Endocrine Diseases Of The Dog

Transcription

1 Peterson ME, Wheeler SH: Endocrine diseases of the dog. American Kennel Gazette 99:42-49, 1982 Endocrine Diseases Of The Dog Cushing's Syndrome, Hypothyroidism and Diabetes Mellitus are the three most common endocrine disorders our canines may be heir to. by Mark E. Peterson, DVM and Steven L. Wheeler, DVM Tr he endocrine system is composed of various glands which produce and secrete chemical messengers called hormones. The endocrine glands include the pituitary gland, located just beneath and attached to the brain; the thyroid gland, located adjacent to the trachea; the parathyroid glands, adjacent to the thyroid; the adrenal glands, situated above each kidney; the islets of Langerhans, located within the substance of the pancreas; the ovaries in the pelvis; and the testes in the scrotal sac. After a hormone is secreted by an endocrine gland, it travels through the bloodstream to other areas of the body where it acts to regulate body function. Table I lists the hormones produced by the various endocrine glands and their functions. Most hormones are necessary for life. Many, including the adrenal hormones (cortisol, aldosterone), thyroid hormones and pancreatic hormones (insulin, glucagon) are impor- tant in metabolism. Some, such as growth hormones, appear to be necessary only in early stages of development; others, such as the gonadal hormones, are necessary only for reproduction of the species. Most glandular function is regulated by negative feedback control. In other words, when the hormone that an endocrine gland is producing is present in adequate or excessive amounts in the bloodstream, production of the hormone is decreased or shut off. Conversely, decrease in a circulating hormone stimulates production of the hormone. An example of negative feedback control is found in the thermostatic control of heating. When the temperature rises, the thermostat senses the excess amount of heat and decreases further heat.production from the furnace. When, / falls, the negative feedback inhibition is removed and the furnace again produces heat. By this method of controt, the temperature is maintained within a narrow range. The pituitary gland has been termed the "master gland" because it controls the function of several other endocrine glands including the thyroid, adrenals, and gonads., An example of the negative feedback control mechanism occurs during pituitary stimulation of thyroid, adrenal and gonad secretion. The pituitary is analogous to the thermostat; the thyroid, adrenals, or gonads to the furnace; and the production of heat to the secretion of thyroid, adrenal and sex hormones. Like the thermostat, the pituitary gland controls the production of these hormones through negative feedback inhibition. In this way, the Drs. Peterson and Wheeler are,associated with the Animal Medical Center in New York City; Dr. Peterson is Staff Endocrinologist and Dr. Wheeler an intern in Medicine.

2 circulating hormones are maintained within well-defined physiological levels. Clinical endocrinology is the study of diseases of the endocrine glands, which result from either overproduction or underproduction of specific hormones. In this review, we will discuss thethree most common endocrine disorders in the dog: hyperadrenocorticism (Cushing's syndrome) resulting from excessive production of cortisol by the adrenal cortex, hypothyroidism resulting from decreased production of thyroid hormones, and diabetes melli- tus resulting from decreased secretion of insulin by the pancreas. Cushing's Syndrome The most common endocrine disease in the dog is hyperadrenocorticism (Cushing's syndrome), caused by the chronic overproduction of cortisol by the adrenal cortex. Two separate conditions may cause Cushing's syndrome in the dog: the pituitary gland may produce excessive amounts of adrenocorticotrophic hormone (ACTH) and cause bilateral adrenal gland enlargement (pituitary-dependent Cushing's disease), or a benign or malignant adrenal gland tumor may autonomously secrete excessive cortisol (adrenaldependent Cushing's). Pituitarydependent Cushing's disease accounts for approximately 85% of all cases in the dog, whereas adrenal tumors are found in 15% of dogs with Cushing's syndrome. In the normal dog, increasing levels of circulating cortisol decrease pitu itary ACTH release through the negative feedback inhibition mechanism (Figure 1); by reducing ACTH secretion, cortisol secretion is also de- TABLE I ENDOCRINE SYSTEM ENDDCRINE GLAND HORMONE(S) F U N C T I O N Pituitary Thyroid Parathyroid Adrenal Cortex Adrenal Medulla Pancreas Gonads Andrenocorticotrophic Hormone (ACTH) Thyroid Stimulating Hormone (TSH) Follicular Stimulating Hormone (FSH) Luteinizing Hormone (LH) Prolactin Growth Hormone (GH) Thyroxine (T4) Trilodothyronine (T3) Parathyroid Hormone Cortisol Aldosterone Epinephrine - (Adrenaline) Insulin Glucagon Estrogens Progesterone Testosterone Promotes growth and secretion of adrenal cortex Promotes growth and secretion of thyroid Promotes growth of ovarian follicle (female) and spermatogenesis (male) Promotes testosterone secretion (male) and ovulation (female) Promotes milk secretion from mammary gland Promotes growth in young dog; elevates blood glucose Increase metabolic rate: necessary for hair growth Increases blood calcium Elevates blood sugar; increases protein and fat breakdown; necessary for "stress" Controls sodium, chloride, and potassium balance Elevates blood glucose: increases blood pressure. and cardiac output Promotes glucose transport from blood to cells Increases blood glucose Necessary for fertility in female Necessary for fertility in male SEPTEMBER

3 , NORMAL PITUITARY FIGURE 1/PITUITARY-ADRENAL AXIS ADRENAL DEPENDENT CUSHING'S PITUITARY PITUITARY DEPENDENT CUSHING'S PITUITARY CORTISOL A C T H _ CORTISOL ACTH CORTISOL A C T H ADRENAL GLANDS ADRENAL ATROPHIED ENLARGED TUMOR ADRENAL ADRENAL GLANDS GLAND Figure 1- Pltultary-adrenal axis in normal dogs and dogs with adrenal tumors and pituitary-dependent Cushing's disease. In normal dogs, ACTH secreted by the pituitary stimulates cortisol production; rising levels of cortisol decrease ACTH secretion through negative feedback inhibition and normal circulation concentrations of cortisol are maintained. In dogs with an adrenal tumor, cortisol secretion is autonomous and not dependent on pituitary ACTH control. Cortisol overproduction by the adrenal tumor in- hibits ACTH secretion, with resultant low-circulating concentrations of ACTH and atrophy of the normal nontumorous adrenal gland. In dogs with pituitary-dependent Cushing's diseas, increased pituitary ACTH secretion produces enlargement of both adrenal glands and cortisol overproduction. Despite high circulating levels of cortisol, pituitary ACTH overproduction continues because of a defect in the negative feedback mechanism. creased, and normal cortisol levels are maintained. In dogs with Cushing's syndrome caused by adrenal tumor, cortisol over-secretion occurs independently of pituitary ACTH control; in fact, ACTH secretion is suppressed by cortisol produced by the tumor. Low circulating concentrations of ACTH result in atrophy of the other, nontumorous adrenal gland (Figure 1). In pituitary-dependent Cushing's disease, excessive cortisol secretion is dependent on secretion of increased amounts oracth by the pituitary. Chronic elevations in circulating ACTH concentrar tion stimulate growth of both adrenal glands, with subsequent overproduction of cortisol. The high circulating cortisol concentrations do not decrease pituitary ACTH secretion, however, because of a defect in the negative feedback mechanism (Figure 1). Cushing's syndrome is most fre- quently observed in middle- to oldaged dogs. Both sexes are equally affected. The disease is common in Poodles, Dachshunds, Boston Terriers and Boxers, but all breeds may be affected. Clinical signs exhibited by dogs with Cushing's syndrome include increased thirst and urination, increased appetite, lethargy, muscle weakness, abdominal distention, mild to severe hair loss, absence of estrus cycles and testicular atrophy (Figures 2 & 3). Complete blood counts and serum biochemical tests may reveal high red blood cell and white blood cell counts, as well as elevations in serum concentrations of cholesterol, liver enzyme and glucose. Extreme elevation in blood glucose levels, diagnostic for diabetes mellitus, is found in 15% of dogs with Cushing's syndrome. In these dogs the diabetes develops secondary to chronic cortisol excess. Although the clinical_ and laboratory abnormalities listed above may suggest Cushing's syndrome, the diagnosis can be made only by documenting that circulating cortisol concentrations are elevated. Single baseline cortisol determinations usually have no diagnostic significance, however, because of the considerable overlap of values that occurs between normal dogs and dogs with Cushing's syndrome. A useful screening test for Cushing's syndrome is the ACTH stimulation test; to perform this test, we collect a blood sample for cortisol determination, inject ACTH, and collect a second blood sample for conisol determination two hours later. Cushing's syndrome is diagnosed if the dog responds to the ACTH injection with a rise in cortisol concentration above the normal range. Although extremely useful in diagnosing Cushing's disease, this test cannot

4 8 be used to differentiate an adrenal tumor from pituitary-dependent Cushing's disease, since both groups of cushingoid dogs usually respond to ACTH with exaggerated responses. Once the diagnosis of Cushing's syndrome is made, a high-dose dexamethasone suppression test is very useful in determining the cause of Cushing's 'syndrome. Dexamethasone is a synthetic steroid which has actions similar to cortisol; however, dexamethasone is more potent than cortisol in inhibiting pituitary ACTH release through negative feedback. The test is performed by collecting blood samples for cortisol determination before, and again eight hours after the injection of dexamethasone. In normal dogs, this dose of dexamethasone completely inhibits pituitary ACTH secretion;. this 'results in marked suppression (lowering) of blood cortisol concentration.' In dogs with adrenal tumors, dexamethasone does not suppress plasma cortisol concentration because ACTH secretion has already been suppressed by high-circulating concentrations of cortisol produced by the tumor (Figure I). Cortisol production by an adrenal tumor is not dependent on ACTH stimulation as in the normal dog. In pituitary-dependent Cushing's disease, ACTH secretion is more resistant to the inhibitory effects of dexamethasone than in normal dogs, but ACTH (and therefore conisol concentration) decreases when large dosages of dexamethasone are given. The cause of Cushing's syndrome determines treatment. Adrenal tumors should be surgically removed. The drug used most frequently for pituitarydependent Cushing's disease is ortha, pars, prime-ddd (o,p'-ddd; lysodrenr, Bristol Myers); it acts to decrease cortisol production by producing partial destruction of the adrenal cortex. 0,p'-DDD is first given daily for seven to ten days to rapidly decrease the elevated cortisol concentrations to within normal range. Once conisol production has normalized, the drug should be given once to twice weekly to maintain the dog in remission. There is no standard dosage of o,p'-ddd that "Clinical signs exhibited by dogs with Cushing's syndrome include increased thirst and urination, increased appetite, lethargy, muscle weakness, abdominal, distension, mild to severe hair loss.." Figure 2- Cushing's syndrome in a 10-year-old Boston Terrier. Note the abdominal distention and thinning of the hair, Figure 3- Cushing's syndrome in a 12-year-old Dachshund. Complete hair loss is present over most of the body and severe abdominal distention is present. SEPTEMBER

5 "The drug used most frequently for pituitary-dependent Cushing's disease is ortha, para, prime-ddd it acts to decrease cortisol production by producing partial destruction of the adrenal cortex." Figure 4- Pituitary-dependent Cushing's disease in a 9-year-old Shih Tzu. Before treatment, severe hair loss and pendulous abdomen are present (top). After five months of therapy with o,p'-ddd, complete regrowth of hair and resolution of abdominal distention is evident (bottom). always decreases the cortisol level to exactly normal in every dog. Some dogs are very resistant to this drug, whereas other dogs, are extremely sensitive. Although chronic excessive cortisol production is life-threatening, a normal level of cortisol is needed in all anim level falls below normal range while a dog is undergoing o,p'-ddd therapy, signs such as vomiting, diarrhea, weakness, lethargy and decreased appetite will be observed. If any of these signs develop during treatment, the o,p'- DDD should be temporarily discontinued and cortisone or another synthetic glucocorticoid given. With two weeks of treatment, an increase in activity and decreased water consumption and urination become evident. Complete hairgrowth and resolution of pendulous abdomen may take three to five months (Figure 4). 0,p'-DDD is helpful in controlling the signs of Cushing's disease by decreasing cortisol levels to normal, but administration of this drug cannot cure the disease. If the drug is stopped, signs of Cushing's disease will reappear. All dogs should be re-examined during o,p require periodic adjustments of the dosage as they are treated. The prognosis for untreated canine Cushing's syndrome is usually poor, with death commonly occurring within two years of onset. With treatment, most dogs with Cushing's syndrome do well and live a reasonably healthy life. Hypothyroidism Hypothyroidism is the generalized metabolic disease resulting from deficiency of the thyroid hormones thyroxine (T4) and trilodothyronine (T3). The cause of canine hypothyroidism is usually atrophy of the thyroid gland. The disease is most common in young to middle-aged adult dogs, with a higher prevalence in the Doberman Pinscher, Great Dane, Golden Retriever, and Irish Setter. The clinical signs of hypothyroidism are variable but usually include lethargy, fatigue, and increased somnolence. Most dogs also exhibit a gradual slowing of mental activity, evidenced

6 by reduced alertness and excitability. "(Hypothyroidism) is most common in young Although some hypothyroid dogs gai weight, others remain at or below their to middle-aged adult dogs, with atigher normal weight. Hypothyroidism can prevalence in the Doberman Pinscher, Great also result in changes in the skin and coat, including increased scaling and a Dane, Golden Retriever and Irish Setter." dry, sparse coat. In some dogs complete hair loss develops, usually over the neck, hind thighs, flanks and abdomen (Figure 5). Others develop thickened skin folds over the face and forehead, giving the face a puffy appearance (Figure 6). Affected skin may be darkly pigmented in some dogs. Although the clinical signs given above may suggest hypothyroidism, an accurate diagnosis can only be made by measurement of circulating thyroxine (T4) concentration. Plasma T4 concentrations are consistently below normal range in dogs with hypothyroidism; however, further confirmation diagnosis is always required since the circulating 14 level is frequently "falsely" lowered by current or recent administration of certain drugs (steroids, anticonvulsants, aspirin) and other diseases (diabetes, liver disease, kidney disease and Cushing's syndrome). A useful test to confirm the diagnosis of hypothyroidism is the thyroid stimulating hormone (TSH) test. In this test, we collect a blood sample for measurement of 14 concentration, inject TSH, and collect a second sample for 14 determination four hours later. In normal - cretion of 14 in response to stimulation by TSH; therefore, the T4 concentration rises two- to four-fold after TSH injection. In hypothyroid dogs, the atrophied thyroid gland cannot increase the production of T4 following TSH administration and the subnormal resting T4 concentration fails to increase after TSH is given. In dogs that have drug or nonthyroidal disease induced lowering of the resting 14 concentration, the subnormal 14 levels increase two- to four-fold in response to stimulation by ISM The TSH test is therefore useful in differentiating dogs with true hypothyroidism from animals in which basal T4 concentrations are depressed by other causes. Treatment of canine hypothyroidism Figure 5-Hypothyroidism in a 3-year-old Doberman Pinscher.Note the complete hair loss on the flanks. 'Figure 6- Hypothyroid dog with thickening of skin folds of the face and eyelids.

7 consists of daily oral replacement with L-thyroxine (14). Most dogs respond well to a single daily dose of this hormone. Within ten days of treatment, a distinct increase in physical and mental activity is evident in most dogs. Most signs of the disease regress within two months, but full regrowth of hair may require six months. Once the diagnosis of hypothyroidism is made, there is no indication for ever stopping the replacement thyroxine. Once treated, the prognosis for this disease is excellent and the dog's lifespan is normal. Diabetes Mellitus Diabetes mellitus is a disorder in the secretion or function or both of the hormone insulin which regulates the metabolism of carbohydrates in the body. In normal dogs, a rise in blood glucose stimulates the secretion of insulin by the islets of Langerhans in the pancreas. Insulin facilitates the entry of blood glucose into tissue cells where glucose is metabolized to produce energy. Diabetes mellitus develops when there is a relative or absolute deficiency of insulin. With insulin deficiency, glucose cannot move into tissue cells to be used for energy; therefore, glucose builds up and reaches higher than normal concentrations in the bloodstream. When blood glucose levels rise to a certain point, the glucose begins to "spill" into the urine. When cells cannot Use glucose to make energy, they attempt to compensate by metabolizing the body's store of fats and proteins. This leads to weight loss, weakness, and excessive hunger, thirst and urination. As the diabetes progresses, ketone bodies are produced as a by-product of fat metabolism in the liver. Ketone bodies are strongly acidic. Accumulation of ketone bodies in the blood results in acidosis which can produce extreme weakness, loss of appetite; vomiting, coma and death. The cause of diabetes in most dogs is not known. In people, diabetes can be subdivided into three main types. Insulin-dependent (juvenile-onset) diabetes usually develops in children and is characterized by an absolute need for insulin to survive. Viral infections, environmental factors, and inheritance are thought to be involved in the development of this type of diabetes. Noninsulin-dependent (mature-onset) diabetes occurs in older people who are genetically predisposed to abnormalities in the interaction of insulin with tissue cells. In this condition the pancreas produces insulin normally, but the insulin is unable to move glucose from the blood into cells. In people thus "Many dogs.. develop diabetes in association with other conditions including Cushing's syndrome, acromegaly, estrus, pancreatitis, and the prolonged administration of glucocorticoids or progesterone-like drugs." predisposed, obesity can trigger the latent condition into overt diabetes. These patients are managed with weight control and oral medication that helps insulin move glucose into cells. The third type of diabetes is that which develops secondary to other conditions including pancreatitis, Cushing's syndrome, acromegaly (growth hormone overproduction) and prolonged administration of certain drugs or hormones. Secondary diabetes may or may not be reversible after correction of the underlying disorder; some patients require lifelong insulin therapy. In diabetic dogs, insulin treatment is almost always required, but true juvenile-onset diabetes is extremely rare. Although diabetes does occasionally develop in young dogs (less than one year), most diabetic dogs are middle- to old-aged. Canine "juvenile-onset" diabetes has been reported in the Keesbond, Golden Retriever, and other breeds. Although most dogs with diabetes are adults, "mature-onset" diabetes appears to be extremely uncommon. Many dogs, however, develop diabetes in association with other conditions including Cushing's syndrome, acromegaly, estrus, pancreatitis, and the prolonged administration of glucocorticoids or progesterone-like drugs. Abnormalities in glucose metabolism occur in most dogs with Cushing's syndrome or following treatment with large dosages of cortisol-like drugs (glucocorticoids) for prolonged periods of time. Fortunately, overt diabetes mellitus develops in only 15% of these dogs. If the underlying cause is not corrected, many of these diabetic dogs tend to be difficult to control and are resistant to the glucose-lowering effects of insulin injections. After overt diabetes has developed, treatment of Cushing's syndrome or cessation of glucocorticoid therapy rarely results in complete reversal of the diabetic State; however, removal of the high circulating concentrations of cortisol of other glucocorticoids does make regulation of the diabetic state easier. Prolonged administration of progesterone-like drugs or chronic ovarian production of progesterone in older, unspayed female dogs can also cause diabetes. In the dog, progesterone has both a direct effect to antagonize the effects of insulin and an indirect effect to stimulate excessive pituitary growth hormone secretion. Growth hormone acts to increase blood glucose through a similar mechanism as cortisol. With time, excessive concentrations of progesterone and growth hormone produce overt diabetes. If the source of the progesterone is removed early enough,

8 43;. growth hormone secretion returns to normal and diabetes resolves. If permanent damage to the pancreatic islet cells has occurred, however,, the diabetic state persists. Again, as in Cushing's syndrome, treatment of the underlying cause by removal of ovaries (spaying) or stopping progesterone therapy makes permanent diabetes much easier to manage. Finally, diabetes can also develop if a major portion of the pancreas is destroyed by either massive inflammation or invasion by neoplastic cells. Pancreatitis is an inflammatory condition of the non-insulin-secreting portion of the pancreas. When severe, destruction of the insulin-producing islets of Langerhans also occurs and diabetes results. In some dogs, the damaged islets regain their function after pancreatic inflammation has resolved and amelioration of the diabetes may occur. In other dogs, however, diabetes is permanent 'despite resolution of the pancreatitis. Fortunately, pancreatic cancer is rare in the dog; therefore, tumors of the pancreas is an extremely uncommon cause for diabetes in the dog. Diabetes mellitus usually develops in middle- to old-aged dogs. All breeds may be affected, but a higher prevalence is observed in Poodles. Intact female dogs are affected more frequently than males. Early clinical signs of diabetes include increased water consumption and urination, increased appetite and weight loss. With pmfression of overt diabetes, ketoacidons develops and the clinical signs change to loss of appetite, vomiting, diarrhea, dehydration, coma and death.. Diabetes mellitus is diagnosed by finding fasting elevations in both blood and urine glucose concentrations. If the diabetes has progressed to ketoacidosis, increased urine and blood concentrations of ketone bodies will also be present. With ketoacidotic.diabetes mellitus, laboratory testing also commonly reveals kidney dysfunction and electrolyte imbalance. No matter what the cause, most dogs with diabetes require insulin injections for survival. Dietary control alone is seldom, if ever, successful in managing the diabetic state. If the dog is extremely ill from ketoacidosis. intensive intravenous fluid and electrolyte therapy is necessary. During this time short-acting insulin is administered four to six times daily. Once the appetite has returned and a nonketotic state Therefore, we routinely treat diabetic is restored, the dog can be treated with a long-acting insulin, injected once or twice daily. If the diabetes has not progressed to ketoacidoils, treatment with "Successful treatment of diabetes mellitus requires capable and willing owners who must accept the responsibility for giving daily insulin injections and feeding their dogs at the proper times of day." a long-term insulin can be initiated at, time of diagnosis. After diabetes mellitus is stabilized, any underlying condition that may have induced the diabetes should be corrected. Administration of glucocorticolds or progesterone agents should be discontinued. Female dogs should be spayed. If Cushing's syndrome is diagnosed, appropriate therapy should be given to normalize high circulating levels of cordsol. The most common type of longacting insulin used is isophane (NP1-1) insulin: In man. NPH insulin's glucose-lowering effect lasts for approximately 24 hours. In most diabetic dogs. however, NPH insulin usually maintains blood glucose levels within normal range for only 12 to 18 hours. dogs with twice daily injections of N PH insulin. Successful treatment of diabetes mellitus requires capable and willing.owners who must accept the responsibility for giving daily insulin injections and feeding their dogs at the proper times of the day. Each morning the dog's urine should be tested for glucose and ketone levels with the use of appropriate test strips. The dose of NPH insulin is then administered subcutaneously and the dog is fed half of the daily food intake. Approximately 12 hours later, the dog is given another insulin injection and fed the remaining half of the daily food intake. The basic objective of insulin therapy is to maintain the urine glucose concentrations at levels, reflecting normal to only slightly elevated concentrations of blood glucose. The insulin dosage is adjusted based on the urine glucose determinations. If ketones are detected in the urine while on insulin therapy, a veterinarian should be notified. If difficulties in regulation of the diabetes occur, the correct insulin dosage may have to be determined by means of serial blood glucose determinations. The two most serious complications that occur in insulin-treated diabetic dogs are hypoglycemia (low blood glucose) attacks and cataract formation. Acute insulin overdosage results in hyt poglycemia, which may be seen as weakness, lethargy, loss of consciousness, or convulsions. If these signs occur, the diabetic dog should immediately be given a glucose-containing syrup such as Karo syrup, and a veterinarian should be notified. Cataracts are a common consequence of chronic insulin underdosage and hyperglycemia. Despite daily insulin injections and careful monitoring, cataracts still develop in many diabetic dogs.' SEPTIMBER