Endocrinology update for practitioners (Proceedings)

There have been several new findings in canine and feline endocrinology. We will highlight those that are useful and applicable to clinical practice. New diagnostic protocols and treatments will be discussed where appropriate.

Long-acting insulin preparations such as PZI or glargine are recommended for diabetic cats. The animal source PZI insulin (PZI-VET), made by IDEXX Pharmaceuticals was recently discontinued. Two recent studies evaluating a recombinant human form of PZI (now available as ProZinc from BIV) showed promising results and the product is approved by the FDA for use in cats. PZI is also available as a compounded product. We do not recommend using compounded PZI, however, because the potency can vary from batch to batch and regulation could be more difficult. Glargine insulin is relatively new human recombinant insulin available as Lantus (manufactured by Sanofi Aventis). It differs from other insulins because it has been genetically modified, by replacing an asparagine with glycine and adding 2 arginine amino-acids to the c-terminal end of the molecule. Currently, our preference for the initial treatment of newly-diagnosed diabetes in cats is ProZinc or glargine insulin administered at an initial dose of 0.25 U/kg administered twice a day. Generally, the initial starting dose should not exceed 3 U/cat BID. In general, the dose should not be increased in the first week, and in many cats, the dose needs to be reduced during the first week of treatment. In some cats, glargine appears to have little glucose lowering effect in the first 3 days. It is important that the dose is not increased during this time, because increasing the dose without monitoring can result in clinical hypoglycemia. Because the majority of diabetic cats require insulin twice a day, we prefer to start with a twice a day therapy while the insulin dose is low to avoid problems with hypoglycemia and development of the Somogyi phenomenon. In dogs, the current insulin of choice is NPH (Humulin N or Novolin N) as a result of the recent issues with Vetsulin. We recommend a starting dosage for NPH insulin of approximately 0.25 U/kg, administered BID. We also recommend initiating treatment with twice daily insulin administration because it will be easier to establish diabetic control with fewer problems associated with hypoglycemia or development of the Somogyi phenomenon. Several recent studies have shown that the feeding of a low carbohydrate, high protein diet (such as Purina DM and Hill's M/D) to diabetic cats receiving appropriate insulin therapy can significantly improve diabetic control, often lower insulin requirements and increase the incidence of remission. Canned formulations are generally preferable. Some nonprescription diets are similarly low in carbohydrates. Unless contraindicated by other medical conditions, feeding such low carbohydrate, high protein diets to diabetic cats is recommended.

There have been two recent studies of feline acromegaly, which concluded that the incidence of acromegaly is significantly greater than previously thought. Diagnosis was based on significantly elevated IGF-1 levels and CT or MRI scans. In one study, the median insulin dose of the acromegalic cats was 9 U compared to 3 U for the other cats. IGF-1 determination may be useful in suspected cases of feline acromegaly. Treatment options are somewhat limited, but confirmation of acromegaly can explain higher than typical insulin requirements or insulin resistance in a diabetic cat.

ACTH stimulation testing is useful in the diagnosis of adrenal disorders and can be performed using synthetic ACTH (Cortrosyn). The ACTH stimulation test can also be performed by determining the serum cortisol concentration before and 2 hours after the intramuscular injection of 2.2 U/kg of ACTH gel. ACTH gel (usually 40 or 80 U/ml) is available from several compounding pharmacies. The bioavailability and reproducibility of all of these formulations have yet to be carefully evaluated. A recent study in dogs using 4 compounded ACTH gels demonstrated increases in serum cortisol concentrations comparable to Cortrosyn injection 1 hour after IM injection of each of the 4 formulations, but considerable variation at 2 hours post-injection. The authors recommended determining serum cortisol concentrations at both 1 and 2 hours post-ACTH administration when using a compounded ACTH gel. The potential for lot to lot variability in compounded ACTH gel formulations has not been evaluated. Therefore, one should consider assessing the activity of each new vial by performing an ACTH stimulation test on a normal dog. We occasionally see a dog with classic historical and clinical findings of Cushing's disease but in which cortisol levels after ACTH stimulation testing and LDDST are normal. An adrenal panel reveals elevations in other adrenal hormones. This has been termed atypical hyperadrenocorticism and in our experience 17-OH progesterone levels are elevated. Whether other adrenal hormone elevations contribute to or cause this condition is somewhat controversial. Treatment with mitotane or trilostane should be considered. Trilostane (Vetoryl, Dechra) was recently approved by the FDA for the treatment of canine hyperadrenocorticism. The currently recommended dosing is 2-5 mg/kg given once daily with food (most recommend starting at the low end of the dose range). Recent work has demonstrated that a sizeable portion of dogs require BID administration to adequately control clinical signs. Therapy is monitored with ACTH stimulation testing. Testing is done 4 hours after trilostane administration if on SID therapy and 8-10 hours after trilostane if on BID therapy. There have been a few reports of adrenal necrosis, sudden death and acute hypoadrenocorticism (sometimes permanent) in dogs treated with trilostane. Studies compared the long-term survival of dogs with PDH treated with mitotane or trilostane. The mean survival time for dogs treated with trilostane were comparable to that of dogs treated with mitotane. Proteinuria and hypertension can be seen in dogs with hyperadrenocorticism. A recent study confirmed this showing an elevated urine protein/creatinine ratio and hypertension in 67% and 75%, respectively, of the dogs with PDH evaluated. Systolic blood pressure did not significantly correlate with the UPC. Monitoring and/or treatment of these abnormalities may be indicated in some cases.

A subset of dogs with primary hypoadrenocorticism appear to develop a selective glucocorticoid deficiency with apparently normal mineralocorticoid secretion, based upon the findings of low basal and ACTH-stimulated serum cortisol values with normal concentrations of serum electrolytes. This type of hypoadrenocorticism is commonly referred to as "atypical" hypoadrenocorticism. In most of these dogs, mineralocorticoid deficiency eventually develops, but a few dogs do not develop deficient mineralocorticoid secretion or serum electrolyte changes when followed for many months or years. Two recent studies proposed that atypical or glucocorticoid deficient hypoadrenocorticism is more common than previously described. However, some of the patients received treatment prior to blood sampling which may have altered the results. Also, multiple electrolyte determinations are needed to demonstrate abnormalities in some patients with Addison's disease. Treatment of hypoadrenocorticism requires the administration of the appropriate mineralocorticoid and/or glucocorticoid replacement. Initial dosage, route of administration and urgency of treatment depend on the clinical presentation. Acute adrenocortical insufficiency (addisonian crisis) is a medical emergency requiring immediate therapy. Given appropriate signalment, history and clinical signs, therapy should begin immediately. Samples for complete blood count, electrolyte levels, serum chemistry and urinalysis must be collected prior to initiating therapy. Maintenance therapy of hypoadrenocorticism consists of lifelong mineralocorticoid and/or glucocorticoid replacement therapy. Desoxycorticosterone pivilate (DOCP, Percorten) is typically instituted at a dosage 2.2 mg/kg given SQ or IM at approximately 1 month intervals. After the first 2 to 3 injections, serum electrolytes are measured at 2,3 and 4 weeks post injection to determine the duration of action. Almost all dogs are well controlled on a maintenance DOCP dosage of 2.2 mg/kg per injection. This eliminates the need to incrementally increase the DOCP dosage over the first 6 to 12 months of therapy, which is necessary in many dogs when DOCP is initiated at a lower dose. Most dogs are well controlled on DOCP every 4 weeks, but a few need injections every 2 to 3 weeks. To maintain a convenient monthly injection schedule, one can incrementally increase the DOCP dosage while monitoring electrolyte levels, but this is not usually necessary. No adverse effects such as hypertension and sodium retention have been reported with the use of a standard dosage of 2.2 mg/kg per injection. One can attempt to lower the monthly maintenance dosage of DOCP if desired to determine a minimal effective dose, particularly if cost is a concern. Alternatively, one can attempt to increase the interval between injections while monitoring electrolyte levels. Florinef is used at an initial dosage of 0.01 – 0.02 mg/kg/day and adjusted by 0.05 – 0.01-mg increments based on serial electrolyte determinations. Electrolyte levels are initially checked weekly until stabilized within the normal range. In many dogs, the dose of Florinef increases incrementally over the first 6 – 24 months of therapy. Considerable individual variation in the dose necessary can be expected. In most dogs, the final Florinef dose needed is 0.02 – 0.03 mg/kg/day. Very few dogs can be controlled on 0.01 mg/kg/day or less. Adverse effects (usually PU/PD), relative resistance to the effects of Florinef or financial concerns may be reasons to change to DOCP therapy in cases initially started on Florinef. Daily glucocorticoid replacement with prednisone (0.2 mg/kg/day) is needed in most but not all dogs with primary hypoadrenocorticism. In general, all dogs are initially placed on both prednisone and mineralocorticoid supplementation. Prednisone can then be tapered to alternate day therapy and then discontinued to determine if mineralocorticoid replacement alone is sufficient. Nevertheless, additional glucocorticoid supplementation is necessary during periods of stress and the client should have some on hand. Dogs with documented secondary hypoadrenocorticism require only glucocorticoid replacement. A dosage of 0.2 mg/kg/day of prednisone is usually sufficient, except during periods of stress.

Adrenal hyperplasia syndrome (also termed alopecia X, adrenal sex hormone imbalance, Nordic breed alopecia and GH responsive alopecia among others) is characterized by endocrine alopecia and hyperpigmentation in the absence of systemic signs of illness and abnormalities on a CBC and serum chemistry. Etiology is thought to be adrenal hormone excess with possibly a hair follicle abnormality contributing. Breed predilections include Pomeranians, Samoyeds, Chows, Keeshonds, Malamutes and Huskies. Tests for hypothyroidism and Cushing's disease are normal. An adrenal panel reveals elevations of one or more other adrenal hormones. Various treatments have been described including benign neglect, melatonin, mitotane and trilostane.

It has recently been reported that some cats develop hypertension following therapy for hyperthyroidism (approximately 20%). Whether this relates to the decline in renal function seen when euthyroidism is established is unknown at this time. Therefore, blood pressure should be monitored both before and during therapy in hyperthyroid cats. In people, a syndrome of subclinical hyperthyroidism has been shown to be present and is associated with normal thyroid hormone concentrations and low serum TSH levels. A recent study identified some euthyroid cats with undetectable serum TSH levels. Histopathological examination of the thyroid glands of these cats revealed adenomatous hyperplastic changes intermediate between normal cats and cats with overt hyperthyroidism. The data suggest that a subclinical hyperthyroidism appears to occur in the cat, and measurement of serum TSH may predict the development of hyperthyroidism. Treatment options are limited for hyperthyroid cats that do not tolerate methimazole and that are not candidates for radioiodine or surgery. A recent study evaluated iopanoic acid, a cholecystographic agent in an experiment model of feline hyperthyroidism.