACTH stimulation testing in dogs. Proceedings of the Fourteenth Annual Veterinary
Medicine Forum (ACVIM), San Antonio, TX, June 1996
16. Rogers W, Straus J, Chew D: Atypical hypoadrenocorticism in thrL>c dogs. JAMA
179:155-158, 1981
17. Schrader LA: Hypoadrenocorticism. Ill Kirk RW (ed): Current Veterinary Therapy, ed
9. Philadelphia, WB Saunders, 1986, pp 972-977
18. Schaer MS, Chen CL: A clinical survey of 48 dogs with adrenocortical hypofunction. J
Am Anim Hosp Assoc 19:443-452, 1983
19. Schaer MS, Riley WJ, Buergel! CD, et al: Autoimmunity and Addison's disease in the
dog. J Am Anim Hosp Assoc 22:789-794, 1986
20. Tyler RD, Qualls CW Jr, Heald RD, et al: Renal concentrating ability in dehydrated
hyponatremic dogs. J Am Vet Med Assoc 191:1095-1100, 1987
21. Willard MD, Schall WD, McCaw DE, et al: Canine hypoadrenocorticism: Report of 37
cases and review of 39 previously reported cases. J Am Vet Med Assoc 180:59-62, 1982

Address repri11t requests to

Peter P. Kintzer, DVM
Staff Internist
Boston Road Animal Hospital
1235 Boston Road
Springfield, MA 01119