A3-year-old female spayed English Cocker Spaniel was referred for investigations of a 2-month history of lethargy. The owner reported episodes of once-weekly mixed bowel diarrhoea and occasional vomiting over the past 18 months. A single tonic-clonic seizure had occurred 7 months before presentation. The owner telephoned the referral veterinary service to inform them about the seizure episode and was advised to monitor the dog. There was no veterinary visit or blood work performed following this episode. The seizure was suspected to be caused by hyponatraemia; however, toxin ingestion could not be excluded (although no toxin exposure was reported by the owner). Idiopathic, structural or congenital reasons for the seizure were considered at the time. These differentials are now considered less likely given the complete resolution of seizures once the electrolyte imbalance was corrected.
The dog had no history of travelling outside the UK, drug administration or toxin exposure, was up to date with vaccinations and received monthly veterinary prescribed flea and worm treatment. The dog was fed a commercial biologically appropriate raw food diet. No abnormalities were detected on physical and neurological examination. Barrier nursing was implemented while the dog was hospitalised.
Initial investigations
Haematology and biochemistry performed by the referring veterinarian had revealed:
- Severe hyponatraemia: 121 mmol/litre (reference range: 144–160 mmol/litre)
- Mild hyperkalaemia: 6 mmol/litre (reference range: 3.5–5.8 mmol/litre)
- Markedly decreased sodium:potassium (Na:K) ratio: 20 (reference range: 27–40)
- Markedly increased alanine aminotransferase levels: 1658 U/litre (reference range: 10–125 U/litre)
- Mildly increased alkaline phosphatase levels: 437 U/litre (reference range: 23–212 U/litre)
- Mildly increased gamma-glutamyl transferase levels: 29 U/litre (reference range: 0–11 U/litre)
- Mildly increased cholesterol levels: 10.5 mmol/litre (reference range: 2.8–8.3 mmol/litre).
Full blood test results are shown in Table 1.
Table 1. Initial haematology and biochemistry results
| Test | Results | Reference value |
|---|---|---|
| *Red blood cell count | 5.4 | 5.8–9.0 x 1012/litre |
| *Haematocrit | 0.3 | 0.4–0.6 litre/litre |
| *Haemoglobin | 120.0 | 122–184 g/litre |
| Mean corpuscular volume | 59.5 | 55.8–71.6 fl |
| Mean corpuscular haemoglobin | 22.4 | 17.8–28.8 pg |
| Mean corpuscular haemoglobin concentration | 376.0 | 309–386 g/litre |
| Reticulocytes | 80.3 | 10–110 k/ul |
| White blood cell count | 10.9 | 5.5–16.9 x 109/litre |
| Neutrophils | 7.6 | 2–12 x 109/litre |
| Lymphocytes | 2.4 | 0.5–4.9 x 109/litre |
| Monocytes | 0.8 | 0.3–2.0 x 109/litre |
| *Eosinophils | 0.1 | 0.1–1.5 x 109/litre |
| Basophils | 0.03 | 0–0.1 x 109/litre |
| Platelets | 282.0 | 175–500 x 109/litre |
| Glucose | 7.56 | 4.1–8.0 mmol/litre |
| Creatinine | 92.0 | 44–159 umol/litre |
| Urea | 7.8 | 2.5–9.6 mmol/litre |
| Phosphorus | 1.7 | 0.8–2.2 mmol/litre |
| Calcium | 2.6 | 2.0–3.0 mmol/litre |
| *Sodium | 121.0 | 144–160 mmol/litre |
| *Potassium | 6.0 | 3.5–5.8 mmol/litre |
| *Na:K ratio | 20.0 | 27–40 |
| *Chloride | 85.0 | 109–122 mmol/litre |
| Total protein | 69.0 | 52–82 g/litre |
| Albumin | 37.0 | 23–40 g/litre |
| Globulin | 32.0 | 25–45 g/litre |
| *Alanine aminotransferase | 1658.0 | 10–125 U/litre |
| *Alkaline phosphatase | 437.0 | 23–212 U/litre |
| *Gamma-glutamyl transferase | 29.0 | 0–11 U/litre |
| Total bilirubin | 4.0 | 0–15 umol/litre |
| *Cholesterol | 10.5 | 2.84–8.26 mmol/litre |
| Creatine kinase | 138.0 | 10–200 U/litre |
| Amylase | 520.0 | 500–1500 U/litre |
| Lipase | 364.0 | 200–1800 U/litre |
The values outside of the reference value are marked with *
Differential diagnoses
The list of differential diagnoses for mild gastrointestinal signs was vast, including extra-gastrointestinal (such as liver disease, renal disease and hypoadrenocorticism) and gastrointestinal causes (such as chronic enteropathy). Lethargy was considered unspecific and likely secondary to another disease causing the other clinical signs. Differential diagnoses for the single seizure included extra-cranial metabolic causes (such as hypoglycaemia, electrolytes disturbances or portosystemic shunt) and intra-cranial causes (such as idiopathic epilepsy). The blood work performed by the referring veterinarian helped reduce the list of differential diagnoses, and emphasis was put into investigating causes of hyponatraemia (including hypoadrenocorticism, gastrointestinal parasitism, effusions) and hyperkalaemia (including hypoadrenocorticism, renal, pseudo-Addison's disease).
The increased levels of liver enzymes (marked alanine aminotransferase and only mild increases in alkaline phosphatase, gamma-glutamyl transferase and cholesterol levels) indicate hepatocellular disease with a secondary cholestatic component (differential diagnoses for hepatic causes include idiopathic chronic hepatitis, infectious or neoplastic. Extra-hepatic causes such as chronic enteropathy or adrenal gland abnormalities were considered less likely because of the severity of increase in alanine aminotransferase).
Further investigations
At the referral hospital, blood work included haematology and blood smear evaluation, venous blood gas analysis, levels of preprandial bile acids, fasting ammonia and triglycerides, clotting times and an adrenocorticotropic hormone stimulation test measuring cortisol levels (Table 1). A voided urine sample was collected to measure specific gravity and dipstick.
Haematology revealed mild normocytic normochromic non-regenerative anaemia, supported by blood smear evaluation. Venous blood gas confirmed severe hyponatraemia (118 mmol/litre; reference range: 144–160 mmol/litre) and low Na:K ratio (22; reference range: 27–40). Pre-prandial bile acids were marginally increased, while ammonia and triglyceride levels and clotting times were normal. An adrenocorticotrophic stimulation test excluded hypocortisolism, with an adequate basal cortisol (103 nmol/litre; reference range: 25–125 nmol/litre) and post-stimulation cortisol concentrations (162 nmol/litre; reference range: 125–520 nmol/litre). Urinalysis revealed appropriately concentrated urine with a specific gravity of 1.044 and trace protein.
Triple-view thoracic radiographs revealed no abnormalities, excluding thoracic effusions as a possible cause of hyponatraemia. Abdominal ultrasound revealed a solitary, ill-defined, hypoechoic nodule in the liver (measuring 12 mm x 7 mm) and slightly small adrenal glands (the caudal pole of the left and right adrenal glands measured 5 mm and 3 mm respectively). It has been suggested that left adrenal gland caudal pole measurements below 3.2 mm support hypoadrenocorticism, but this has not been established for the right adrenal gland (Wenger et al, 2010). Ultrasound-guided fine needle aspirations from the liver and liver nodule revealed mild vacuolar hepatopathy, which is a non-specific finding and does not rule out significant underlying pathology.
The dog was started on a strict hydrolysed veterinary prescription diet and a 5-day course of fenbendazole at 50 mg/kg/day (Panacur; MSD) was prescribed. Cobalamin was measured given the chronic gastrointestinal signs (347 ng/litre; reference range: ≥275 ng/litre) and a 12-week course of supplementation (Cobalaplex; Protexin) was started, following Texas A&M recommendation to supplement when serum concentrations are <400 ng/litre (Kather et al, 2020; Texas A&M University, 2023). Gastrointestinal signs resolved completely within 2 weeks following the dietary change. The dietary response alongside low serum cobalamin levels raises the suspicion of food-responsive chronic enteropathy as a cause of the gastrointestinal signs.
A bile acid stimulation test was not supportive of liver dysfunction, with marginally raised pre-prandial (17 μmol/litre; reference range: 0–5 μmol/litre) and post-prandial levels (18 μmol/litre; reference range: 0–10 μmol/litre). A bile acid stimulation test estimates the efficacy of the enterohepatic circulation, where the gallbladder contracts 1–2 hours after feeding and the bile acids are released into the intestine. Approximately 90–95% of the bile acids are reabsorbed at the level of the ileum and taken back to the hepatocytes for re-excretion into the bile. Bile acid concentrations >25–30 umol/litre in dogs is suggestive of hepatobiliary disease. In some occasions, the pre-prandial levels can be higher than the post-prandial; this is usually as a result of gallbladder contraction during fasting or delayed gastric emptying. Serology for Toxoplasma gondii (immunoglobulin G and immunoglobulin M antibody titres measured by immunofluorescence), Neospora caninum (antibody titres measured by enzyme-linked immunosorbent assay) and Leptospira spp. (extensive panel of paired antibody titres measured by microagglutination test) were negative.
Revised differential diagnoses and treatment
The main differential diagnoses for seizures with persistently normal neurological examination included idiopathic epilepsy and seizures resulting from hyponatraemia. The dog was started on levetiracetam (Keppra 250 mg; GSK) 30 mg/kg every 8 hours orally. Magnetic resonance imaging of the brain was declined by the owner, because of a higher anaesthetic risk associated with the severe hyponatraemia. Most differential diagnoses for raised levels of liver enzymes had been excluded and, taking into consideration the age and breed of the dog, idiopathic chronic hepatitis was highly suspected (Webster et al, 2019).
Liver biopsies were declined by the owner. The patient was started on prednisolone (Prednicare 5 mg; Animalcare) 1.8 mg/kg every 24 hours orally, which was reduced after 14 days to 0.9 mg/kg once daily. Ursodeoxycholic acid (Destolit; Norgine 15 mg/kg every 24 hours orally was also started to support the liver. After 4 weeks, alkaline phosphatase levels had normalised, and alanine aminotransferase levels had markedly improved to just above reference (140 U/litre; reference range: 10–125 U/litre). Oral prednisolone was reduced to 0.45 mg/kg every 24 hours. Despite the liver parameters improving and the resolution of the gastrointestinal signs, lethargy and severe hyponatraemia persisted. The remaining differential diagnoses for severe hyponatraemia included:
- Gastrointestinal loss of sodium (considered unlikely since the gastrointestinal signs had resolved)
- Renal loss of sodium (urine fractional excretion was not measured)
- Syndrome of inappropriate antidiuretic hormone secretion (which is extremely rare)
- Primary hypoaldosteronism (extremely rare in dogs).
Serum aldosterone level before and after adrenocorticotrophic hormone stimulation was <20 pmol/litre (reference ranges: 0–393 pmol/litre) and 82–859 pmol/litre respectively. Aldosterone was measured from an adrenocorticotrophic hormone stimulation test performed 3 months after the initial presentation, from a new sample. The laboratory was contacted to discuss how to handle the sample before performing this test to ensure it would be reliable. Desoxycorticosterone pivalate (also known as Zycortal; Dechra) was administered at 1.3 mg/kg subcutaneously (Table 2). A few days after this injection, lethargy resolved; 3 weeks later, hyponatraemia also resolved.
Table 2. Changes in serum electrolytes and alanine aminotransferase over time and desoxycorticosterone pivalate administration
| Test | Reference value | Day 1 | Day 3 | Day 28 | Day 59 | Day 82 | Day 92 | Day 127 | Day 143 | Day 153 | Day 203 | Day 217 | Day 240 | Day 309 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Sodium | 144–160 mmol/litre | 121 | 118 | 120 | 127 | 122 | 127 | 145 | 142 | 139 | 147 | 146 | 148 | 145 |
| Potassium | 3.5–5.8 mmol/litre | 6 | 4.3 | 5.3 | 5 | 4 | 4.9 | 4.5 | 4.9 | 4.8 | 4.3 | 4.3 | 4.3 | 4.1 |
| Sodium:potassium | 27–40 | 20 | 27 | 22 | 25 | 30 | 26 | 32 | 29 | 29 | 34 | 34 | 34 | 35 |
| Chloride | 109–122 mmol/litre | 85 | 89 | 87 | 94 | 92 | 94 | 112 | 108 | 107 | 115 | 114 | 117 | 115 |
| Alanine aminotransferase | 10–125 U/litre | 1658 | 866 | 514 | 140 | 172 | 218 | 93 | 153 | |||||
Diagnosis
The resolution of the chronic gastrointestinal signs following the dietary change support the diagnosis of food-responsive chronic enteropathy, although gastrointestinal parasitism responsive to fenbendazole cannot be excluded given that the dietary trial and the treatment were given concurrently. The rapid normalisation of alkaline phosphatase and marked reduction of alanine aminotransferase levels to values close to normal after steroid therapy led to a presumptive diagnosis of idiopathic chronic hepatitis. Low serum aldosterone levels before and after adrenocorticotrophic stimulation, as well as resolution of the lethargy and hyponatraemia after mineralocorticoid therapy, support a diagnosis of mineralocorticoid deficiency.
Follow up
At the time of writing, the patient has been monitored for 15 months and remains asymptomatic. Since initiation of steroid therapy, alkaline phosphatase levels have remained normal, and alanine aminotransferase levesl have remained normal to slightly elevated. Different doses of steroids have been trialled while monitoring alanine aminotransferase levels, aiming to find the lowest effective dose for the patient.
The patient has not experienced further seizures since the hyponatraemia was corrected. Levetiracetam was stopped after 6 months without seizures. It is suspected that seizures were caused by the electrolyte imbalance, although idiopathic epilepsy and other less likely differential diagnoses cannot be excluded.
Serum sodium levels remained normal 37 days post desoxycorticosterone pivalate injection, but marginal hyponatraemia (139 mmol/litre; reference range: 140–154 mmol/litre) was observed 48 days post injection. Desoxycorticosterone pivalate injection was repeated at 1.3 mg/kg subcutaneously. The dog was scheduled to have electrolyte measurements every 7–10 days in order to find the longest interval time between desoxycorticosterone pivalate injections rather than administering them every 28 days. The dog's electrolytes, Na:K ratio and clinical signs remained normal for those 80+ days. The authors advised injecting a lower dose of desocycorticosterone pivalate as it is unknown whether it would last longer than that.
Repeated desoxycorticosterone pivalate administration was scheduled every 70–87 days via subcutaneous injection at 1 mg/kg and the owner was instructed to seek veterinary attention if the dog became lethargic or inappetent, began vomiting or had diarrhoea, with the intention of checking the electrolyte levels and administer desoxycorticosterone pivalate injection sooner if indicated.
Discussion
Hypoaldosteronism is seen alongside hypocortisolism in dogs with typical hypoadrenocorticism, usually resulting from immune-mediated destruction of the adrenal cortex (Klein and Peterson, 2010). Isolated hypoaldosteronism is very rare in dogs, (Lobetti, 1998; Kreissler et al, 2011; Béguin et al, 2020; Kather et al, 2020; Raj et al, 2021; Park et al, 2022).
There are only two case reports of dogs with isolated hypoaldosteronism who were successfully treated and had a long-term follow up (Raj et al, 2021; Park et al, 2022). One of these cases was treated with oral mineralocorticoid, using fludrocortisone at 0.01–0.03 mg/kg. A trial with desoxycorticosterone pivalate as a substitute for fludrocortisone was performed; however, despite a normal electrolyte balance, the dog's owners expressed their concerns about a change in the dog's behaviour and elected to switch back to oral mineralocorticoid supplementation (Raj et al, 2021).
The most recent case report used desoxycorticosterone pivalate to treat isolated mineralocorticoid deficiency in a dog with chronic kidney disease, hypercortisolism, diabetes mellitus and myxomatous mitral valve degeneration stage B2. Desoxycorticosterone pivalate was initially started at 0.5 mg/kg subcutaneously alongside a decrease in the dose of trilostane; however, an increase in the desoxycorticosterone pivalate dose to 1 mg/kg and reduction of the trilostane dose were necessary to achieve a normal electrolyte balance (Park et al, 2022).
The current case report is the second case report where canine isolated hypoaldosteronism has been treated long-term with desoxycorticosterone pivalate, leading to complete resolution of the clinical signs and the electrolyte imbalance.
The patient is strongly suspected to have idiopathic chronic hepatitis alongside isolated hypoaldosteronism and food-responsive enteropathy. The presumptive diagnosis of food-responsive enteropathy was based on the chronicity of the gastrointestinal signs and rapid resolution following a dietary change, the lack of remarkable changes on abdominal ultrasound and the age of the dog, alongside serum cobalamin levels of <400 ng/litre. Serum folate concentration was not measured given that, when decreased, supplementation has not shown benefits; therefore, it would not change the treatment prescribed to the dog. However, a low result would have added to the suspicion of chronic enteropathy. Serum cobalamin concentrations were measured approximately 30 days after the change of diet. Ideally, serum cobalamin and folate concentrations would have been measured at the time of initial presentation.
A faecal analysis for parasitology and culture should have been performed before prescribing fenbendazole to exclude presence of parasites such as Giardia spp. and Trichuris spp. and infections such as Salmonella spp. or Campylobacter spp. as a cause of or contributing factor to the hyponatraemia and/or gastrointestinal signs.
The presumptive diagnosis of idiopathic chronic hepatitis was made by exclusion, after ruling out infectious agents that could affect the liver of dogs living in the UK, ruling out clinically relevant diagnostic imaging and fine-needle aspirate results, and also based on the following criteria: female predisposition, favourable response to immunosuppression and association with other immune-mediated disorders (Webster et al, 2019). Moreover, young English Cocker Spaniels have shown to have a strong predisposition for idiopathic chronic hepatitis (Webster et al, 2019). Paired sampling was performed approximately 30 days after the first Leptospirosis spp. microagglutination test in order to confirm the negative result (a second blood sample is needed 2–4 weeks later to give the body enough time to seroconvert and reduce the false negative results in the case of recently infected animals). This was not performed in the case of Toxoplasma gondii and Neospora caninum, as the serological testing was performed approximately 30 days after initial presentation and, given that the liver parameters had been increased for over 1 month, seroconversion would have been expected by that point. Moreover, despite the dog previously being raw fed, and therefore having increased risks of obtaining infectious diseases, the prevalence of these infectious diseases in the UK remains low.
A definitive diagnosis for the cause of high liver enzymes would require liver biopsies, which were not performed as a result of concerns about the risks of general anaesthesia; this is one of the main limitations of this case report. One of the main concerns with putting this patient under general anaesthetic was the risk of rapid correction of the severe hyponatraemia by administering fluid therapy, which could be needed if hypotension occurred. Overly rapid correction of chronic severe hyponatremia can result in brain dehydration, leading to osmotic demyelination syndrome. This complication may occur 48 hours to several days after treatment. When correcting hyponatraemia, the serum sodium levels should not increase more than 10 mEq/litre during any 24-hour period, as this will reduce the likelihood of such brain lesions occurring.
Another limitation of this case report is that brain magnetic resonance imaging and cerebrospinal fluid analysis were not performed to investigate the cause of the seizures, also because of concerns about the risks of general anaesthesia. However, the patient has not had further seizures since the hyponatraemia was corrected, despite no longer taking antiseizure medications. Severe hyponatraemia can cause cerebral oedema and life-threatening, diffuse encephalopathy. Therefore, it is suspected that the seizures were related to the electrolyte imbalance (Brauer et al, 2011). Other seizure causes, such as structural brain changes or idiopathic epilepsy, remained a possible differential diagnosis; however, the authors would have expected to have seen further seizure episodes despite correcting the sodium imbalance, especially when the dog was no longer taking antiepileptic medication. Seizure episodes were reported in two other cases of isolated hypoaldosteronism (Kreissler et al, 2011; Raj et al, 2021).
As a result of the need of prednisolone to control the patient's chronic hepatitis, it was not possible to perform a follow-up adrenocorticotrophic hormone-stimulation test to establish if hypocortisolaemia would develop at a later stage. In dogs with atypical hypoadrenocorticism, it is recommended to frequently monitor electrolytes, as mineralocorticoid deficiency can develop days to years after the onset of cortisol deficiency (Thompson et al, 2007; Wakayama et al, 2017). It would be interesting to know if dogs with isolated hypoaldosteronism also develop hypocortisolism at a later stage.
Isolated hypoaldosteronism was speculated to have developed as a consequence of an immune-mediated condition (Raj et al, 2021). The authors support this statement, given what is known about canine hypoadrenocorticism, the age and breed of the patient, as well as the suspicion of two immune-mediated comorbidities.
Conclusions
This case report describes a dog with isolated hypoaldosteronism, concurrent chronic hepatitis and food-responsive enteropathy. Isolated hypoaldosteronism was treated for the second time with desoxycorticosterone pivalate instead of using fludrocortisone. The dog was started at a dose of 1.3 mg/kg subcutaneously, resulting in immediate and complete resolution of the clinical signs and electrolyte imbalance. The treatment was repeated every 70–87 days at 1 mg/kg subcutaneous injection. In the current case, the diagnosis of primary hypoaldosteronism took several months, which delayed treatment for the patient and therefore, the dog experienced clinical signs (lethargy and seizure episodes) for longer, increasing the owner's frustration and the risks for the patient to develop irreversible brain damage. The delay in diagnosis high-lights how rare and unknown this disease is. Isolated hypoaldosteronism should be considered a differential diagnosis for dogs with hyponatraemia, when hypocortisolism has been excluded by an adrenocorticotrophic hormone-stimulation test.
KEY POINTS
- Isolated hypoaldosteronism is a rare disease affecting the glomerulosa layer of the adrenal cortex in dogs.
- Isolated hypoaldosteronism was diagnosed by performing an adrenocorticotrophic hormone-stimulation test measuring serum aldosterone levels; results pre- and post-test were both <20 pmol/litre.
- Isolated hypoaldosteronism was treated with desoxycorticosterone pivalate, initially at 1.3 mg/kg subcutaneously resulting in immediate and complete resolution of the clinical signs and electrolyte imbalance. The treatment was repeated every 70–87 days at 1 mg/kg.
- Isolated hypoaldosteronism should be considered as a differential diagnosis for dogs with hyponatraemia, when hypocortisolism has been excluded by an adrenocorticotrophic hormonestimulation test.