Diabetes & Hyperadrenocorticism in Dogs: Diagnosis & Management

Concurrent
diabetes
mellitus and
hyperadrenocorticisrn
in the dog:
Diagnosig and
management
of e i g h cases
A. C. Blaxter and T. J. Gruffydd-Jones
Department of Veterinary Medicine, Langford House, Langford. Bristol BS18 7DU
Iournal of Small Animal Practice (1990) 31, 117-122
ABSTRACT
Eight cases of concurrent diabetes mellitus and
hyperadrenocorticism are described. In all but
one dog diabetes mellitus was the first condition
recognised and, in these, clinical signs attributable to hyperadrenocorticism developed further while the dogs received replacement insulin
therapy. The most common signs were resistance
to exogenous insulin with daily insulin replacement dosage requirements exceeding 2 iu/kg,
erratic insulin requirements, continuing polydipsia/polyuria and weight loss. Lethargy and muscle weakness were variable and dermatological
abnormalities were present in only four cases.
Six dogs were treated with op’DDD and clinical
signs resolved with improvement of glycaemic
control.
INTRODUCTION
Diabetes mellitus and hyperadrenocorticism
are both well documented and commonly recognised endocrinopathies of dogs (Ling and others
1979, Chastain and Nichols 1984, Peterson 1984,
Doxey and others 1985). Both conditions occur in
middle aged to elderly animals and have a number of clinical signs in common. These include
polydipsia, polyuria, polyphagia and an increase
in abdominal size. Intermittent lethargy, vague
dullness and exercise intolerance may be features
of diabetes mellitus. However, profound lethargy,
muscle wasting and weakness are frequently
important features of hyperadrenocorticism
(Cushings syndrome). Similarly, non-specific
skin and coat changes can occur in diabetes but,
in hyperadrenocorticism, more specific changes
are common and include bilateral symmetrical
alopecia, skin thinning, cutaneous hyperpigmentation and calcinosis cutis. Despite these
features, differentiation of the two conditions
clinically can be problematic.
Diagnosis of diabetes mellitus is made by
demonstration of fasting hyperglycaemia and an
abnormal response to a glucose load. Other
common biochemical abnormalities detected
include elevated levels of serum liver enzymes,
and elevated levels of serum cholesterol and
triglycerides. Dogs with hyperadrenocorticism
demonstrate similar biochemical abnormalities
with fasting hyperglycaemia in up to 60 per cent
of cases (Ling and others 1979).
The situation is further complicated by reports
of concurrent diabetes mellitus and hyperadrenocorticism in dogs in the USA (Katherman and
others 1980, Peterson and others 1981, Eigenmann and Peterson 1984). The purpose of this
paper is to report the simultaneous occurrence of
these two conditions in dogs in Britain with
details of the diagnosis and management of eight
cases.
MATERIALS AND
METHODS
The eight dogs were referred between January
1986 and December 1987, seven for investigation
of glycaemic instability of pre-existing diabetes
mellitus under replacement insulin therapy and
one for stabilisation of diabetes. Glycaemic instability was defined as a variable elevation in
blood glucose and frequent glycosuria with
increasing insulin requirements and accompanied by the clinical signs of diabetes mellitus,
such as polydipsia/polyuria, nocturia, weight
loss and polyphagia.
117
A. C. BLAXTER AND T. J. GRUFFYDD-JONES
Haematology, serum biochemistry and urinalysis were carried out by standard methods. Serum
biochemical parameters assayed included total
protein, albumin, globulin, alanine aminotransferase, serum alkaline phosphatase, y-glutamyl
transferase, glutamate dehydrogenase, cholesterol, triglyceride, amylase and glucose. Serum
cortisol levels were determined by radioimmunoassay (Serono Laboratories) before and two
hours after the intravenous administration of 250
or 125 Fg of tetracosactrin or adrenocorticotrophin (ACTH) (Synacthen; Ciba Laboratories), dogs over 10 kg bodyweight receiving the
higher dose. A post stimulation cortisol of over
660 mmol/litre was considered diagnostic for
hyperadrenocorticism. All the cases were considered to be of the pituitary dependent form as survey radiographs or abdominal ultrasonography
did not reveal evidence of adrenal neoplasia.
Endogenous insulin was determined on fasting
serum samples, after 48 hours withdrawal of
exogenous insulin therapy, by radioimmunoassay
(Insulin assay kit, RIA [UKI Ltd).
Six dogs were hospitalised and glycaemic control was assessed by serial estimation of blood
glucose. Diet and insulin therapy were modified
to achieve optimum control. Six cases were treated with op’DDD (Lysodren; Bristol-Myers) at the
dose rate of 50 mg/kg/day for a loading period
of seven to 10 days. Thereafter, 50 mg/kg/day
was given once every seven to 14 days for
maintenance, according to the animal’s clinical
response. The op’DDD was given as a divided
dose throughout 24 hours. Clinical and biochemical re-examinations were performed every one to
three months to ensure continuing glycaemic
control and efficacy of op’DDD therapy. The two
remaining cases did not receive treatment and
were euthanased within 14 days of initial consultation. Post mortem examinations were not
performed.
RESULTS
Important clinical features are summarised in
Tables 1and 2.
Three of the dogs were miniature poodles, and
five of the eight cases were entire or neutered
bitches. The most common reason for referral
was inability to maintain glycaemic control in a
diabetic dog, with five dogs demonstrating severe
resistance to exogenous insulin, Only four cases
had notable lethargy or muscle weakness and
dermatological changes suggestive of hyperadrenocorticism were only recognised in four
animals (cases 4, 6, 7 and 8). Other clinical signs
included polyphagia (all cases), abdominal distension (all but case 1) and bilateral keratoconjunctivitis sicca (cases 2 , 4 and 7).
Relevant haematology and serum biochemistry
results are summarised in Tables 3 and 4. Five
animals had a leucocytosis with neutrophilia, but
the ‘classical’ features of hyperadrenocorticism
Table 1. Historical features of eight cases of concurrent diabetes mellitus and hyperadrenocortismin the dog
Case
number
118
Breed
Age (years)
Sex
Length of therapy
for diabetes
mellitus (months)
Reason for referral
Miniature poodle
8
M
5
Variable insulin requirements
resulting in frequent unpredictable
hypoglycaernia
Cavalier King
Charles spaniel
8
M
2
Continuing lethargy, dullness,
and polydipsia
Collie cross
8
F
2
Insulin resistance, bouts of dullness
and anorexia
Miniature poodle
5
NF
1-5
Insulin resistance and variable
insulin requirements
Labrador
9
F
6
Insulin resistance, continuing
lethargy and dullness
Labrador retriever
11
NF
2
Insulin resistance, continuing
polydipsia and lethargy
Yorkshire terrier
10
NM
3
Insulin resistance, continuing
depression, lethargy and hair loss
Miniature poodle
10
F
0
Routine referral for stabilisation
of diabetes mellitus
Concurrent diabetes and hyperadrenocorticism in the dog
Table 2. Clinical signs at initial presentationof eight cases of concurrent diabetes mellitus and hyperadrenocorticism
3
+
+
+
+/-
+
+
-
+/-
+
-
-
-
4
+
+
+
-
+
-
-
+
+
+
-
+
6
+
+
+
+
+
-
+
+
+
+
-
-
-Absent,
+/- Intermittently present, NIA Not applicable as insulin therapy not given
+ Present,
Tabte 3. Haematologicalfindings at initial presentationof eight cases of concurrent diabetes mellius and hyperadrenocorticism
Case
White blood
Bands
Neutrophils
Lymphocytes
Monocytes
Eosinophils
number
cell count
(%, X lW/litre)
(%, x loenitre)
(%, x I(Y/litre)
(%, x 10s/litre)
(%, X 10Wtret
( X 109/litre)
8.5-14.0
67-ai,7.5-9.1
15-25, 1.7-2.9
1-7,0.2-0.a
0-4,0-0*4
1
9.6
65, 6.2
19, 1.8
a, 0.8
7, 0.7
2
19.0
ao, 15.2
7, 1-3
a, 1.5
or0
3
11.9
70,8.3
20,2*4
6, 0.7
4'0.5
4
16.3
aa, 14.3
5,0.a
1,o.z
1,0*2
5
14.6
78, I I 4
13, 1.9
6, 0.9
1,O.l
6
13.2
80, 10.6
15,2.0
1,O.l
4'0.5
7
16.0
82, 13.1
7,l.l
10, 1-6
1,0.2
a
28.9
a3,24.0
12,3.5
4, 1.2
1,0.3
Normal
such as lymphopenia occurred in only three animals (cases 2, 5, and 7) and absolute eosinopenia
occurred in only one (case 2).
Serum protein levels were low in two animals
(cases 1 and 7) at presentation, but this feature
did not persist. All eight cases had moderate to
high elevations of serum alanine aminotransferase levels and dramatic elevations in serum
alkaline phosphatase. The range of serum alkaline phosphatase levels at presentation of 43 nonhyperadrenocorticoid diabetics, seen over the
same period of referral, was 76 to 15, 863 idlitre,
although some of the higher serum alkaline
phosphatase levels (over 1400 iu/litre) were
associated with cases with other problems, such
as hepatic cirrhosis or ketoacidosis. The cases
presented here also demonstrated mild to moderate elevations in other liver enzymes, such as yglutamyl transferase and glutamate dehydrogenase, and in serum cholesterol and triglyceride.
Endogenous insulin levels in the three animals in
which the assay was performed were grossly elevated, suggesting peripheral tissue resistance to
insulin.
119
A. C. BLAXTER AND T. J. GRUFFYDD-JONES
DISCUSSION
The features of the eight cases reported here
resemble those reported from the USA (Katherman and others 1980, Peterson and others 1981)
although there are a number of further observations to be made.
The breeds represented in the present case
series are all acknowledged as being predisposed
to both diabetes mellitus (Foster 1975, Marmor
and others 1982) and to hyperadrenocorticism
(Ling and others 1979, Peterson 1984). Miniature
poodles have been suggested to be at high risk of
concurrent diabetes mellitus and hyperadrenocorticism (Katherhman and others 1980, Peterson
and others 1981) and accounted for three of the
eight cases reported here.
Seven cases reported here were initially recognised as diabetic but over a relatively short
period of insulin replacement therapy (from six
weeks to six months), poor clinical responses to
treatment prompted further investigation. Only
one case had achieved glycaemic stability with
resolution of clinical signs of diabetes mellitus
before referral. This is in contrast to the series of
cases reported by Peterson and others (1981)
where 50 per cent of 30 cases had concurrent diabetes mellitus and hyperadrenocorticism at initial presentation, 25 per cent first presented with
hyperadrenocorticism one to 52 weeks before
diabetes, and the remaining 25 per cent presented as diabetics two to 22 months before recognition of hyperadrenocorticism. Although only one
case (case 8) was diagnosed as both diabetic and
hyperadrenocorticoid at initial presentation, ret-
rospective examination of clinical histories suggests that in two further dogs (cases 2 and 6)
signs of hyperadrenocorticism and diabetes mellitus probably developed simultaneously. It has
been postulated that increased levels of glucocorticoid alter the binding of insulin to its receptor,
and impair the post receptor intracellular
response, resulting in poor insulin action and a
compensating secondary hyperinsulinaemia
(Eigenmann and Peterson 1984). Thus, it would
be more logical to see diabetes secondarily to
hyperadrenocorticism. Although this work was
based on a project involving diabetic dogs,
hyperadrenocorticoid referrals have been closely
examined for evidence of diabetes mellitus. and
none have been observed. The most consistent
reason for the presentation of the cases in this
series was a complication or failure of insulin
therapy in diabetes. Peripheral tissue resistance
to insulin was substantiated by demonstrating
hyperinsulinaemia in three cases.
The most notable feature of the presenting clinical signs of the cases reported is the absence of
those signs considered to be common features of
hyperadrenocorticism. Lethargy was recognisd in
four cases, and intermittently in a fifth, and in
only four cases were there skin or coat abnormalities and these were not prominent. Similarly,
although almost all the animals remained
polyphagic and pot-bellied, polydipsia was not
consistent, and in two cases (cases 2 and 5) was
readily reduced by improvement in glycaemic
control on hospitalisation. As polydipsia is the
most consistent clinical sign in reports of hyperadrenocorticism (Ling and others 1979, Peterson
1984) this finding was surprising. There are
Table 4. Relevant serum biochemistryfindings at initial presentationof seven cases of concurrent diabetes mellitus and
hyperadrenocorticisrn
Case
Total
protein
(gilitra)
Albumin
(g/litre)
Globulin
(g/litrel
Alanineaminotransferase
(iullitre)
Glutamate
dehydrog
enase
Wlitre)
Cholesterol
(mmol/litre)
63-71
36-44
27-35
20-60
21-106
110
<10
4-6
<1.0
1
59.6
28.5
31.1
108
542
7
41
2.4
2
61.3
32.5
28.8
112
705
24
3
3
75.1
41.5
33.7
1272
1727
13
4
73.0
44.9
28.1
70
2745
5
57.6
30.2
27.4
77
6
60.1
43.5
16.6
7
56.4
4-8
15.6
Normal
range
120
Serum
Gamma
alkaline
glutamyl
phosphatase
trans(iujitre)
ferase
(iu/litre)
Triglyceride
(mmol/litre)
Cortisol Endogenous
(mmol/litre)
insulin
pre post
(uiulml)
ACTH ACTH
20 <660
250
4-16
0.5
127
1142
486
2.8
-
366
983
-
138
7.6
-
43
1086
438
22
37
10.9
4.1
51
716
-
2545
8
41
5.7
1.8
79
934
-
173
1567
35
34
12.6
1.5
252
1442
-
100
2188
48
120
17.6
1.8
230
1240
239
Concurrent diabetes and hyperadrenocorticisrn in the dog
obvious problems associated with assessing
water intake that may result from a compensation
for the osmotic diuresis of glycosuria and a primary polydipsia associated with hyperdrenocorticism. These cases suggest primary polydipsia to
be both difficult to assess, and infrequent, in
controlled concurrent diabetes and hyperadrenocorticism. Pre-existing keratoconjunctivitis sicca
was present in three cases, tear secretion improving with op’DDD therapy. Such a relationship
between adrenocorticoid disease and tear secretion has not previously been reported, although it
is known to occur in concurrent diabetes and
hypothyroidism. Keratoconjunctivitis sicca may
therefore be an important clinical sign to appreciate in diabetic animals.
The main indication of hyperadrenocorticism
in these diabetic dogs was glycaemic instability.
Five cases presented with severe resistance to
exogenous insulin, and one case (case 2) later
developed resistance, with dosages greater than
2 iu/kg/24 hours. This is defined as the maximal
limit for ‘normal’ insulin requirements in man,
although the normal human secretory rate is
between 0-4 and 0.5 iu/kg/24 hours (Kahn 1986).
Peripheral tissue resistance to insulin is commonly recognised as a phenomenon in hyperadrenocorticism in man (Karnieli and others
1985), in the aetiology of both insulin dependent
diabetes mellitus (Defronzo and others 1982) and
non-insulin dependent diabetes (Olefsky and
Kolterrnan 1981) and as a complication to diabetic therapy related to a range of disorders including anti-insulin antibody formation, hepatic
cirrhosis, hormonal and non-hormonal insulin
antagonists (Olefsky 1982). In dogs peripheral tissue resistance may also be associated with the
aetiology of diabetes (Kaneko and others 1977)
and is most commonly thought to be associated
with diabetogenic hormones, particularly hyperprogesteronaemia-associated growth hormone
overproduction in entire bitches, and to elevated
endogenous cortisol (Nelson and Feldman 1983).
It is estimated that 40 to 60 per cent of spontaneous hyperadrenocorticoid dogs demonstrate
fasting hyperinsulinaemia with moderate to
severe hypoglycaemia (Peterson and Altszuler
1981, Peterson and others 1984), and the hyperinsulinaemia demonstrated in three of the cases
reported here supports these observations.
Serum biochemistry findings were unremarkable although the hepatic isoenzyme of serum
alkaline phosphatase induced by glucocorticoids
might have been expected to contribute to serum
alkaline phosphatase elevation in those diabetics
with concurrent hyperadrenocorticism as compared with non-hyperadrenocorticoid diabetics.
The most commonly used treatment for the
pituitary dependent form of hyperadrenocorticism assumed to be present in these cases is
op’DDD administration although bilateral
adrenalectomy (Emms and others 1987) and
hypophysectomy (Nabarro 1986) have been suggested for both human and canine patients.
Op’DDD is a cytotoxic agent (2, 4’- dichlorophenyldichloroethane or mitotane) that causes
selective necrosis of the glucocorticoid producing zones of the adrenal cortex. The mineralocorticoid secreting zona glomerulosa is relatively
resistant to the cytotoxic effects of op’DDD and
aldosterone secretion is maintained. Occasionally total ablation of the zona fasiculata and zona
reticularis is produced by continuous therapy for
20 days, inducing hypoadrenocorticism (Rijnberk
and Belshaw 1988), but more commonly a loading dose is given for 10 to 14 days, and maintenance dosages given every seven to 14 days
thereafter (Watson and others 1987). This regime
was used for the cases reported but two areas
proved problematic. Only two of the six cases
treated had marked polydipsia or eosinopenia
with which to monitor the response to op’DDD,
treatment normally being stopped with the
appearance of eosinophils on daily routine
haematology, or on the resumption of a normal
water intake. In the remaining four cases loading
was continued for three days after resolution of
insulin resistance, two animals having seven
days of therapy and the remaining two, 10 days
of therapy. Problems were also associated with
this resolution of insulin resistance which consistently occurred over 24 hours resulting in
rapid falls in insulin requirements to the normal
range (less than 2 iu/kg/24 hours) with severe
hypoglycaemia as a side effect over 24 to 48
hours. In two animals this occurred on day 4 of
therapy, in a further two on day 7 of therapy, and
in one animal monitored by water intake (case 5)
insulin requirements fell over 48 hours immediately after completion of 11 days loading. In all
cases hypoglycaemia necessitated glucose therapy and intensive monitoring. Peterson (1984)
advises reducing the loading dose of op’DDD to
25 to 35 mg/kg/day and supplementing with 0.4
mg/kg prednisolone daily, but in one dog
supplemented with prednisolone a similar rapid
reduction in insulin requirements occurred. Total
cytotoxic ablation may be appropriate in those
where maintenance op’DDD dosing results in
variable insulin requirements (case 3) (Rijnberk
and Belshaw 1988).
The long term response to therapy is difficult
to assess in such a small series although it has
been unproblematic in three cases (cases 1, 5 and
7), clinical signs having resolved and continuous
diabetic stability maintained for 36 months, 34
months and nine months at the time of writing.
Two animals died, apparently for unrelated reasons (pyometritis and enteric parvovirus infection) after seven months and eight months of
121
A. C. BLAXTER AND T. J. GRUFFYDD-JONES
diabetic and hyperadrenocorticoid therapy. The
remaining treated case developed uncontrollable
signs of hyperadrenocorticism and insulin resistant diabetes after 12 months of therapy, related
to adrenal medulla and pituitary neoplasia.
In conclusion, concurrent hyperadrenocorticism should be considered in any unstable diabetic dog, especially in those with resistance to
exogenous insulin. The response to op’DDD
appears to be good with resumption of glycaemic
stability and reversal of continuing clinical signs.
Association 174,1211-1215
MARMOR,
M., WILLEBERG,
P., GLICKMAN,
L. T., PRIESTER,
W. A.,
CYPESS,
R. H. & HURVITZ,
A. I. (1982)Epizootologic patterns
of diabetes mellitus in dogs. American Journal of Veterinary Research 43,465-470
NABARRO,
J. (1986)Tkanssphenoidal surgery for Cushings syndrome. Journal of the Royal Society of Medicine 79, 253-
ACKNOWLEDGEMENTS
OLEFSKY,
J. M. (1982)Insulin resistance in humans. Gastroenterology 83,1313-1321
PETERSON,
M.E.,NESBITT,
G. H. & SCHAER,
M. (1981)Diagnosis
and management of concurrent diabetes mellitus and
hyperadrenocorticism in 30 dogs. Journal of the American
Veterinary Medical Association 178,66-69
PETERSON,
M. E. & ALTSZULER,
N. (1981)Spontaneous canine
Cushings syndrome: Decreased insulin sensitivity and
glucose intolerance. Diabetes 30,73A
PETERSON,
M. E. (1984). Hyperadrenocorticism. Veterinary
Clinics of North America: Small Animal Practice 14,
254
NELSON,R. W. & FELDMAN,
E. C. (1983) Complications of
insulin therapy in canine diabetes. Journal of the American
Veterinary Medical Association 182,1321-1325
OLEFSKY,
J. M. & KOLTERMAN,
0. G. (1981) Mechanisms of
insulin resistance in obesity and non-insulin dependent
(Type 11) diabetes. American Journal of Medicine 70,
151-168
___
The authors are grateful to the practitioners
who referred these cases and to colleagues at
Langford for their assistance in nursing and management during hospitalisation. Alison Blaxter
was supported by the Wellcome Foundation
through a Wellcome Training Scholarship, and by
the Peoples Dispensary for Sick Animals through
a Royal College of Veterinary Surgeons Trust
Fund Scholarship.
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ABSTRACT
Homer’s syndrome in dogs and
cats
CASES of 74 dogs and 26 cats with Homer’s syndrome were reviewed. No breed, sex or side
(right or left) incidence was found. The most
important causes in dogs and cats were trauma,
brachial plexus root evulsion, intracranial and
thoracic neoplasia and otitis media/interna. In
dogs, Homer’s syndrome was associated with
increasing age. Dogs with hypothyroidism,
intracranial or thoracic neoplasia were more likely to develop the condition than those in road
accidents. This is also true in cats with otitis
media/interna and both species with brahial
plexus avulsion. Animals with otitis externa
were less likely to develop Homer’s syndrome
than those hit by a car. In 52 per cent of dogs and
42.3 per cent of cats and the cause of Homer’s
syndrome was unknown. In dogs, location of the
affected site with topical adrenergic drugs was
inconclusive.
KERN,T. J., AROMANDO,
M. C. & Em, H. N. (1989) Journal of
the American Veterinary Medical Association 195,369