Atypical hypoadrenocorticism in a Birman cat

Abstract

A 1-year-old female spayed Birman cat was presented with a history of inappropriate urination and defecation, lethargy, anorexia, and weight loss. After intermittent responses to non-specific therapy she was diagnosed with atypical hypoadrenocorticism from the results of an adrenocorticotropic hormone stimulation test.

Introduction

A 1-year-old spayed female Birman cat was referred to SouthPaws Veterinary Specialists and Emergency Center in Fairfax, Virginia with a history of decreased appetite, vomiting, lethargy, inappropriate urination and defecation, and possible feline infectious peritonitis (FIP). The referring veterinarian suspected FIP because the disease is overrepresented in the Birman breed. The inappropriate urination and defecation was first noted 1 mo previously when the patient was originally presented to the referring veterinarian. At this time, complete blood (cell) count (CBC) revealed a thrombocytopenia [32 × 10³/μL; reference interval (RI): 200 to 500 × 10³/μL] which was attributed to platelet clumping prior to sample processing. No abnormalities were seen on the serum biochemical profile. Urinalysis detected high levels of whole red blood cells in the sediment and on the dipstick. The cat was negative on the FIP 7B ELISA titer and the thyroxine (T4) level was within the RI (16.7 nmol/L; RI: 10.3 to 51.5 nmol/L). One week later, the owners noticed that the cat became lethargic, had a decreased appetite, and was more “clingy” than normal.

Case description

On presentation to the referral hospital, the cat was quiet, but alert and responsive. She had a temperature of 37.8°C, a heart rate of 164 beats per minute (bpm), and a respiratory rate of 44 breaths per min; all were within normal limits. Her mucous membranes were pink and moist with a capillary refill time of < 2 s and her hydration status estimated by skin turgor was good. The cat weighed 1.3 kg and had a body condition score (BCS) of 1.5 out of 5. She had a scruffy hair coat, but no alopecia or other lesions. On abdominal palpation her intestines felt thick, but no pain was elicited.

A CBC and serum biochemistry panel revealed a mild anemia (Hct: 26.5%; RI: 29% to 48% and RBC: 5.3 × 10⁶/μL; RI: 5.92 to 9.93 × 10⁶/μL) with low hemoglobin (Hgb: 88 g/L; RI: 93 to 159 g/L). A thrombocytopenia (73 × 10³/μL; RI: 200 to 500 × 10³/μL) was present, but the sample was clotted. A mild neutrophilic leukocytosis was also found (WBC: 18.5 × 10³/μL; RI: 3.5 to 16 × 10³/μL and neutrophils: 11 470 absolute number; RI: 2500 to 8500). An elevated blood urea nitrogen (BUN) and BUN:Creatinine ratio (BUN: 15.0 mmol/L; RI: 5.0 to 12.9 mmol/L and creatinine: 70.7 μmol/L; RI: 53.0 to 212.2 μmol/L) were noted, suggesting an increase in protein conversion to urea or mild dehydration. On urinalysis the patient had an elevated specific gravity (1.074; RI: 1.015 to 1.060) and bilirubinuria which was verified by an Ictotest (Miles Laboratories, Elkhart, Indiana, USA).

After completing the initial minimum database, potential causes for the patient’s decreased growth rate, lethargy, and anorexia were investigated. A thyroid profile was repeated to rule out the possibility of congenital hypothyroidism. The T4 was low, but still within the normal range (11.6 nmol/L; RI: 10.3 to 51.5 nmol/L), thereby ruling out congenital hypothyroidism. Resting bile acids were submitted to investigate the possibility of a portosystemic shunt and were found to be in the normal range (5.4 μmol/L; normal value: < 10 μmol/L). An abdominal ultrasound was performed to look for any obstructions or effusive patterns associated with FIP. The kidneys were small (3 cm in length; expected between 3.8 to 4.4 cm) with a prominent internal rim sign which is often incidental in cats. The intestinal wall thickness appeared to be within normal limits. There was one loop of bowel in which the lumen was dilated but gently tapered back down to normal width. No foreign objects, fluid, or other lesions were associated with this area of the bowel. In addition, the wall architecture was preserved in this region. All other abdominal structures were of normal echogenicity and size. No lymphadenopathy was observed.

In light of the diagnostic tests performed we were able to rule out several conditions that may have lead to the patient’s clinical signs, but did not reach a definitive diagnosis. The most significant findings were the anemia and elevated BUN, which could have been caused by an ulcer or another source of blood in the gastrointestinal tract although no melena or frank blood was reported to be seen in her stool. Had this been the case, it may have caused her to be nauseated and subsequently inappetent. It was recommended that the owners give famotidine (Pepcid AC; Johnson & Johnson — Merck Consumer Pharmaceuticals, Fort Washington, Pennsylvania, USA), 2.5 mg, PO, SID to help decrease acid production, sucralfate (100 mg/mL solution), 2 mL, PO, TID to coat a potential gastrointestinal ulcer, and ondansetron (Zofran; GlaxoSmithKline, Research Triangle Park, North Carolina, USA) 1 mg, PO, BID to help relieve nausea associated with gastrointestinal ulcers. The owners were advised that if the cat’s symptoms persisted other diagnostic tests could be performed to rule out inflammation in the bowel and, in rare cases, hypoadrenocorticism.

Two weeks later, the patient was returned to the referral hospital for an appointment to re-evaluate the elevated BUN and low hematocrit from the previous appointment. The owners had been administering sucralfate only, but felt that the patient had marginally improved. They still did not find her very playful, but were satisfied that her appetite had picked up. There were no episodes of vomiting, but the owners reported that mild diarrhea had started the day before presentation to the referral hospital. On presentation the patient was bright, alert, and responsive. Her weight was 1.4 kg, which was slightly up from her last presentation. A portable patient-side testing device (I-STAT) was used to measure the patient’s BUN (10.7 mmol/L) which was within the normal range. Her hematocrit was now at 28%, which was stable, but not as high as it should be. Because the patient appeared to be doing well no new diagnostic tests were performed on this day and a recheck was scheduled for 1 mo to repeat a CBC, serum biochemistry, and urinalysis. The owners were instructed to continue to administer sucralfate (100 mg/mL solution), 2 mL, PO, TID and famotidine, 2.5 mg, PO, SID to relieve her gastrointestinal signs.

Twelve days later the cat was presented to the emergency service of the referral hospital for several episodes of vomiting and lethargy. The owners had observed her staring off into space during the day and were concerned that she may be blind. On physical examination the cat weighed 1.36 kg and had a BCS of 1.5 out of 5. Her mucous membranes were pink and moist. An ophthalmic examination revealed bilateral mydriasis; however, no other ocular lesions were noted. She was ambulatory on all 4 limbs and no weakness was present.

The in-house laboratory performed a CBC and partial serum biochemistry, which revealed a moderate leukocytosis (26.2 × 10³/μL), a mild lymphopenia (1.0 × 10³/μL; RI: 1.8 to 7 × 10³/μL), and a moderate neutrophilia with a left shift (24.2 × 10³/μL) with 66% segmented neutrophils (normal value: 35%) and 29% band neutrophils (normal value: 0%). The hematocrit was 39.8%, but macrocytosis and moderate amounts of polychromasia were seen on the peripheral blood smear. A partial serum biochemistry revealed a mildly elevated BUN (13.6 mmol/L) and a low normal glucose (3.8 mmol/L; RI: 3.3 to 7.2 mmol/L).

The cat was placed on IV fluids (0.9% NaCl) with 5% dextrose to prevent hypoglycemia, ampicillin sodium and sulbactam sodium (Unasyn; Pfizer, New York, New York, USA), 30 mg/kg, IV, q8h for potential infection based on the leukogram, and ondansetron 0.14 mg, IV, q24h for nausea possibly associated with her history of vomiting. It was noted that whenever attempts were made to reduce the fluid rate overnight the patient’s blood glucose would fall.

The next day the cat was given 0.4 mg of dexamethasone IV once. After the administration of the dexamethasone her blood glucose levels stabilized. A CBC, pre- and post-prandial bile acids, and an adrenocorticotropic hormone (ACTH) stimulation test were submitted to Antech Diagnostics. The CBC showed a low hemoglobin (90 g/L; RI: 93 to 159 g/L), a low hematocrit (27.4%; RI: 29% to 48%), a moderate anemia (RBC 4.7 × 10⁶/μL; RI: 5.92 to 9.93 × 10⁶/μL), and a moderate leukocytosis (18.9 × 10³/μL; RI: 3.5 to 16 × 10³/μL). On the differential blood smear, a mild lymphocytosis (9639 absolute number; RI: 1200 to 8000) paired with a marked eosinophilia (2646 absolute number; RI: 0 to 1000) was present. Due to the absence of band neutrophils on this differential the ampicillin/sulbactam antibiotic treatment was discontinued.

The pre- and post-prandial bile acid concentration definitively excluded the possibility of hepatic dysfunction or a portosystemic shunt. The bile acid concentration prior to a meal was normal (5.0 μmol/L; normal value: < 10.0 μmol/L) and the post-meal concentration was also normal (5.9 μmol/L; normal value: < 20.0 μmol/L). An ACTH stimulation test was run to check for the presence of hypoadrenocorticism. The patient’s cortisol levels were measured prior to receiving 125 μg cortrosyn (Amphastar; Rancho Cucamonga, California), IV, and were low (< 28 nmol/L; RI: 124 to 414 nmol/L). Cortisol levels were also measured at 30 min (< 28 nmol/L) and 60 min (< 28 nmol/L) post-cortrosyn administration. Both post-stimulation cortisol levels were also subnormal. Due to the fact that the cat’s electrolyte levels were normal she was diagnosed as having atypical Addison’s disease (atypical hypoadrenocorticism). The cortisol deficiency is in accordance with the lymphocytosis and eosinophilia found on the leukogram. The cat was prescribed prednisolone 2.5 mg PO, SID with plans to re-evaluate her blood glucose and perform a physical examination in 1 wk.

Four days later the cat was presented again. The owners felt that she was quiet following her discharge, but were pleased that she was eating and more playful than she had been before. However, the cat had stopped eating the day before presentation and the owners indicated that she had had another episode of staring off into space. The owners thought that her glucose may have been low again and had administered a corn syrup which seemed to improve her attitude temporarily. They observed that her eyes were dilated and still questioned that she may be blind. In addition, the patient had fallen down the stairs the night before presentation. They had been treating the cat’s hypoadrenocorticism with 2.5 mg of prednisolone, PO, SID.

On presentation the cat was hypothermic (36.1°C), her heart rate was 160 bpm with strong and synchronous pulses, and her respiratory rate was 40 breaths per min and of normal depth and effort. She had a prolonged skin turgor test and her mucous membranes were pink and tacky. She weighed 1.27 kg and had a BCS of 1 out of 5. She had lost weight and muscle mass over the past 2 wk. She was ambulatory on all 4 limbs with no apparent weakness. On ophthalmic examination she had mydriasis and decreased pupillary light reflexes in both eyes, and both the menace and the dazzle reflexes were present. The findings from her retinal examination were normal. Her blood glucose was normal (5.3 mmol/L) even though she had not eaten in 24 h. The cat was given Vitamin B12 500 μg SC, dexamethasone 0.18 mg SC, and 60 mL of SC crystalloid fluid. The owners were instructed to continue with the prednisolone 2.5 mg, PO, SID for her Addison’s disease and to give mirtazapine (Remeron; Schering-Plough, Kenilworth, New Jersey, USA), 0.9 mg, PO, SID to help stimulate her appetite. The owners were cautioned that if she did not improve over the next few days that an underlying problem in addition to hypoadrenocorticism might be present.

The cat initially responded well to prednisolone therapy. The owner was instructed to taper the dose of prednisolone to 1.25 mg, PO, SID. The patient was gaining weight and had a good appetite as described by the owner. However, the owners did not taper the prednisolone dose according to the recommendations provided and subsequently the cat became anorexic. Serum biochemistry 1 mo later revealed a mildly elevated alkaline phosphatase (119 IU/L; RI: 6 to 102 IU/L), a marked hyperglycemia (24.1 mmol/L), and a marked elevation in triglycerides (15.9 mmol/L; RI: 0.3 to 1.8 mmol/L). It was recommended that the prednisolone dosage continue to be slowly tapered to a physiologic dose, but as the tapering continued the cat’s health slowly declined. One week later, a fructosamine level was measured and found to be elevated (509 μmol/L; RI: 142 to 450 μmol/L) suggesting persistent hyperglycemia. At this time, the owners elected to humanely euthanize the cat due to failure of treatment response as well as concurrent diabetes mellitus.

Discussion

Hypoadrenocorticism (Addison’s Disease) is an endocrine disorder that has been described in dogs and cats. The first documented case in a cat was described in 1983 and less than 40 cases have been documented in the literature, making this a rare disease in cats (1–3). There does not appear to be a breed or sex predilection in cats and the age range of diagnosis is from 1.5 to 14 y. This is in contrast to dogs where females and certain breeds are overrepresented (1,2,4–6). The disease can be categorized into primary and secondary hypoadrenocorticism. In primary hypoadrenocorticism there is destruction of the adrenal cortices while in secondary hypoadrenocorticism there is a decrease in ACTH secretion from the pituitary gland. In most cases of hypoadrenocorticism there is 90% destruction of the adrenal cortices resulting in both glucocorticoid and mineralocorticoid deficiency (3). In cats and dogs, immune-mediated destruction of the adrenal cortices is thought to cause primary hypoadrenocorticism; however, in cats there have been 2 documented cases in which lymphoma had infiltrated the adrenal cortices resulting in primary hypoadrenocorticism (1,3–6). Secondary hypoadrenocorticism is due to a congenital disorder of the pituitary, a pituitary tumor, or may be iatrogenic due to over administration of corticosteroids (1–3,5,7–9). Administration of progesterone hormones such as megestrol acetate (1–3,5,7–9), which results in decreased ACTH production and subsequent adrenal gland atrophy, has also been implicated in cats.

Hypoadrenocorticism can also be classified into typical or atypical forms. In the typical form the patient is deficient in both glucocorticoids and mineralocorticoids in contrast to the atypical form where there is glucocorticoid deficiency only. In a small number of cases of dogs and cats, the atypical form will progress to the typical form within a few months of the initial diagnosis (4,7).

Atypical hypoadrenocorticism is often missed at the initial presentation due to the non-specific clinical signs such as lethargy, depression, anorexia, and weight loss (1–3,5,6,9) and also because it is the mineralocorticoid deficiency that causes the serum biochemical abnormalities, bradycardia, and weak peripheral pulses (4,8). Common differential diagnoses for this set of clinical signs include ileus, renal insufficiency, and gastro-enteritis (1,2,4,6,9). Initially, these signs may respond to non-specific therapy as was the case with the patient described here. Other less common findings include vomiting and polyuria with polydipsia (in the typical form) (1,3,5). In dogs, diarrhea has also been reported, but this has not been observed in cats (2,3).

Common clinical signs include depression, weakness, dehydration, and hypothermia (1–3,5). However, with typical Addison’s disease there may be more severe signs such as increased capillary refill times, weak pulses, bradycardia, collapse, and abdominal pain in both dogs and cats (1–3,5). With typical hypoadrenocortism, complete blood chemistry commonly reveals a normocytic, normochromic, nonregenerative anemia with the absence of a stress leukogram, whereas in the atypical form anemia may not be present (5,10). Rarely, lymphocytosis and eosinophilia have also been described in hypoadrenocorticism due to the decrease in cortisol production (2,3,6). The most important difference between typical and atypical hypoadrenocorticism are the serum biochemistry abnormalities. In typical hypoadrenocorticism hyperkalemia, hyponatremia, hypochloremia, renal azotemia, and metabolic acidosis are present with the potential to have hypercalcemia, hypoglycemia, and hypoalbuminemia, whereas atypical hypoadrenocorticism has no consistent electrolyte abnormalities and only occasionally is associated with hypoglycemia (2,3,5). It is important to note that low sodium to potassium ratios are supportive of a diagnosis but are not diagnostic of typical hypoadrenocorticism because an abnormal ratio can also be seen in other disorders such as renal insufficiency, diabetes mellitus, and gastrointestinal disease (4,5). It is also interesting to note that the hyperkalemia seen in typical hypoadrenocorticism of cats is not as severe as that in dogs (2,3) which may explain why the typical electrocardiographic changes associated with hyperkalemia in cats with this disease are rare (2).

The gold standard for diagnosis for hypoadrenocorticism is an ACTH stimulation test which is performed by drawing a pre-stimulation blood sample to test for resting cortisol and then administering 125 μg of cortrosyn IV or 2.2 U/kg of the ACTH gel IM and drawing blood at 30 min and then 60 min later to evaluate post-ACTH stimulation blood cortisol levels (1–3,5,7). Cortisol levels < 2 μg/dL post-ACTH stimulation are considered to be diagnostic for hypoadrenocorticism (1–3,5). To differentiate between primary and secondary hypoadrenocorticism endogenous ACTH can be measured to determine if the patient’s value is within its species reference interval (3,5).

Hypoadrenocorticism is treated by supplementing the glucocorticoids and mineralocorticoids that are missing for the lifetime of the patient. In cats, prednisolone is preferred over prednisone to replace the glucocorticoid deficiency and is usually given at a dose of 0.25 to 1 mg per cat, PO, SID or 10 mg of methylprednisone acetate IM every month (2,3,5), but there have been reports that methylprednisone acetate may lead to congestive heart failure or diabetes mellitus (3). For typical Addison’s disease, mineralocorticoids can be replaced with fludrocortisone acetate at a dose of 0.05 to 0.1 mg PO q12h (2,5). The doses of glucocorticoids and mineralocorticoids for cats have been extrapolated from dogs, so it is important to monitor the efficacy of the treatment regimen to prevent signs of iatrogenic hyperadrenocorticism (3,5). Cats, in contrast to dogs, may appear lethargic and weak for 3 to 5 d after proper therapy has been initiated and this should not be considered as a therapeutic failure but rather a slow response to treatment (2,3,5,6).