Severe hypoglycaemia in a cat with primary hypoadrenocorticism

Abstract

This case report describes a 3-year-old, castrated male, mixed-breed cat with historical, clinical and laboratory findings compatible with primary hypoadrenocorticism, confirmed by adrenocorticotropic hormone stimulation test. Severe but asymptomatic hypoglycaemia was an unexpected biochemical finding and resolved after fludrocortisone acetate and prednisolone treatment. This case demonstrates that hypoadrenocorticism should be included in the differentials list of severe hypoglycaemia in cats.

Case Report

Hypoadrenocorticism is a rare endocrinopathy in cats with less than 40 cases reported in the peer-reviewed literature.^1,2 It is usually primary and of unknown aetiology, although lymphocytic inflammation of the adrenals suggesting an immune-mediated process, neoplastic infiltration and external trauma have been implicated in some cases.^3–7 Isolated glucocorticoid deficiency due to atypical primary or naturally occurring secondary hypoadrenocorticism has been recently documented in one cat ⁸ and it may also occur after withdrawal of corticosteroid or megestrol acetate administration.^1,9–11

A 3-year-old, castrated male, mixed-breed cat, weighting 6.5 kg, that had up-to-date vaccinations and lived exclusively indoors, presented with a 1-month history of poor appetite and weight loss. Over the previous 3–4 days the cat was anorectic, lethargic and constipated, and demonstrated front limb ataxia. Upon physical examination, lethargy, mucosal pallor, weak femoral pulses, mild (5–7%) dehydration, profound generalised muscle weakness, hypometria and a reluctance to walk were observed, with the cat refusing to move for more than a few paces and preferring to lie in sternal recumbency. Cranial and segmental spinal nerve reflexes were normal, postural reactions markedly reduced-to-absent and muscular tone decreased. No pain response was elicited during manipulation of muscles, joints and bones.

Haematology showed mild anaemia (packed cell volume: 26%; reference interval (RI) 27–45%). Lymphocyte (5167/μl; RI 1500–7000/μl) and eosinophil (195/μl; RI 0–700/μl) counts were within reference intervals. Upon serum biochemistry, increased urea nitrogen, creatinine and total bilirubin concentrations, alanine aminotransferase activity, total calcium, inorganic phosphorus and potassium concentrations, and a decreased sodium-to-potassium ratio were found (Table 1). Unfortunately, serum glucose measurement was not done because of an oversight. Urine specific gravity was 1026. Electrocardiogram, abdominal radiography and ultrasonography did not reveal any abnormalities.

Table 1

Results of serum biochemistry in a cat with hypoadrenocorticism and hypoglycaemia, before (days -10 and -4) and after (days 10, 113, 138, 206 and 294) treatment initiation; values outside reference interval appear in bold

Parameter	Units	Days							Reference interval
		−10	−4	10	113	138	206	294
Total solids	g/dl	7.2							6.5–8.5
	g/l	72							65–85
Urea nitrogen	mg/dl	48.0	26.4	21.5	27.2	22.8	22.1		<37.2
	mmol/l	17.1	9.4	7.7	9.7	8.1	7.9		<13.3
Creatinine	mg/dl	2.5	2.2	1.0	1.2	1.2	1.5	1.7	<1.8
	μmol/l	220.1	194.5	90.2	107.8	105.2	131.7	145.9	<159.1
Glucose	mg/dl		25.1	111.0	165.0				71.0–136.0
	mmol/l		1.4	6.2	9.2				4.0–7.6
Total bilirubin	mg/dl	0.6							<0.5
	μmol/l	9.3							<8.6
ALP	U/l	46.8							<89.0
γ-GT	U/l	<2.8							<6.0
ALT	U/l	51							<44
Total calcium	mg/dl	13.5							9.3–12.1
	mmol/l	3.4							2.3–3.0
Inorganic phosphorus	mg/dl	7.9							1.9–5.0
	nmol/l	2.6							0.6–1.6
Potassium	mEq/dl*	6.1	5.0	4.6	5.3	4.9	4.3	4.2	3.8–5.0
Sodium	mEq/dl*	142	142	153	139	139	142		141–152
Sodium/potassium	–	23.3	28.5	33.6	26	28.7	32.8		<30.0
Chlorine	mEq/dl*	105		111					102–117

ALP = alkaline phosphatase, γ-GT = gamma-glutamylotransferase, ALT = alanine aminotransferase

*

Same figures for SI units (mmol/l)

The main differential diagnoses at this timepoint included chronic kidney disease (that could explain lethargy, anorexia, weight loss, constipation, dehydration, anaemia, and the biochemical abnormalities), polymyopathy and polyneuropathy (that could explain the neurological signs) and hypoadrenocorticism (that could explain all clinical and laboratory abnormalities).

Isotonic fluids (approximately 300 ml of 0.9% normal saline) were administered subcutaneously leading, within hours, to a marked improvement of demeanor, appetite and muscle strength. Six days later, clinical improvement was still apparent, azotaemia and hyperkalaemia had resolved and the sodium-to-potassium ratio had increased. Severe [25.1 mg/dl (1.4 mmol/l); RI 71–136 mg/dl (3.98–7.62 mmol/l)], though asymptomatic, hypoglycaemia was found (Table 1). Serum cortisol concentrations, measured before, and 1 h and 3 h after adrenocorticotropic hormone (ACTH) stimulation [0.125 mg tetracosactide (Synacthen; Novartis), IV] according to the instructions of the laboratory (Cambridge Specialist Laboratory Services, UK), were undetectable [<0.72 μg/dl (<20 nmol/l)] at all three timepoints and the diagnosis of hypoadrenocorticism was established.

Treatment was initiated with oral fludrocortisone acetate (Florinef; Squibb) at a dose of 0.1 mg (twice daily) and oral prednisolone (Prezolon^®, Nycomed Hellas) at a dose of 1.25 mg (twice daily). Ten days later the cat was clinically normal and the biochemical profile was normal with the exception of mild hypernatraemia [Table 1 (day 10)]. Approximately 3 months later, the owners noticed polyuria and polydipsia that prompted them to reduce the frequency of administration of both drugs to once daily. This was not followed by clinical deterioration, although increased serum potassium, and decreased sodium and sodium-to-potassium ratio, along with hyperglycaemia, were found at re-examination approximately 3 weeks later [Table 1 (day 113)]. Subsequently, the dose of fludrocortisone acetate was increased to 0.15 mg twice daily and that of prednisolone was decreased to 1.25 mg every second day and, later on, to 2 days per week, resulting in a progressive normalisation of serum electrolyte concentrations [Table 1 (days 138, 206 and 294)]. At the time of writing, 32 months after the diagnosis, the cat is clinically normal.

Signalment (middle-aged, mixed-breed cat), history (vague signs of anorexia, weight loss and lethargy), physical examination (mostly non-specific signs of dehydration, decreased peripheral perfusion, weak pulses and muscle weakness), haematology (anaemia, normal lymphocyte and eosinophil counts despite systemic illness), serum biochemistry and urinalysis (increased urea nitrogen, creatinine and phosphorus concentrations along with reduced urine-specific gravity in the face of dehydration; mildly increased total bilirubin and alanine aminotransferase; hypercalcaemia; hyperkalaemia; and reduced sodium-to-potassium ratio) findings, results of the ACTH stimulation test (no response), response to non-specific (rehydration) and specific (mineralocorticoid and glucocorticoid supplementation) treatment and the favourable long-term outcome of our case were all compatible with that already reported in cats with hypoadrenocorticism,^{1–7,9,10,12–17} and similar to those seen in dogs with the same disease. ¹⁸ However, there are some notable differences between cats and dogs with adrenal insufficiency, including: (i) no female predisposition in the feline disease;^1,4,18–21 (ii) the lack of diarrhoea, which is quite common in dogs (instead, the cat of this report presented with constipation that may be attributed to the dehydration and possibly to hypecalcaemia);^{4,10,14,21,22} (iii) the rarity of electrocardiographic abnormalities in cats that can be explained by the milder degree of hyperkalaemia compared to dogs [indeed, serum potassium concentration was in the upper-normal range in this cat when the electrocardiogram was done on day -4 (Table 1)];^1,2,4,10,15 (iv) the slower response to treatment, which, however, was not encountered in the present case,^2,4,11,17 and (v) the lack of severe hypoglycaemia or even the presence of hyperglycaemia in the feline disease.^4,12,14,23

To the best of our knowledge, only two cats with hypoadrenocorticism and hypoglycaemia have been reported in the peer-reviewed literature; ⁵ in one of them hypoglycaemia was very mild [71 mg/dl (3.98 mmol/l); RI 75–134 mg/dl [4.2–7.5 mmol/l]) and in the second one glucose concentration was not reported. ⁵ In both cats hypoadrenocorticism appeared secondary to disseminated lymphoma that infiltrated the adrenals and, therefore, hypoglycaemia could be also interpreted as a paraneoplastic syndrome. ⁵ Also, hypoglycaemia has been mentioned in a single cat with hypoadrenocorticism in a book chapter, but further details were not given. ² The reasons for this difference from dogs, where hypoglycaemia is present in up to 37.5% of adrenal insufficiency cases and may be the only biochemical abnormality in the atypical form of the disease, have not been explained.^{18,20–22,24–26} Similar to our case, most hypoglycaemic dogs with hypoadrenocortcism do not present clinical signs of glucosopaenia, perhaps because the decline of blood glucose concentration occurs progressively.^18,21

In canine hypoadrenocorticism, hypoglycaemia is attributed to the hypocortisolaemia that results in a reduction of glucose precursor mobilisation from muscle (alanine, lactate) and adipose tissue (glycerol), diminished hepatic glycogen storage, glycogenolysis and gluconeogenesis, and in increased peripheral glucose consumption due to enhanced receptor sensitivity to insulin and reduced sensitivity to its counter-regulatory hormones (glucagon, epinephrine).^{2,12,18,21,27–29} In addition, anorexia due to hypoadrenocorticism and exercise (ie, in hunting dogs) may precipitate hypoglycaemia.^21,29 In the cat studied in this report similar mechanisms (hypocortisolaemia and anorexia) are considered responsive for the severe hypoglycaemia, as other causes of this biochemical abnormality (neonatal hypoglycaemia, glycogen storage disease, insulinoma, non-islet cell neoplasia, sepsis, liver disease, portosystemic shunts, chronic renal failure, polycytaemia and, drug administration) can be excluded based on the signalment, history, clinical and laboratory findings, and long-term response to treatment of hypoadrenocorticism.^{2, 30–35}

At day -4, when blood glucose was first measured and hypoglycaemia was documented, serum potassium and sodium concentrations were in the upper and the lower reference intervals, respectively, and their ratio was only mildly decreased (Table 1). As a strict cut-off value for sodium-to-potassium ratio is hard to establish and depends on the desired sensitivity and specificity, ¹⁹ the reduced ratio at day -4 could have been easily overlooked and the biochemical profile could mimic that of canine atypical primary hypoadrenocorticism.^{24–26,28,29} It is not known if the normokalaemia was the result of the administration of normal saline 6 days earlier or if potassium concentration fluctuated in and out of the reference range independent of the previous treatment. The only cat with naturally-occurring isolated glucocorticoid deficiency reported so far also had a ‘tendency’ to develop hypoglycaemia (exact values not reported). ⁸

In conclusion, severe hypoglycaemia can appear in cats with primary hypoadrenocorticism and may be considered by itself an indication for ACTH stimulation testing, even if the typical electrolyte abnormalities are mild or absent, especially after fluid administration.