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. REFERENCES CHASWIN, C. B. & NICHOLS, C. E. (1984)Current concepts on the control of diabetes mellitus. Veterinary Clinics of North America: Small Animal Practice 14,859-872 DEFRONZO,K. A., HENDLER, R. & SIMPSON, D. (1982)Insulin resistance is a prominent feature of insulin-dependent diabetes. Diabetes 31,795-801 DOXEY, D. L., MILNE,E. M. & MACKENZIE, C. P. (1985)Canine diabetes mellitus: A retrospective survey. Journal of Small Animal Practice 26,555-561 EIGENMANN, J. E. & PETERSON, M. E. (1984)Diabetes mellitus associated with other endocrine disorders. Veterinary Clinics of North America: Small Animal Practice 14,837-858 EMMS,S.G.,JOHNSTON, D. E., EIGENMA”,J. E. & GOLDSCHMIDT, M. H. (1987)Adrenalectomy in the management of canine hyperadrenocorticism. Journal of the American Animal Hospital Association 23,557-564 FOSTER, S. J. (1975)Diabetes mellitus - A study of the disease in the dog and cat in Kent. Journal of Small Animal Practice 16, 295-31 KAHN,C. R. (1986)Insulin resistance: a common feature of diabetes mellitus. New England Journal of Medicine 315, 252-253 KANEKO,J. J., MATTHEELJWS, D., ROTTIERS,R. P. & VERMENTEN, A. (1977)Glucose tolerance and insulin response in diabetes mellitus of dogs. Journal of Small Animal Practice 18, 85-94 KARNIELI,E., COHEN, P., BARZILAI,N., ISH-SHALOM, Z., ARMONI, M., RAFAELOW, R. & BARZILAI, D. (1985)Insulin resistance in Cushings syndrome. Hormonal Metabolic Research 17,518521 KATHERMAN,A. E.,O’LEARY, T. P., RICHARDSON, R. C., POLZIN, D. J. & KAVFMAN, G. M. (1980)Hyperadrenocorticism and diabetes mellitus in the dog. Journal of the American Animal Hospital Association 16,705-717 LING,G. V., STABENFELDT, G. H., COMER, K. M., GRIBBLE, D. H. & SCHECHTER, R. D. (1979)Diabetes mellitus in dogs: a review of initial evaluation, immediate and long term management and outcome. Journal of the American Veterinary Medical 122 731-749 PETERSON, M. E., ALTSZULER, N. & NICHOLS,C. E. (1984) Decreased insulin sensitivity and glucose intolerance in spontaneous canine hyperadrenocorticism. Research in Veterinary Science 36,177-182 RIJNBERK, A. & BELSHAW,B. E. (1988)An alternative protocol for the medical amangement of canine pituitary-dependent hyperadrenocorticism. Veterinary Record 122,486-488 WATSON, A. D. J., RIJNBERK, A. & MOOLEMAR, A. J. (1987)Systemic availability of op’DDD in normal dogs, fasted and fed, and in dogs with hyperadrenocorticism. Research in Veterinary Science 43,160-165 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
