Hypoadrenocorticism in a kindred of Pomeranian dogs

Abstract

Three adult Pomeranian dogs, full siblings from 2 litters, were diagnosed with primary hypoadrenocorticism following onset of hypoadrenal crisis. Review of the family history revealed the dogs’ maternal grandmother also had hypoadrenocorticism. All 4 dogs were pedigree-certified by the American Kennel Club. An inherited basis for hypoadrenocorticism is proposed in these Pomeranian dogs.

Hypoadrenocorticism is an uncommon endocrine disease of dogs. Most cases are classified as idiopathic, with an inherited basis proposed in some breeds. This report describes 3 closely related Pomeranian dogs, which presented at different times with clinical signs and laboratory findings consistent with primary hypoadrenocorticism including cardiovascular collapse and severe hyponatremia. Adrenocorticotropic hormone (ACTH) stimulation tests confirmed hypoadrenocorticism in all dogs. All the dogs made a full recovery following standard treatment for hypoadrenal crisis. Historical and clinicopathologic evidence suggests an inherited idiopathic cause for hypoadrenocorticism in these dogs.

Case description

A 26-month-old, 4.3 kg intact male Pomeranian (dog 1) was referred to the emergency service with a 4-week history of lethargy, a 2-day history of anorexia and diarrhea, and 1 episode of vomiting. He had been taken to his regular veterinarian earlier that day obtunded, non-ambulatory, and severely hypothermic (temperature < 32°C). A venous blood gas with electrolytes revealed severe hyponatremia [125 mmol/L; reference range (RR): 144 to 160 mmol/L] and hypoglycemia (blood glucose, 1.6 mmol/L; RR: 4.1 to 7.9 mmol/L), moderate hypochloremia (100 mmol/L; RR: 109 to 122 mmol/L), mild hyperkalemia (6.0 mmol/L; RR: 3.5 to 5.8 mmol/L), and elevated blood urea nitrogen (BUN) (18.6 mmol/L; RR: 2.5 to 9.6 mmol/L). Complete blood (cell) count (CBC) was normal apart from hemoconcentration (hematocrit 65%). There was no stress leukogram. On presentation to the emergency service the dog was quiet and responsive. Rectal temperature was 36.7°C, heart rate was 100 beats/min with weak pulse, and respiratory rate was 30 breaths/min. Serum sodium was rechecked with a blood gas analyzer (Stat Profile Critical Care Xpress; Nova Biomedical, Waltham, Massachusetts, USA), and was 121.9 mmol/L (RR: 142 to 149.3 mmol/L). A 100-mL bolus of 0.9% NaCl (Hospira, Lake Forest, Illinois, USA) was administered IV. After this, systolic blood pressure was 60 mmHg, measured indirectly via Doppler ultrasonography (811-BL, Parks Medical Electronics, Aloha, Oregon, USA). The fluid bolus was repeated and the systolic blood pressure increased to 120 mmHg. Further treatment included an IV infusion of 0.9% NaCl supplemented with 2.5% dextrose (Hospira) at 6.5 mL/kg body weight (BW) per hour, dexamethasone sodium phosphate (DexaJect SP; Butler Schein Animal Health, Dublin, Ohio, USA), 0.7 mg/kg BW, IV, once, and external warming. Blood glucose was measured serially and dextrose supplementation was discontinued once the blood glucose had reached 6.39 mmol/L, 4 h later. Famotidine (West-ward Pharmaceutical, Eatontown, New Jersey, USA) 0.5 mg/kg BW, IV, q12h, and metronidazole (Hospira) 10 mg/kg BW, IV, q12h, were added when the dog developed melena.

An ACTH stimulation test was performed on day 2 using a low-dose cosyntropin (Cortrosyn; Amphastar Pharmaceuticals, Rancho Cucamonga, California, USA) protocol, 5 μg/kg BW, IV, validated elsewhere (1). The pre-ACTH cortisol (resting) was 8.3 nmol/L (RR: 55.2 to 165.5 nmol/L) and the post-ACTH was < 5.5 nmol/L (RR: 165.5 to 496.6 nmol/L). Abdominal ultrasound revealed no abnormalities apart from the adrenal glands not being visible. Glucocorticoid supplementation was continued as dexamethasone sodium phosphate, 0.5 mg/kg BW, IV, q24h, during hospitalization. Despite 0.9% NaCl supplementation and assessment of adequate fluid resuscitation, on day 2 the dog’s serum sodium dropped to 119.2 mmol/L so deoxycorticosterone privalate (DOCP; Percorten-V, Novartis, Greensboro, North Carolina, USA), 2.2 mg/kg BW, IM, was administered. The dog was discharged on day 4 on prednisone (West-ward Pharmaceutical), 1.16 mg/kg BW, PO, q24h, with instruction to reduce this by half after 3 d, and to return for electrolytes and the next injection of DOCP in 27 d. At the time of writing, 44 mo after diagnosis, the dog is doing well on prednisone (0.29 mg/kg BW, PO, q48h) and DOCP (2.2 mg/kg BW, IM, q30d).

Four months later, a 30-month-old, 3.7 kg intact female Pomeranian (dog 2) was presented for anorexia and weakness. This dog was a littermate of dog 1. Over the preceding 2 wk she had twice been treated elsewhere on an outpatient basis for these signs with metronidazole and SQ fluids (doses unknown). Abdominal radiographs taken the day prior to presentation showed no abnormalities. On physical examination the dog was obtunded and non-ambulatory. Rectal temperature was 36.7°C, heart rate was 80 beats/min with normal pulse quality, and respiratory rate was 16 breaths/min. Indirect systolic blood pressure measured via Doppler ultrasonography was 90 mmHg. Blood work revealed marked hypoglycemia (1.4 mmol/L), hyponatremia (118 mmol/L), and hypochloremia (93 mmol/L). Serum potassium was within the normal range (5.3 mmol/L). There was a mildly elevated BUN (13.6 mmol/L). The CBC submitted the day prior by the referring veterinarian was within normal limits. There was no stress leukogram. The dog was treated with a 75-mL bolus of 0.9% NaCl IV, 50% dextrose diluted to 25% concentration in 0.9% NaCl, 1 mL/kg BW, IV, and dexamethasone sodium phosphate, 0.5 mg/kg BW, IV. Recheck systolic blood pressure was 100 mmHg. The dog continued to receive 0.9% NaCl supplemented with 2.5% dextrose at 3.3 mL/kg BW/h and was started on famotidine, 0.5 mg/kg BW, IV, q12h. Dextrose supplementation was discontinued once the blood glucose reached 9.33 mmol/L, 8 h later. Adrenocorticotropic hormone stimulation testing was performed as described for dog 1. The pre-ACTH cortisol was 8.3 nmol/L and the post was < 5.5 nmol/L. Eight hours after initiation of IV fluids, the dog’s serum sodium was 121.8 mmol/L. Twelve hours after presentation the dog was started on prednisone, 1.35 mg/kg BW, PO, q24h, and DOCP, 2.2 mg/kg BW, IM. She was discharged the following day on prednisone, 0.68 mg/kg BW, PO, q24h for 2 d, followed by half this dose indefinitely with instructions to return for recheck electrolytes in 7 d, and again in 27 d at which time she would receive the next DOCP injection. The dog returned for recheck 8 d after discharge. The owner reported the dog to be doing well. The serum sodium was 150.2 mmol/L and the serum potassium was 3.17 mmol/L. At 28 days post-discharge, both the serum sodium and potassium levels were within normal limits (sodium was 147.2 mmol/L, potassium was 4.3 mmol/L). Follow-up abdominal ultrasound revealed no abnormalities other than small adrenal glands. At the time of writing, 41 mo after diagnosis, the dog was doing well on prednisone, 0.27 mg/kg BW, PO, q24h and DOCP, 2.2 mg/kg BW, IM, q27d.

Nine months after dog 1 was presented, a 3.5 kg, 12-month-old neutered male Pomeranian (dog 3) was evaluated for sudden-onset shaking, lethargy, anorexia, and vomiting. This dog was a full sibling to dogs 1 and 2, from a subsequent litter. He was treated as an outpatient, at the owner’s request, with subcutaneous fluids, famotidine, 1 mg/kg BW, SQ, and dolasetron (Anzemet — Sanofi-Aventis, Bridgewater, New Jersey, USA), 0.6 mg/kg BW, SQ. Abdominal radiographs, CBC, and a chemistry panel were declined by the owner. However, due to the family history of hypoadrenocorticism, the owner consented to a baseline cortisol, which, while within the normal reference range (80 nmol/L), was considered relatively inappropriate given the stress of illness. Initially the dog improved with the conservative therapy noted, but 3 d later he was returned for ongoing vomiting, lethargy, anorexia, and shaking. He was assessed as quiet, responsive, and approximately 5% dehydrated. Rectal temperature was 37.8°C, heart rate was 160 beats/min with normal pulse quality, and he was panting. Systolic blood pressure, via Doppler ultrasonography, was normal at 115 mmHg. Two-view abdominal radiographs showed no abnormalities. Point-of-care blood work revealed severe hyponatremia (111.8 mmol/L; RR: 142 to 149.3 mmol/L) and hypochloremia (92.8 mmol/L; RR: 112.7 to 118.3 mmol/L) with a mildly elevated BUN (11 mmol/L). Serum potassium was normal at 4.56 mmol/L (RR: 3.62 to 4.6 mmol/L), as was the serum glucose at 7.1 mmol/L. The CBC was within normal limits, with no stress leukogram. The dog was treated with a 100 mL bolus of 0.9% NaCl IV, followed by a continuous rate infusion at 5 mL/kg BW per hour, dolasetron, 0.6 mg/kg BW, IV, q24h, and famotidine, 0.5 mg/kg BW, IV, q12h. The dog’s serum sodium levels 10 h and 16 h post-initiation of IV fluids were 115.3 and 114.2 mmol/L, respectively. The day after admission, an ACTH stimulation test was performed as described in the previous 2 dogs. The pre-ACTH cortisol was 52.4 nmol/L and post-ACTH cortisol was 33.1 nmol/L. Later that day, the dog was administered DOCP, 2.2 mg/kg BW, IM, and dexamethasone sodium phosphate, 0.5 mg/kg BW, IV. Twelve hours later, the dog’s serum sodium was 121.4 mmol/L. The dog was discharged later that day on prednisone, 1 mg/kg BW, PO, q24h, for 3 d, tapered over 1 wk to a maintenance dose, 0.29 mg/kg BW, PO, q24h, as well as metronidazole, 10 mg/kg BW, PO, q12h, for diarrhea that developed shortly before discharge. The dog was scheduled for recheck electrolytes at 14 d and again at 27 d along with the next DOCP injection. The dog returned 27 d post-discharge at which time her owner reported no problems. Recheck blood work showed a normal serum sodium, at 145.2 mmol/L (RR: 142 to 149.3 mmol/L) and normal serum potassium, at 4.13 mmol/L (RR: 3.62 to 4.60 mmol/L). A post-treatment abdominal ultrasound revealed small adrenal glands and no other abnormalities. At 35 mo after diagnosis the dog was doing well on prednisone, 0.29 mg/kg BW, PO, q24h, and DOCP, 2.2 mg/kg BW, IM, q27d.

Review of the dog’s family history revealed that the maternal grandmother — common to all 3 dogs — was diagnosed with hypoadrenocorticism at 8 years of age. Her full medical record was not available; however, it is known that she presented to an emergency hospital for collapse, and the following electrolyte abnormalities were found: hyponatremia (132 mmol/L), hyperkalemia (6.0 mmol/L) and hypochloremia (94 mmol/L). A low-dose ACTH stimulation test (cosyntropin at 5 μg/kg BW, IV) was performed. The pre-ACTH cortisol (resting) was 22.1 nmol/L and the post-ACTH was 35.9 nmol/L. Treatment included fludrocortisone and prednisone. Her owner reported that the dog did well for 1.5 y before she developed seizures and was euthanized. At the time of writing, this dog’s daughter — the mother of the 3 dogs described in this report — is alive and healthy, with no clinical signs of hypoadrenocorticism. The breeder reports that the siblings of dogs 1, 2, and 3 are all healthy. If this information is correct, pedigree analysis (Figure 1) is highly suggestive of an autosomal recessive mode of inheritance.

Figure 1.

Pedigree analysis of the family of Pomeranian dogs.

Discussion

Hypoadrenocorticism (Addison’s disease) is an uncommon endocrine disorder in dogs that typically affects middle-aged females (2). It can be caused by primary atrophy of the adrenal gland, causing glucocorticoid +/− mineralocorticoid deficiency, or secondary to hypothalamic or pituitary insufficiency, causing glucocorticoid deficiency (2). Idiopathic adrenal gland atrophy is the most common cause and is suspected to result from immune-mediated destruction (3). Familial hypoadrenocorticism has been reported in several breeds including Leonberger (4), standard poodles (5), bearded collies (6), Nova Scotia duck tolling retrievers (7,8), and Portuguese water dogs (9). The mode of inheritance in standard poodles (10), Nova Scotia duck tolling retrievers (8), and Portuguese water dogs (9) is believed to be autosomal recessive, and is unknown in other breeds. The mean age of onset of hypoadrenocorticism in all affected dogs is 4 to 5 y, compared to a median age of onset of 2.6 y in Nova Scotia duck tolling retrievers (8). The dogs in this report were also young, being between 1 and 2.2 y of age at time of diagnosis. Furthermore, 2 of the 3 dogs were male, whilst most studies report females to be over-represented (3). In standard poodles (10), bearded collies (6), and Portuguese water dogs (9), males appear to be equally affected as females.

Levels of ACTH were not measured in these dogs due to the strong laboratory evidence of both glucocorticoid and mineralocorticoid deficiency. All 3 dogs had profound hyponatremia upon presentation to the hospital. To prevent myelinolysis during treatment of hypoadrenocorticism, serum sodium should not be increased more than 10 to 15 mmol/L in the first 24 h (11). Despite being administered a bolus of 0.9% saline solution, hyponatremia persisted in all 3 dogs throughout hospitalization. It seemed unlikely that normonatremia was going to be achieved without DOCP, and so the dogs were discharged when clinically improved, albeit still hyponatremic. Both dogs that returned for rechecks were normonatremic at those times and were clinically normal, with no evidence of myelinolysis.

Other reported causes of hypoadrenocorticism in dogs include iatrogenic disease from mitotane or trilostane administration (12,13), bilateral primary (14), or metastatic (15) adrenal malignancy, bilateral adrenal infarction (16), bilateral abscessing adrenalitis (17), exposure to aerosols of plutonium-238 dioxide (18), and traumatic brain injury leading to panhypopituitarism (19). None of the dogs in this study had access to adrenotoxic drugs. Dog 1 had an abdominal ultrasound as part of the diagnostic workup and the adrenal glands were not found, presumably because they were smaller than normal, consistent with primary hypoadrenocorticism (20). Abdominal ultrasound examinations of dogs 2 and 3 after diagnosis and treatment revealed adrenal glands that were smaller than normal. This makes infiltrative and inflammatory diseases of adrenal glands less likely.

We propose an inherited basis as the cause of early onset, primary hypoadrenocorticism in the family of Pomeranian dogs; however, due to the small number of dogs, further documentation will be required to confirm a breed predisposition. Hypoadrenocorticism should be included on the list of differentials in young Pomeranians with supportive clinical signs and clinicopathologic changes. This recommendation is in contrast to a previous report, which suggests that Pomeranians are at decreased risk for hypoadrenocorticism (21). With prompt diagnosis and appropriate treatment the prognosis is excellent. CVJ