Canine Hyperadrenocorticism, Diabetes Mellitus, or Both?

Kirsten Zwicker, DVM; Perry J. Bain, DVM, PhD; Pauline M. Rakich, DVM, PhD; Kenneth S. Latimer, DVM, PhD

Class of 2003 (Zwicker), Department of Pathology (Latimer), and Athens Veterinary Diagnostic Laboratory (Rakich), College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7388

Introduction

Hyperadrenocorticism (HAC) and diabetes mellitus (DM) are relatively common endocrine diseases in dogs. These diseases are sometimes difficult to differentiate, as they share many clinical signs and laboratory abnormalities. Diagnosis may be further complicated when concurrent HAC and DM is present. A thorough history, physical exam, and diagnostic evaluation are often required to be able to accurately diagnose HAC, DM, or concurrent HAC and DM.

Overview of Hyperadrenocorticism

Incidence and Predisposition

Hyperadrenocorticism (HAC), also known as Cushing’s syndrome, refers to the clinical signs associated with chronic, excessive glucocorticoid exposure. The causes of HAC include excess ACTH production by the pituitary gland with secondary hyperplasia of the adrenal cortex, excess cortisol production by the adrenal cortex independent of ACTH, and iatrogenic causes such as excessive ACTH or glucocorticoid administration. Approximately 85 – 90% of naturally occurring cases of canine HAC are due to pituitary adenomas, carcinomas, or hyperplasia. The average age at the time of diagnosis of pituitary dependent HCM is 10 years. Poodles, Dachshunds, Beagles, German Shepherds, and terrier breeds are predisposed to the development of pituitary dependent HAC, with 75% of cases occurring in dogs less than 20 kg.² Adrenal adenomas and carcinomas account for the remaining 10-15% of naturally occurring cases of HAC. Roughly 50% of adrenal tumors are malignant.⁵ The median age at the time of diagnosis is 11.3 years. Poodles, German Shepherds, Dachshunds, and Labrador Retrievers predominate, with nearly 50% of adrenocortical tumor cases occurring in dogs over 20 kg.²

Clinical Signs of Hyperadrenocorticism

Clinical signs of HAC result from cortisol’s multisystemic gluconeogenic, protein catabolic, lipolytic, immunosuppressive, and anti-inflammatory effects (Table 1). Commonly seen signs include polyuria, polyphagia, vomiting, calcinosis cutis, lethargy, and weakness (Figs. 1 and 2).⁷ These signs typically progress slowly and are often mistaken by the animal’s owner as signs of aging. Other clinical signs that can be seen are associated with the life threatening complications that can occur with HAC. Complications include pulmonary thromboembolism, DM, acute pancreatitis, pyelonephritis, congestive heart failure, urolithiasis, and neurologic signs due to compression damage associated with large pituitary tumors.⁸ Less serious complications include lower urinary tract infection, glomerular disease, and systemic hypertension.⁹

Table 1. Characteristics of hyperadrenocorticism

Figure 1. Dog with hyperadrenocorticism showing symmetrical alopecia and pendulous abdomen (© Noah's Arkive, University of Georgia).	Figure 2. Calcinosis cutis in a dog with hyperadrenocorticism (© Noah's Arkive, University of Georgia).

Laboratory Diagnosis of Hyperadrenocorticism

Common diagnostic test results seen with HAC are presented in Table 3. The type of HAC present can only be determined with specific endocrine function tests since the clinical signs are related to hypercortisolemia, which is present in all types. An ACTH stimulation test will help differentiate pituitary-dependent and adrenal HAC from iatrogenic HAC or normal patients. With pituitary dependent and adrenal HAC, the ACTH stimulation test will result in an exaggerated cortisol response (22 µg/dl or more). Normal patients will have a post stimulation cortisol concentration of 17µg/dl or less. Iatrogenic HAC results in hypoplastic adrenals that have little to no response to the ACTH stimulation test.² Measuring endogenous plasma ACTH concentrations can also be helpful in differentiating pituitary dependent HAC from adrenal dependent and iatrogenic HAC. In pituitary dependent HAC, the ACTH concentration should be normal to high (>40 pg/ml) in contrast to adrenal and iatrogenic HAC which have undetectable to low normal ACTH concentrations (<20 pg/dl).⁵ Urine cortisol to creatinine ratio is sensitive, but not specific for HAC. A normal ratio excludes HAC, but an abnormally high ratio could be HAC or a number of other conditions that cause adrenocortical stress.¹

A low-dose dexamethasone (0.01 mg/kg) test is another tool that can be helpful in diagnosing HAC, and in some cases can be used to differentiate pituitary from adrenal HAC. In normal patients, dexamethasone administration has a negative feedback effect on ACTH secretion, which leads to decreased (<1.0 µg/dl) cortisol concentrations 8 hours later. In all cases of HAC, cortisol levels are not suppressed below 1.4 µg/dl, as they would be in a normal patient. If slight suppression of cortisol levels occurs and the total remains above 1.4 µg/dl, then pituitary dependent HAC is diagnosed. If no suppression is observed, the HAC could be either pituitary dependent or adrenal in origin.² High-dose dexamethasone (0.1-1.0 mg/kg) suppression test results in cortisol suppression in 75% of pituitary dependent HAC and lack of cortisol suppression in 25% of pituitary and 100% of adrenal HAC. A cortisol concentration below 1.5 µg/dl after administration of high-dose dexamethasone is diagnostic for pituitary dependent HAC, versus adrenal dependent HAC where cortisol levels are above 1.5 µg/dl at all samplings.⁵ Survey radiographs may also be helpful since 30-50% of patients with adrenal tumors will have a detectable unilateral soft tissue mass or mineralization in the adrenal gland.⁵ On ultrasound, a single enlarged adrenal is consistent with an adrenal tumor versus the bilaterally enlarged adrenals seen with pituitary dependent HAC.

Overview of Diabetes Mellitus

Incidence and Predisposition

Diabetes mellitus (DM) is the condition that results from an absolute or relative deficiency of insulin secretion by pancreatic beta cells. DM is a fairly common disease affecting 0.2 to 1% of the general canine population, with the incidence in females twice that in males.² A genetic predisposition for DM is suspected in Keeshonds, Puliks, Cairn Terriers, Miniature Pinschers, Poodles, Dachshunds, Miniature Schnauzers, and Beagles. Most dogs are diagnosed between 4 and 14 years old.²

Types of Diabetes Mellitus

Type 1 DM results from decreased insulin secretion due to beta cell destruction or loss. Type 2 DM is a consequence of insulin resistance and ineffective beta cell function. In type 2 DM the insulin level may be increased, decreased, or within the reference interval, but in all cases insulin is deficient relative to the level of insulin resistance in peripheral tissues. A third category of DM, secondary DM, occurs when carbohydrate intolerance results from an insulin antagonistic disease or medication. In secondary DM, beta cells initially try to overcome the insulin antagonism by producing and secreting more insulin. If the antagonism persists, the beta cells eventually become exhausted and permanent hypoinsulinemia and irreversible DM result.² Excessive cortisol in HAC antagonizes the action of insulin by either interfering with receptor binding or causing an abnormal intracellular response to insulin. The resulting secondary DM can obscure the diagnosis of HAC due to the many similar clinical signs (see Tables 1 and 2).

Clinical Signs of Diabetes Mellitus

The clinical signs of DM are similar to HAC and include polydipsia, polyuria, polyphagia, and weight loss (Table 2). If uncontrolled, severe DM can lead to anorexia, lethargy, depression, vomiting, cataracts, ketoacidosis, dehydration, and death.¹⁰

Table 2. Characteristics of diabetes mellitus

Laboratory Diagnosis of Diabetes Mellitus

Persistent hyperglycemia (>250 mg/dl) with concurrent glucosuria and ketonuria are common signs associated with DM. Inadequate insulin decreases the peripheral tissues’ ability to uptake and use glucose. As a result, hyperglycemia occurs which exceeds the renal threshold (180 – 220 mg/dl) leading to glucosuria. Glucosuria is detectable with urine dipsticks and causes an osmotic diuresis resulting in polyuria and polydypsia. Glycosylation of plasma proteins results in an increased fructosamine concentration which can be helpful in monitoring glycemia status.¹ Effective tissue starvation results in weight loss despite polyphagia. Mobilization of fatty acids as an alternative energy source leads to hepatic lipidosis and ketogenesis.¹⁰ Without effective treatment, DM ultimately can lead to ketoacidosis and death.

Summary and Conclusions

Table 3 compares and contrasts HAC and DM. Items that can be used to help differentiate between the two disorders are highlighted. A brief glance at the charts reveals why veterinarians often have difficulty in distinguishing HAC and DM. Specifically, concurrent HAC often is missed when a diagnosis of DM is made because many complications of DM such as ketoacidosis, uremia, and pancreatitis can lead to severe adrenocortical stress and signs identical to those seen with HAC.⁷ Polyuria, polydipsia, polyphagia, lethargy, and hepatomegaly are commonly seen with both conditions. Leukocytosis, neutrophilia, lymphopenia, and eosinopenia are seen in both HAC and stressed diabetics. Increased alkaline phosphatase, alanine aminotransferase, and cholesterol are also common in both DM and HAC. The presence of persistent fasting hyperglycemia and glycosuria may tempt the veterinarian to jump to a DM diagnosis, leaving the concurrent HAC undetected until complications with insulin regulation and/or progression of clinical signs are encountered.

Table 3. Similarities and differences of hyperadrenocorticism and diabetes mellitus.

Diagnostic Test	Hyperadrenocorticism	Diabetes Mellitus
CBC	Leukocytosis – impaired emigration of neutrophils from microvasculature Neutrophilia usually without a left shift Lymphopenia Eosinopenia Polycythemia if dehydrated due to diuresis Mild erythrocytosis in females	Leukocytosis – due to secondary infection and inflammation Neutrophilia with a left shift if due to a secondary infection Lymphopenia from stress in unregulated diabteic Eosinopenia from stress in unregulated diabetic Polycythemia if dehydrated due to diuresis
Serum Chemistry	High serum alkaline phosphatase activity - both hepatic and steroid induced isoenzymes may be increased Increased ALT activity Lipemia and high cholesterol concentration Fasting hyperglycemia (~40-60%) Abnormal bile acids Decreased BUN concentration Mild electrolyte abnormalities (hypernatremia, hypokalemia) Fructosamine concentration may be increased	High serum alkaline phosphatase activity – due to induction of steroid isoenzyme, hepatic lipidosis, and/or cholestasis secondary to pancreatitis Increased ALT activity Lipemia and high cholesterol concentration Fasting hyperglycemia (~100%) Increased bile acids and bilirubin Decreased BUN concentration Abnormal electrolytes and acid- base values (ketoacidosis) Fructosamine concentration increased
Urinalysis	Isosthenuria (Sp.Gr. < 1.015) or Hyposthenuria (Sp.Gr. <1.008) Glucosuria if hyperglycemia exceeds renal threshold UTI w/ minimal pyuria Increased Urine Cortisol:Creatinine Ratio	Sp.Gr. usually > 1.012 Glucosuria (~100%) UTI +/- pyuria and hematuria Increased Urine Cortisol:Creatinine Ratio in stressed DM patient Ketonuria in ketoacidotic patient
Figure 5A. Fine-needle aspirate from the liver of a healthy dog. The hepatocytes have a round nucleus, single nucleolus, and abundant, gray, granular cytoplasm (Wright-Leishman stain). Figure 5B. Fine-needle aspirate of the liver of a dog with hyperadrenocorticism and steroid hepatopathy. The hepatocytes are swollen and the cytoplasm is less opaque due to glycogen accumulation (Wright-Leishman stain). Figure 5C. Fine-needle aspirate of the liver of a dog with diabetes mellitus and hepatic lipidosis. The hepatocytes are swollen and the cytoplasm has clear, round, unstained vacuoles indicating lipid accumulation (Wright-Leishman stain).
Radiography Ultrasonography	Hepatomegaly – steriod hepatopathy (Fig. 5B) Potbelly Increased intra-abdominal fat Distended bladder Osteoporosis Calcinosis cutis / dystrophic calcification Adrenal calcification (with adrenal tumors) Congestive heart failure – rare Pulmonary thromboembolism – rare Pulmonary metastasis	Hepatomegaly – hepatic lipidosis (Fig. 5C) Obesity Distended bladder
ACTH stimulation test	Exaggerated cortisol response (22 µg/dl or more) in pituitary and adrenal HAC Little to no response (17 µg/dl or less) in iatrogenic HAC and normal patients	Endocrine tests can be abnormal in stressed DM patients
Plasma ACTH concentration	Pituitary HAC – normal to high (>40 pg/ml) Adrenal and Iatrogenic HAC - <20 pg/dl	Can be increased in a stressed DM patient.
Low-dose dexamethasone suppression test	No cortisol suppression with either pituitary or adrenal HAC Slight suppression, but total still >1.4 µg/dl seen with pituitary dependent HAC	Endocrine tests can be abnormal in stressed DM patients
High-dose dexamethasone suppression test	Cortisol suppression in ~ 75% of pituitary HAC No suppression in ~ 25% of pituitary HAC and 100% of adrenal HAC	Endocrine tests can be abnormal in unregulated diabetics
Other	Thin skin Bilaterally symmetrical alopecia Calcinosis cutis Low T3/T4 concentrations Hypertension Increased or normal insulin concentrations	Low T4 in poorly regulated diabetics High T4 in geriatric diabetics High, low, or normal insulin concentrations Hyperlipasemia and/or hyperamylasemia associated with pancreatitis Ketonemia and ketonuria

Insulin antagonism in HAC will cause patients with DM to have a high daily insulin requirement, often greater than 1.5 units per kg body weight per dose.⁸ An increased and/or fluctuating insulin dosage requirement in a DM patient should raise the level of suspicion for concurrent HAC.⁴ A pendulous abdomen, alopecia, thin hyperpigmented skin, and/or calcinosis cutis should also increase the level of suspicion concerning concurrent HAC (Fig. 3 and 4).⁹ Stress caused by poorly controlled DM can alter test results used to confirm HAC, so testing should only be done following several weeks of stable diabetic control. An ACTH stimulation test, low and high-dose dexamethasone suppression tests, and the urine cortisol to creatinine ratio can then be used to confirm concurrent HAC.

Figure 3. Macroscopic view of a skin biopsy from a dog with hyperadrenocorticism. Deposits of calcium salts appear as chalky, white discoloration of the dermis (© Noah's Arkive, University of Georgia).	Figure 4. Histologic section of skin from a dog with hyperadrenocorticism. Mineralized deposits of calcium salts appear as purple, granular material.

Overt DM may develop secondary to HAC when the insulin antagonistic action of hypercortisolemia leads to pancreatic B-cell exhaustion and hypoinsulinemia.⁹ A diagnosis of DM should be considered when a well-managed patient with HAC develops polyuria, polydipsia, polyphagia, weight loss, anorexia, or vomiting. DM in the HAC patient is confirmed upon finding hyperglycemia (>250 mg/dL) with glucosuria and/or ketonuria. Elevated fasting blood glucose is present in 40-60% of HAC cases, but only 10-15% have overt DM with severe hyperglycemia, glucosuria, and ketosis. Evidence of insulin resistance was present in 85% of dogs with spontaneous HAC in one study, as indicated by hyperinsulinemia with either normal or elevated blood glucose.⁶ This resistance is thought to be due to the hypercortisolemia either altering the binding of insulin at the receptor or somehow altering the intracellular response to insulin.⁶ Regardless, the insulin resistance will be corrected with treatment of the HAC, allowing for better regulation of concurrent DM.

References

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Acknowledgement

The image of the mural "Three Poodles" © by George Ratkevich is from the Gallery of the Off-The-Wall website and is used with permission of the artist.

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