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COMPLICATIONS AND CONCURRENT DISEASE ASSOCIATED WITH CANINE HYPERADRENOCORTICISM
Rhett Nichols, DVM
Spontaneous canine hyperadrenocorticism (canine Cushing’s syn- drome) is a constellation of clinical signs and biochemical abnormalities that result from chronic exposure to elevated concentrations of gluco- corticoids.12, 37 Because of the multisystemic effects of long-term hyper- cortisolemia, dogs with Cushing’s syndrome usually develop clinical signs that reflect dysfunction of many organ systems. In some dogs, however, one clinical sign may predominate. Sometimes the common clinical signs associated with hyperadrenocorticism may mask more serious problems. For example, the frequent clinical sign of polyuria and polydipsia may obscure other underlying or concurrent polyuric disorders such as pyelonephritis or diabetes mellitus. Although most dogs with hyperadrenocorticism appear healthy when examined, serious and life-threatening complications can occur secondarily to cortisol ex- cess. Complications associated with hyperadrenocorticism include, but are not limited to, pyelonephritis, diabetes mellitus, systemic hyperten- sion, pancreatitis, congestive heart failure, glomerulonephritis, pulmo- nary thromboembolism, advanced neurologic dysfunction secondary to large tumors of the pituitary gland, and iatrogenic glucocorticoid insuf- ficiency after medical therapy with mitotane.12, 33, 37 These complications may occur insidiously over long periods of time or, in some cases, cause sudden death. General awareness, recognition, and treatment of complications associated with hyperadrenocorticism may improve the
quality of life, decrease the severity of illness, and improve the prognosis (long-term survival) of dogs with this disorder.
COMPLICATIONS ASSOCIATED WITH MITOTANE THERAPY
Mitotane (o,p’-DDD) is the most frequently used drug in the treat- ment of canine hyperadrenocorticism.12, 38 This drug can be used in the management of pituitary-dependent hyperadrenocorticism (PDH) or cortisol-secreting adrenal tumors.12, 21, 22, 38 It decreases cortisol production by selective necrosis and atrophy of the adrenocortical zona fasciculata and zona reticularis. Because the zona glomerulosa is relatively resistant to the cytotoxic effects of mitotane, normal secretion of aldosterone is usually maintained.
Adverse effects to mitotane (overdosage), although usually not life threatening, should be anticipated when the drug is administered. The side effects most commonly observed are weakness, vomiting, anorexia, diarrhea, and ataxia.12, 21, 22, 38 These adverse effects most often result from low or rapidly falling cortisol concentrations, or, less commonly, from direct drug toxicity. If adverse effects occur after administration of mitotane, assume until proven otherwise that the “drug reaction” is caused by low cortisol levels. The mitotane should be stopped immedi- ately and glucocorticoids administered until the patient can be reevalu- ated. Direct toxicity to mitotane is usually associated with treatment of adrenocortical tumors, apparently because of the very high doses that are required to control clinical signs in some patients.22 If a direct toxic effect of mitotane is suspected, the dose is lowered by 25% to 50% after clinical signs of toxicity have resolved.22 Rarely, drug-induced central nervous system (CNS) signs occur.12 These adverse signs include ataxia, aimless wandering, circling, and head pressing.12 The drug-induced syn- drome is transient, (lasting 12 to 48 hours) usually occurs after 3 to 24 months of therapy, and usually responds to giving lower doses more frequently.12
In a retrospective study of 200 dogs with PDH treated with mito- tane, 25% developed one or more side effects during the initial induction period, and 30% had adverse effects at some time during the mainte- nance phase of treatment.21 Most dogs show mild and transient signs with clinical improvement occurring 1 to 3 hours after receiving 5 to 10 mg of prednisone. A minority of dogs (2% to 5%) develop permanent Addison’s disease characterized by low basal and post-ACTH cortisol levels and electrolyte changes of hyponatremia and hyperkalemia.12, 21 Occasionally, dogs may die of this complication, especially if the owner delays seeking veterinary attention. Adverse effects associated with mi- totane can be prevented or reduced in severity (especially in the loading phase of therapy) if close veterinarian and client contact is maintained and attitude and appetite are used as behavior markers of mitotane overdosage.12 Because most dogs with hyperadrenocorticism have excel-
lent to ravenous appetites, anorexia or poor appetite during treatment with mitotane suggests overdosage. Administration of glucocorticoid (prednisone, 0.2 mg/kg) daily during the loading phase appears to decrease the severity of or prevent adverse effects by mitigating the rapid fall in serum cortisol levels (glucocorticoid withdrawal).21, 37, 38
EXACERBATION OF SUBCLINICAL DISEASE DURING THERAPY
Subclinical inflammatory or allergic disorders such as degenerative arthritis and flea-bite hypersensitivity are sometimes exacerbated during treatment with mitotane (or other therapy) for hyperadrenocorticism.12 Less commonly, dogs treated for hyperadrenocorticism develop im- mune-mediated or neoplastic disorders such as hemolytic anemia, thrombocytopenia, mastocytosis, or lymphosarcoma.12 Apparently, the anti-inflammatory and immunosuppressive effects of cortisol can mask or cause remission of concurrent problems that become clinically obvi- ous after resolution of the hypercortisolemia.
DIABETES MELLITUS
Alterations of glucose metabolism frequently occur in dogs with hyperadrenocorticism. Approximately 40% to 60% of dogs have fasting hyperglycemia, whereas the prevalence of overt diabetes mellitus in dogs with hyperadrenocorticism is about 10%.11, 40, 42 Insulin resistance, characterized by the presence of endogenous hyperinsulinemia in the face of a normal or high plasma glucose concentration, also is a common feature of hyperadrenocorticism in dogs.11, 40, 42 Factors that affect glucose metabolism in dogs with glucocorticoid excess include increased hepatic gluconeogenesis and decreased glucose uptake by peripheral tissues from altered insulin receptor binding and impaired intracellular re- sponse to insulin.43
The diagnosis of diabetes mellitus in a patient with established hyperadrenocorticism is usually straightforward (blood glucose concen- tration > 250 mg/dL with glucosuria and/or ketonuria). Often the owner notes a sudden increase in thirst, appetite, and urination in a Cushing’s dog that has been reasonably well-controlled.
The diagnosis of hyperadrenocorticism in dogs with overt diabetes mellitus, on the other hand, is difficult on clinical grounds alone because many clinical signs (polyuria, polydipsia, polyphagia, and hepatomeg- aly) are common to both disorders.11, 42 In addition, the complete blood cell count (leukocytosis), serum biochemical profile (increases in serum alkaline phosphatase, alanine aminotransferase, and cholesterol), radio- graphs, and ultrasound results of the two diseases are often similar. Underlying hyperadrenocorticism should be suspected in any diabetic dog that has or develops bilaterally symmetrical hair loss, abdominal
distention, calcinosis cutis, or other clinical signs suggestive of cortisol excess. In many diabetic dogs with untreated hyperadrenocorticism, resistance to the glucose-lowering effects of insulin therapy also devel- ops. Therefore, concurrent hyperadrenocorticism should be considered in any diabetic dog that has sustained hyperglycemia and glycosuria despite high daily insulin doses (>1.5 U/kg per dose).11, 42
Specific laboratory tests (adrenocorticotropic hormone [ACTH] stim- ulation test, low-dose dexamethasone suppression test, urine corti- sol:creatinine ratio) must be used to confirm hyperadrenocorticism and to differentiate pituitary-dependent adrenal hyperplasia from adrenal tumors.37 Caution should be used when interpreting test results because the stress associated with poorly controlled diabetes mellitus could alter the test results (i.e., produce false-positive test results).20 Dogs with diabetes should not be evaluated for hyperadrenocorticism with these testing procedures until azotemia and ketoacidosis (if present) are re- solved and diabetic control with insulin is stable for a few weeks. If slightly abnormal results suggestive of hyperadrenocorticism are ob- tained, withholding treatment for hyperadrenocorticism and recon- firming the abnormal test results 1 to 3 months later is usually wise to prevent unnecessary and potentially dangerous treatments.39
In dogs with glucose intolerance or overt diabetes mellitus associ- ated with hyperadrenocorticism, the cause of the underlying hypera- drenocorticism determines treatment. Functional adrenocortical tumors should be removed surgically, whereas PDH is usually managed most easily with mitotane.21, 22, 39 In dogs with hyperadrenocorticism and overt diabetes, treatment should be initiated and the diabetes stabilized before treatment of the hyperadrenocorticism. A serious complication associ- ated with the standard mitotane treatment protocol during the initial treatment period in diabetic dogs with insulin resistance is a rapid decrease in daily insulin requirements predisposing to insulin overdos- age and hypoglycemia. Use of a lower initial dose of mitotane (25 mg/kg/d) and a high maintenance dose of prednisone (0.4 mg/kg/d) prevents rapid reductions in circulating cortisol levels and daily insulin requirements and allows for easier regulation of the diabetic state.11, 37, 42
URINARY TRACT INFECTION AND UROLITHIASIS
Urinary tract infection (including pyelonephritis) and urolithiasis (usually struvite or calcium oxalate or phosphate) are common problems associated with hyperadrenocorticism.26 Lowered resistance to infection may result from glucocorticoid-induced inhibition of neutrophil and macrophage migration into affected areas. Chronic infection predisposes to struvite urolithiasis, whereas increased calcium excretion associated with cortisol excess is believed to predispose to calcium uroliths. Clinical signs include pollakiuria, dysuria, and hematuria. Surprisingly, many
dogs are asymptomatic for lower urinary tract disease despite the pres- ence of cystic calculi or significant bacteriuria, presumably because of the anti-inflammatory effects of cortisol.
Severe, chronic lower urinary tract infection may enhance potential for ascending infections (pyelonephritis) and renal failure. Pyelonephri- tis should be suspected when a urinary tract infection cannot be cleared with appropriate antibiotic therapy (based on culture and sensitivity results on urine collected by cystocentesis). Persistent polyuria and poly- dipsia in well-controlled, nondiabetic Cushing’s dogs (pre- and post- ACTH cortisols in normal basal cortisol range) also suggests upper urinary tract infection. Pyelonephritis is best diagnosed by contrast dye studies of the kidneys, renal biopsy, or renal ultrasonography. Clinically, pyelonephritis often mimics antibiotic-responsive polyuria and polydip- sia.
ACUTE PANCREATITIS
Dogs with hyperadrenocorticism are predisposed to acute pancreati- tis. A recent study concluded that hyperadrenocorticism, prior gastroin- testinal disease, diabetes mellitus, and hypothyroidism as well as certain breeds (Yorkshire Terrier, Miniature Schnauzer, Toy Poodle), obesity, and small body size are risk factors for the development of acute pancreatitis.15, 50 Other risk factors include hyperlipidemia, pancreatic duct obstruction, and, possibly, the use of high doses of corticosteroids.50 Because the clinical signs of pancreatitis are similar to adverse effects of mitotane, the diagnosis and treatment of acute pancreatitis is sometimes delayed in Cushing’s dogs being treated with this drug. As a general rule, any dog suspected of mitotane overdosage that doesn’t respond to glucocorticoid supplementation (0.4 mg/kg) within several hours should be evaluated for another illness. The diagnosis of pancreatitis can often be supported by history (recent fatty meal), physical exam (abdominal pain on palpation), laboratory evaluation (elevated white blood cell count, elevated amylase and lipase levels, rising serum alkaline phospha- tase, total bilirubin and cholesterol concentrations), radiography (loss of detail in the cranial abdomen), and ultrasonography (finding an edema- tous pancreas).
With regard to recommendations for dogs with hyperadrenocorti- cism and a history of pancreatitis, weight control and low-fat diets should be considered. In dogs suspected of having an adrenocortical tumor with concurrent or previous pancreatitis, the use of the high- dose dexamethasone suppression test for diagnostic purposes should probably be avoided. Instead, endogenous ACTH level determination, adrenal ultrasonography, magnetic resonance imaging or computed to- mography scanning can be used to confirm the diagnosis of an adreno- cortical tumor.
HYPERTENSION
Systemic hypertension, a classic feature of Cushing’s syndrome in humans, occurs in over 50% of dogs with untreated hyperadrenocorti- cism.19, 34 Possible mechanisms for sustained increases in blood pressure include secretion of renin substrate (the circulating protein upon which renin acts to release angiotensin I), reduction of vasodilator prostaglan- dins, increased vascular responsiveness to catecholamines and angioten- sin II, and secretion of non-zona glomerulosa mineralocorticoids.31 More recently, hyperaldosteronism, which may contribute to increased sodium and water retention, has also been linked to Cushing’s syndrome and hypertension.35 Plasma aldosterone levels (pre- and post-ACTH adminis- tration) were highest in dogs with untreated pituitary-dependent Cushing’s disease, moderately elevated in treated but poorly controlled Cushing’s dogs, and near normal in dogs with well-controlled Cushing’s disease.35
Elevations in blood pressure may cause or contribute to blindness (from intraocular hemorrhage and retinal detachment), thromboembo- lism, intrarenal hypertension and glomerulosclerosis with proteinuria, left ventricular hypertrophy and congestive heart failure, and pulmonary thromboembolism.12, 27 In most cases, the hypertension resolves after successful management of the hyperadrenocorticism (improvement can take up to 6 months or longer). However, some dogs remain hyperten- sive despite good control with medical therapy (mitotane).12, 33 Addi- tional treatment with antihypertensive medications should be considered in Cushing’s dogs with (1) severe hypertension (systolic blood pressure > 190 mm Hg and/or diastolic blood pressure > 130 mm Hg), (2) persistent hypertension despite therapy, or (3) concurrent disorders that may be aggravated by sustained high blood pressure, such as retinopa- thies, compensated mitral or tricuspid insufficiency, congestive heart failure, glomerulopathies, or pulmonary thromboembolism.
GLOMERULAR DISEASE
Glomerulonephritis is also associated with hyperadrenocorticism.6,33 Factors that may predispose dogs with hyperadrenocorticism to glomer- ulonephritis include altered immune complex solubility (relative antigen excess), frequent occurrence of chronic infections, and decreased clear- ance of immune complexes by the reticuloendothelial system.5, 12, 33 In one study, the incidence of glomerular lesions consistent with glomeru- lonephritis at necropsy of confirmed cases of Cushing’s disease was 15% (R Justin, S Moroff, and ME Peterson; unpublished observations, 1991). In other studies, the incidence of significant proteinuria (urine protein to creatinine ratio > 1) in dogs without urinary tract infection (inactive urinary sediment and negative urine culture) ranged from 44% to 75%.16, 34 These studies suggest that although proteinuria is quite com- mon in dogs with hyperadrenocorticism, not all dogs with proteinuria
and hyperadrenocorticism have glomerulonephritis. Other causes of pro- teinuria that may be associated with hypercortisolemia include glomeru- losclerosis, increased glomerular pore size, altered permselectivity, and amyloidosis.4,6,27,28, 49 In general, proteinuria in most dogs with Cushing’s disease is usually mild (urine protein to creatinine ratio, 1.0 to 5.0) and tends to improve or resolve after successful treatment of the hyperad- renocorticism.12, 33
The clinical significance of glomerular disease and proteinuria in dogs with hyperadrenocorticism is unclear; however, extrarenal manifes- tations of glomerulonephritis include thromboembolism and hyperten- sion, which are also serious complications of Cushing’s syndrome. Therefore, one could make a strong argument for treatment of all dogs with Cushing’s disease and proteinuria and/or hypertension, even if the other clinical signs related to hyperadrenocorticism are mild.
PITUITARY MACROTUMORS
The most common causes of PDH are small ACTH-secreting tumors of the pars distalis (microadenomas).5, 41 Less commonly, PDH results from a large, so-called macrotumor (tumor size > 1 cm in diameter)2, 9, 10, 12, 29, 32 (see also the article by Dr. Ihle). These tumors may invade or compress adjacent neural structures resulting in clinical signs that often reflect both the endocrine and space-occupying effects of the tumor.2, 32 In most cases, CNS signs develop weeks to months after the diagnosis and treatment of PDH, although in some cases neurologic signs precede the diagnosis of hyperadrenocorticism.3, 8, 9, 10, 12, 45 Early CNS signs noted by owners, which are often subtle, include dullness, anorexia, restless- ness, loss of interest in household activities, and brief episodes of disori- entation.3, 8, 9, 10, 12, 45 More definitive signs related to the presence of a macrotumor include ataxia, obtundation and stupor, symmetrical tetra- paresis, and pacing.3, 8, 9, 10, 12, 45 Other neurologic signs such as severe behavior changes, head pressing, blindness, seizures, and coma tend to occur with advanced disease.3, 8, 9, 10, 12, 45
The only reliable means of establishing an antemortem diagnosis of pituitary macrotumor is diagnostic imagery (computed tomography or magnetic resonance imaging).2, 10, 23 Because approximately 15% to 20% of dogs with PDH and visible pituitary tumors (>3 mm) develop neuro- logic signs within the first year after diagnosis, diagnostic imaging is recommended as a predictor of which dogs are likely to develop prob- lems from an enlarging pituitary tumor and for dogs with PDH that develop CNS signs not attributable to a metabolic cause.2, 3, 9, 12
Treatment of pituitary tumors may be attempted with radiotherapy (cobalt irradiation), especially if the diagnosis can be made before pro- found neurologic signs develop. Dogs showing no or mild CNS signs (subtle behavior abnormalities) tend to have more complete and rapid
remission of neurologic signs.3, 9, 12, 29 Dogs showing more advanced neurologic signs such as stupor, head pressing, or coma often have minimal or no response to radiotherapy.9, 29 A study at The Animal Medical Center showed that the median survival time of dogs with pituitary macrotumors and severe neurologic signs was 50 days (range, 1 to 104 days), compared to a median survival time of 852 days (range, 145 to 1179 days) in dogs with minimal or no neurologic signs.30 Without treatment, most dogs with CNS signs develop progressive neurologic deterioration within weeks to months.3, 12
CONGESTIVE HEART FAILURE
Often, dogs with hyperadrenocorticism have compensated tricuspid or mitral valvular insufficiency. Although uncommon, volume overload from cortisol excess and pressure overload from systemic hypertension may cause cardiac decompensation and congestive heart failure. Treat- ment of hyperadrenocorticism is therefore recommended for dogs with compensated valvular heart disease.12 In dogs with congestive heart failure, improved response to cardiac drugs is observed with control of the hyperadrenocorticism.12
PULMONARY THROMBOEMBOLISM
Pulmonary thromboembolism (PTE) is a potentially serious and often deadly complication of hyperadrenocorticism.1, 4, 17, 25, 47, 48 Condi- tions that predispose to thrombosis and thromboembolism are vascular stasis or turbulence, vascular endothelial injury, and hypercoagu- lability.1, 25 Dogs with untreated hyperadrenocorticism have increased plasma concentrations of vitamin K-dependent factors (II, VII, IX, X) and platelet-derived factors V and vWF:Ag compared to normal dogs.36 Increased hepatic synthesis of vitamin K-dependent coagulation factors and platelet synthesis or release of factors V and vWF:Ag plays a major role in causing hypercoagulability in dogs with Cushing’s syndrome.36 Other conditions or disorders that predispose to thrombosis in humans and that are common to dogs with hyperadrenocorticism include in- creased hematocrit (vascular stasis), obesity, hypertension, acute pancre- atitis, protein-losing nephropathies, and diabetes mellitus.1, 12, 17, 25
No clinical signs are pathognomonic for PTE, although affected dogs usually develop an acute onset of respiratory distress (tachypnea, cyanosis, dyspnea).1, 4, 7, 12, 13, 49 Thoracic radiographs may be normal in dogs with PTE.2,7, 12, 13, 49 Usually, however, radiographic changes include pleural effusion, pulmonary infiltrates, increased diameter and blunting of pulmonary arteries, decreased vascularity of affected lung lobes, and increased vascularity of lobes without thrombosis.1, 4,7, 12, 13 Arterial blood
gas determinations usually reveal a decrease in PO2 below 70 mm Hg (normal 80 to 100 mm Hg) and a decrease in PCO2 in the range of 12 to 30 mm Hg (normal 35 to 45 mm Hg).1, 7, 12, 17 Thrombosis may be con- firmed with pulmonary angiography or a radionuclear lung scan.1, 12, 24
Because no pathognomonic signs exist for PTE and definitive diag- nostic tests are either invasive (pulmonary angiography) or not widely available (radionuclear scans) and, if performed, may actually jeopardize the life of the patient (removing dyspneic and cyanotic patients from oxygen support to perform diagnostic procedures is unwise), the diagno- sis of PTE is often made based on clinical impression. Dogs that have risk factors for PTE, a history of acute nonspecific cardiopulmonary signs, and supportive radiographs (although radiographs may reveal no abnormalities) and blood gas analysis have PTE until proven otherwise and should be treated aggressively.
Treatment of PTE in dogs with hyperadrenocorticism is based on clinical experience and extrapolation from human studies and includes cage rest, provision of oxygen and anticoagulants, and general support- ive care. Heparin is considered the mainstay of therapy for PTE. It is effective in preventing reembolization while allowing fibrinolysis to proceed. Treatment begins with an intravenous bolus of heparin (100 to 200 U/kg), usually followed by maintenance heparin (250 U/kg SC every 6 to 8 hours).1,7 Maintenance heparin should be titrated to achieve an activated partial thromboplastin time (APTT) or activated clotting time (ACT) of at least 1.5 times the control values.1,7, 14 The use of plasma to replenish antithrombin III is probably not necessary because recent studies suggest that the hypercoagulable state associated with hypera- drenocorticism is not related to antithrombin III deficiency.36 Recently, the thrombolytic agent streptokinase was used successfully in four dogs with PTE, with minimal side effects.44 Because of extreme expense and the increased risk of bleeding associated with thrombolytic agents (strep- tokinase and recombinant tissue plasminogen activator), thrombolytic therapy is usually reserved for massive PTE with cardiovascular compromise.1,7
Because the prognosis for PTE is guarded to grave, prophylactic low-dose heparin may be appropriate in dogs with Cushing’s disease that have increased risk of thrombosis. Low-dose heparin administration has been documented to provide efficacious and safe prophylaxis in human patients with low to moderate risk of deep vein thrombosis.1 This situation in dogs would include surgical patients with adrenocorti- cal tumors who are scheduled for adrenalectomy, because surgery and neoplasia are additional risk factors for PTE.12 The low-dose heparin regimen for dogs is 70 U/kg SC every 8 to 12 hours, starting before the surgical procedure and continuing until the day of hospital dismissal.1 Monitoring anticoagulation effects is not necessary because the low dose of heparin usually does not alter the APTT or ACT.1 Limited clinical experience in dogs suggests that low-dose heparin administration is safe; however, efficacy studies have not been performed.1
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Address reprint requests to Rhett Nichols, DVM Regional Director of Consulting Services Antech Diagnostics 10 Executive Boulevard Farmingdale, NY 11735