Introduction

Hypoadrenocorticism is a rare disease in cats with fewer than 70 cases reported in the literature since it was first described in 1983.^1–8 This endocrinopathy is characterized by an inadequate production of glucocorticoids and mineralocorticoids by the adrenal glands. Glucocorticoid deficiency results in inability to maintain vascular tone, hypoglycemia, gastrointestinal signs, impaired fat and protein mobilization, and muscle weakness.¹ Lack of mineralocorticoids results in electrolyte and acid-base abnormalities such as hyponatremia, hyperkalemia, and metabolic acidosis.¹ Primary hypoadrenocorticism results from destruction of the adrenal cortex.¹ In dogs and humans, immune-mediated destruction is the most common etiology.¹ Although the most common pathogenesis of primary hypoadrenocorticism in cats is unknown, lymphocytic inflammation of the adrenal gland, neoplastic infiltration, and congenital adrenal hyperplasia secondary to 11 β-hydroxylase deficiency have been described.^1,8–11 Secondary hypoadrenocorticism is the result of decreased production or release of adrenocorticotropic hormone (ACTH) by the pituitary gland.¹ It is most commonly associated with the administration of drugs or withdrawal of exogenous corticosteroid administration, but it can also be secondary to hypothalamic-pituitary disorders such as tumors, inflammation, trauma, or congenital abnormalities.¹ Secondary hypoadrenocorticism is extremely rare in cats.^1–3 There is only one previous report of hypoadrenocorticism in a cat younger than 1 year of age, and this is the first report of transient hypoadrenocorticism in this species.²

Case Report

A 7 wk old female spayed domestic shorthair weighing 1.05 kg presented to the Washington State University Veterinary Teaching Hospital for further evaluation of lethargy and anorexia. The cat had a routine ovariohysterectomy performed 6 days before presentation. She was adopted by the current owners from a shelter after the procedure, and the medical history prior to adoption is unknown. She had received her initial vaccinations and was housed indoors with no access to potential toxins or plants. She lived with her littermate, who was adopted at the same time and was clinically normal. Both cats had a similar body condition and size. For the ovariohysterectomy, a routine physical examination was performed and no abnormalities were detected. No blood work was performed at the time. She was premedicated with dexmedetomidine 10 mcg/kg intramuscular (IM), ketamine 5 mg/kg IM, and butorphanol 0.2 mg/kg IM. Anesthesia was induced with propofol 3.5 mg/kg IV and maintained with isoflurane. She received Lactated Ringer’s^a solution IV at 12 mL/hr during the 1 hr procedure. She recovered from the procedure uneventfully but 3 days later had an episode of vomiting, became lethargic, and stopped eating.

On presentation, the kitten was dull and hypothermic (97.3°F, 36.3°C) and had dry and pale pink mucous membranes. She had a decreased body condition score of 3/9 and was estimated to be 8–10% dehydrated. Respiratory rate and effort were normal, and no abnormalities were found on thoracic auscultation. She had a heart rate of 210 beats per min, weak femoral pulses, and abdominal discomfort on palpation. Her systolic blood pressure was 70 mm Hg, she had a normal sinus rhythm on electrocardiogram, and there was no free fluid on point-of-care ultrasound of the thorax and abdomen. Hematologic, biochemical, and urine testing performed on initial presentation are displayed in Table 1. Pertinent changes included a stress leukogram, thrombocytosis (790 × 10³/µL; reference interval [RI] 200–500 × 10³/µL), azotemia (creatinine 4.0 mg/dL; RI 0.9–2 mg/dL; blood urea nitrogen 203 mg/dL; RI 14–35 mg/dL), hyperglycemia (156 mg/dL; RI 61–135 mg/dL), hyperproteinemia (8.3 g/dL; RI 5.5–7.6 g/dL), hyperglobulinemia (4.9 g/dL; RI 2.7–4.7 g/dL), and hyperphosphatemia (16.5 mg/dL; RI 6.1–10.4 mg/dL). There was marked hyponatremia (128 mEq/L; RI 143–155 mEq/L), with hyperkalemia (6.9 mEq/L; RI 3.6–5.6 mEq/L), hypochloremia (88 mEq/L; 114–125 mEq/L), and a high anion gap (32.4 mEq/L; RI 12–26 mEq/L). Urine collected by cystocentesis had a specific gravity of 1.017, pH of 7.0, 4+ protein, 0–2 red blood cells per high-power field, 3–5 white blood cells per high-power field, and inactive sediment. There was no growth on the urine culture and survey abdominal radiographs were unremarkable. On focal urinary tract ultrasound, both kidneys had normal architecture and there were no signs of ureteral ligation. IV fluid resuscitation was initiated with a 10 mL/kg plasmalyte^b bolus followed by a rate of 4.5 mL/kg/hr IV. She was also started on maropitant^c 1 mg/kg IV q 24 hr and ampicillin sulbactam^d 30 mg/kg IV q 24 hr. The next morning, the cat was urinating but had persistent dehydration, and the azotemia had worsened with a creatinine of 5.2 mg/dL and blood urea nitrogen >140 mg/dL. She remained hyperkalemic at 5.2 mmol/L and hyponatremic at 133 mmol/L. The fluid rate was increased to 11 mL/kg/hr and a full abdominal ultrasound was performed by a board-certified radiologist and was unremarkable. The left adrenal gland was normal in size (0.25 cm), but the right adrenal gland could not be identified. Serum cortisol was measured at baseline and again 1 hr after adrenocorticotropic hormone^e administration. Baseline cortisol was <1 µg/dL and did not increase in response to ACTH stimulation (Table 2). Based on these results, the cat was diagnosed with hypoadrenocorticism. Treatment was initiated with dexamethasone sodium phosphate^f 0.07 mg/kg IV q 24 hr and desoxycorticosterone pivalate (DOCP)^g 2.2 mg/kg subcutaneously (SQ). The maropitant was discontinued as she showed no further gastrointestinal signs and had a good appetite. Serum electrolyte concentrations and creatinine were measured ∼24 hr after initiation of these therapies and had normalized, with a sodium of 150 mmol/L and a creatinine of 0.7 mg/dL. Fluid therapy was decreased over the next 24 hr and then discontinued. Serial laboratory results are displayed in Table 3. The cat was clinically much improved and was discharged from the hospital 48 hr after starting hormone replacement. She was switched to oral prednisolone^h 0.42 mg/kg per os (PO) q 24 hr. Blood from the initial visit, obtained before dexamethasone and DOCP administration, was submitted to the Michigan State University Veterinary Diagnostic Laboratory for baseline aldosterone concentrations, and insulin-like growth factor 1 (IGF1) measurement. Baseline serum aldosterone was low, and IGF1 was within normal limits. Another blood sample, obtained after treatment initiation, was sent to the same laboratory for a thyroid panel. She had an increase in total thyroxine (T4) and free thyroxine (FT4).

TABLE 1 Laboratory Results from Initial Presentation

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TABLE 2 Endocrine Result from Initial Presentation and After Discontinuation of Treatment

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TABLE 3 Laboratory Values and Body Weight Before, During, and After Discontinuation of Treatment (Presentation to Day 29 After Diagnosis)

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Upon recheck examination 9 days after initial diagnosis (6 days after discharge), the cat was reportedly playful, active, and eating normally. Point-of-care blood workⁱ showed normal sodium concentration with mild hyperkalemia (Tables 3, 4). The prednisolone dosage was decreased to 0.35 mg/kg PO q 24 hr by keeping the amount administered constant as the cat continued to grow and gain body weight. Sixteen days after initial diagnosis, the cat presented for her vaccine boosters. She continued to have normal activity and appetite at home. Her physical examination and electrolyte concentrations were within normal limits. The amount of prednisolone was maintained, accounting for a dosage of 0.3 mg/kg PO q 24 hr. Twenty-nine days after initial diagnosis (27 days after DOCP administration), the cat was rechecked again. She was clinically normal, and the electrolyte panel showed no abnormalities. Another dose of DOCP at 2.2 mg/kg SQ was administered and the prednisolone amount was maintained, accounting for a dose of 0.26 mg/kg PO q 24 hr. Fifty-five days after initial diagnosis (29 days after the second DOCP), the cat was clinically normal, and her electrolyte panel showed mild hyponatremia (Na 146 mEq/L) with normal potassium concentrations (K 3.3 mEq/L). It was therefore decided to not repeat DOCP administration but to monitor electrolyte concentrations. The dose of prednisolone was 0.21 mg/kg PO q 24 hr, and she received the remaining vaccinations of the initial series. The electrolyte panel was rechecked every 5 days for the next 18 days and remained within normal limits. Thus, no additional doses of DOCP were administered. Ninety-two days after initial diagnosis, the owners reported no abnormalities, and the cat’s physical examination and electrolyte panel were within normal limits. Her dose of prednisolone was 0.17 mg/kg PO q 24 hr. Because the cat was clinically normal, it was decided to stop the prednisolone administration. Eighteen days after discontinuing the prednisolone (110 days after initial diagnosis), she was rechecked, and endocrine testing was repeated. The owners reported that she was acting normally at home, and her physical examination was unremarkable. Baseline cortisol and aldosterone were obtained and measured again 1 hr after ACTH administration (Table 2). Cortisol concentrations were compatible with normal function of the adrenal glands. The baseline aldosterone concentration was low but increased appropriately 1 hr after ACTH administration. One hundred forty-seven days after initial diagnosis, an abdominal ultrasound was repeated under sedation with dexmedetomidine^j 5 mcg/kg IM, and butorphanol^k 0.2 mg/kg IM, and was unremarkable with normal sized adrenal glands (left 0.33 cm and right 0.24 cm). Dexmedetomidine was reversed with atipamezole^l IM once the ultrasound was completed and she recovered uneventfully. The cat described in the present study was clinically managed according to contemporary standards of care. Informed owner consent was obtained for treatment of the animal and publication of the present report. At the time of manuscript submission, the cat had been clinically normal at home 10 mo after discontinuation of the prednisolone and 12 mo after the last DOCP dose.

TABLE 4 Laboratory Values and Body Weight Before, During, and After Discontinuation of Treatment (Days 55–147 After Diagnosis)

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Discussion

Based on evaluation of veterinary scientific reviews, original articles, and endocrinology books identified through PubMed and Google Scholar, this is the first report of transient hypoadrenocorticism in a cat. Hypoadrenocorticism is a rare disease in cats and there is no age, sex, or breed predisposition described in the literature. This cat’s history, physical examination findings, and clinicopathologic abnormalities are typical for cats with hypoadrenocorticism.^{1,5,7–9,12–15} The gold standard test for diagnosing hypoadrenocorticism is the ACTH stimulation test. In affected animals, the pre-ACTH plasma cortisol concentration is undetectable to low-normal, and the poststimulation cortisol is similar to baseline.¹ Because of the persistent dehydration, electrolyte abnormalities, and worsening azotemia with no obvious cause of acute kidney injury in the cat of the present report, cortisol was measured before and after ACTH stimulation and confirmed the diagnosis of hypoadrenocorticism. An endocrine panel was submitted to rule out panhypopituitarism, which is very rare in cats but has been previously described.³ The T4 and FT4 concentrations were above normal ranges. Unpublished data from the Michigan State University Veterinary Diagnostic Laboratory showed that young kittens may exhibit transient increase above adult reference ranges for serum T4 and FT4, similar to what has been described in young dogs (Kent R. Refsal, communication from Michigan State University in received endocrinology report, June 9, 2021). Therefore, the thyroid profile may be normal for a kitten her age (Kent R. Refsal, communication from Michigan State University in received endocrinology report, June 9, 2021). The IGF1 concentration was within normal adult ranges, but reference intervals for kittens have not been established. The IGF1 concentration in three 12 wk old kittens was between 51 and 80 mmol/L, whereas it was 3 nmol/L in a kitten from the same litter with evidence of growth hormone insufficiency.¹⁶ The IGF1 concentration in a 16 wk old kitten with failure to thrive was 2 nmol/L, and it was 107 nmol/L in a normal littermate.¹⁶ The concentration for the cat in the present study was 29 nmol/L, which is in between kittens with evidence of growth hormone insufficiency and normal littermates, making the interpretation of the result difficult. On presentation, she had a decreased body condition score, but over the course of treatment and further rechecks, she showed no evidence of failure to grow or reduced activity level compared with her littermate, who lived in the same household. Baseline aldosterone concentration from the initial panel (before ACTH stimulation) was extremely low, supportive of adrenal gland insufficiency rather than reduced secretion of ACTH from the pituitary gland. Loss of ACTH causes atrophy of the adrenal cortex and impaired secretion of glucocorticoids but not mineralocorticoids.¹ The lack of aldosterone is compatible with the electrolyte abnormalities and the severe dehydration observed on presentation because aldosterone plays a critical role in tubular reabsorption of sodium and chloride and the excretion of potassium in the distal nephron.¹ However, results have been variable in dogs,¹⁷ and low aldosterone concentrations can also result from fluid administration and expansion of the extravascular compartment, which increases distal tubular flow and chloride delivery to the macula densa, inhibiting renin release.¹⁸ The assay for aldosterone used at Michigan State University^m has been previously validated in cats.¹⁹ The cat had proteinuria on presentation based on the results of the urinalysis, which unfortunately was not quantified or rechecked. Acute kidney injury leading to tubular proteinuria is thought to be most likely in this case.¹

There are only a few reports of the use of DOCP in cats.^7,8,14 Most cats described in the literature were treated with oral fludrocortisone.^4,5,8,9,15 The recommended DOCP dosage by the manufacturer is 2.2 mg/kg IM every 25 days in dogs. However, the duration of action and dose required to maintain normal electrolyte concentrations can vary considerably among patients, ranging from 38- to 90-day intervals and dosages of 0.7 to 2.2 mg/kg, respectively, in dogs.^20,21 In this cat, DOCP was initially administered at 2.2 mg/kg SQ and the second dose was administered after 27 days. Because of cost concerns, the decision was made to see whether the dosing interval could be extended. Electrolyte concentrations were normal at 29 days and continued to be normal for the next 18 days. Because values were normal 47 days after the second dose, a transient adrenal insult was suspected. No additional DOCP doses were administered, and the prednisolone was also progressively decreased and discontinued while closely monitoring the cat’s activity level and clinical signs. The repeat cortisol and aldosterone ACTH stimulation tests confirmed the transient nature of the hypoadrenocorticism.

There are reports in people of spontaneous recovery of adrenal function after a confirmed diagnosis of hypoadrenocorticism.^22–24 Causes of transient hypoadrenocorticism include hemorrhage, ischemia, drug-related, and autoimmune disease.^22–25 Adrenal hemorrhage (AH) in people has been associated with recent surgery, septicemia, anticoagulation therapy/coagulopathy, idiopathic causes, trauma, critical illness, neoplasia, and incidentaloma.²⁴ Most cases of AH have bilateral involvement, but unilateral AH has also been reported.²⁴ Adrenal hemorrhage is usually recognized as enlarged adrenal glands with a heterogeneous mass effect.^24,26 It is mostly identified in people by computed tomography and has been recognized by ultrasound in three cats with adrenal neoplasia.²⁶ The right adrenal gland could not be observed in the cat of the present report, so unilateral AH remains a potential cause of her hypoadrenocorticism. Adrenal ischemia/infarction is rare but has also been reported in people as a cause of hypoadrenocorticism and is mainly associated with hypovolemia, pregnancy, and thrombosis.²³ The infarcted areas can be detected on computed tomography and MRI, but the adrenal glands can appear normal on ultrasound. Thus, adrenal ischemia/infarction is another differential diagnosis for the cat in the present report.²³ Opioid-induced adrenal insufficiency has also been rarely reported in people with both acute and chronic opioid therapy.²⁵ Opioids associated with hypoadrenocorticism are fentanyl, morphine, tramadol, and hydrocodone. The use of a single dose of butorphanol before spay might be another potential cause of transient hypoadrenocorticism in this cat. However, butorphanol use is not specifically reported to cause adrenal insufficiency in people, and the cat showed no adverse reactions after the sedation with butorphanol for the second ultrasound.²⁵ Other drugs associated with adrenal suppression are ketoconazole and etomidate, neither of which was given to this cat.¹ Adrenal insufficiency of critical illness has been reported in people, dogs, and cats and is transient.¹ However, this cat had no other illness factors or documented infection, and this syndrome is not associated with mineralocorticoid deficiency, making this cause unlikely.¹ Finally, spontaneous recovery of immune-mediated hypoadrenocorticism has also been rarely reported in human medicine.²² Recent reports have also described the presence of autoantibodies in dogs with spontaneous hypoadrenocorticism, suggesting an immune-mediated disease.²⁷ Unfortunately, measurement of autoantibodies is not a routinely available test in veterinary medicine, so spontaneous recovery of immune-mediated hypoadrenocorticism cannot be ruled out.

Submission of plasma for endogenous ACTH and post-ACTH stimulation aldosterone concentrations on initial presentation could have improved the strength of the initial diagnosis. Unfortunately, because of the size of the cat and subsequent limitations on blood sampling and analyte stability, those tests were not performed.

Conclusion

Hypoadrenocorticism is rare in cats but should be considered in patients presenting with nonspecific clinical signs, shock, dehydration, azotemia, and hyponatremia with hyperkalemia, even in young kittens. In addition, spontaneous recovery from hypoadrenocorticism is possible in young patients or those diagnosed after a surgery or hypoxic insult, so dose revision and repeated endocrine testing should be considered depending on the patient’s clinical signs and electrolyte concentrations.

We would like to thank Dr. Kent R. Refsal, DVM, MS, PhD, endocrinology professor at Michigan State University, for contributing the baseline aldosterone concentrations and for case discussion.