Ferret endocrine conditions (Proceedings)

Adrenal Gland Disease

Hyperadrenocorticism is a common and complex clinical condition in the pet ferret. This disease occurs most frequently in ferrets three years or older but has been reported in animals as young as one year. There is no obvious gender predisposition. The most common clinical sign of hyperadrenocorticism in ferrets is progressive alopecia of the tail, tail base and trunk, continuing until the affected ferret is partially or completely bald. Either gender can exhibit pruritis. Some ferrets exhibit a return to sexual behavior or emit a musky odor that is stronger than normal. Vulvar enlargement may be seen in spayed females. Male ferrets may present with a history of stranguria or urinary tract obstruction due to metaplastic, hyperplastic, or cystic prostatic tissue. Rarely, either gender can exhibit hyperpigmentation of the skin or anemia due to bone marrow toxicity from the associated hyperestrogenemia.

The hypothetical etiology of this disease involves early neutering and long light cycles to which pet ferrets are exposed in the United States. These factors may trigger a "perpetual breeding season" syndrome. Early neutering may remove negative feedback from the adrenal glands, which have the capacity to produce androgenic hormones. Long photoperiods may stimulate the production of gonadotropin-releasing hormone (Gn-RH) by the hypothalamus, which stimulates pituitary gland secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH). With lack of an LH surgery to decrease the production of gonadotropic hormones, subsequent constant stimulation of the adrenal gland may progress to the development of adrenal hyperplasia or neoplasia (adenoma or adenocarcinoma).

Presumptive diagnosis of adrenal disease in the ferret is based on history, clinical signs, imaging diagnostics, and/or steroid hormone assay. Surgical biopsy of the affected adrenal gland provides a definitive diagnosis. Adrenal enlargement can involve one or both glands. Experiences ultrasonographers can often detect adrenomegaly or abnormal adrenal structure. The adrenal glands can be measured at the time of ultrasound to determine if they are normal in size and shape. In addition, abdominal ultrasound may detect retained reproductive tissue (in females), prostatic enlargement (in males), or bladder abnormalities, which could be differential diagnoses for the clinical signs. On rare occasions, the adrenal glands of clinically affected ferrets may be normal in size and shape, especially early in the disease process. The ferret androgen panel includes validated assays for estradiol, androstenedione, and 17-hydroxyprogesterone. Most affected ferrets will have elevated blood level of one or more of these hormones.

Affected ferrets should have a thorough diagnostic workup because some of these animals have concurrent disease such as islet cell neoplasia and/or cardiac disease. In the majority of ferrets, results of a complete blood cell count and chemistry profile are within normal limits. Ferrets affected with adrenal disease can live with the hair loss. If the animal is not treated, however, the potential exists for urinary tract obstruction (in males), bone marrow suppression, tumor-related invasion of the vena cava, or metastasis.

Treatment options include surgical or medical therapy. Adrenalectomy (either unilateral or partially bilateral) is the treatment of choice because the affected tissue can be removed. Because of the intimate association of the right adrenal gland to the vena cava, a complete right adrenalectomy may not be possible.i If both glands are affected, then surgical therapy includes total resection of the largest gland and subtotal of the contralateral. Total bilateral adrenalectomy is not recommended because of the postoperative potential for hypoadrenocorticism to develop.

Research using cryosurgery has been reported, but no long term results have been published. Symptoms are often mitigated for some time after surgery, but clinical signs can recur. Clinical signs in treated patients usually resolve within two to four months of treatment.

Palliative medical treatment options currently being utilized include leuprolide acetate depot (Lupron Depot™, TAP Pharmaceuticals, Inc., Deerfield, IL), a synthetic, long-acting gonadotropin-releasing hormone (Gn-RH) analog.Leuprolide may also be useful for the treatment of prostatic hyperplasia, which often occurs in conjunction with the adrenal disease. Treatment with mitotane (Lysodren™ , Bristol-Myers Squibb Oncology, Princeton, N.J.) is effective in dogs for treatment of pituitary-dependent hyperadrenocorticism. This form of hyperadrenocorticism has not been recognized in ferrets and this treatment is rarely successful in ferrets. Destruction of the cortisol-producing cells can lead to clinical hypoglycemia if the ferret is subclinical for insulinoma.

Prostatomegaly Secondary to Adrenal Disease

Urethral obstruction is most commonly seen in male ferrets greater than two years of age. Urethral obstruction in the male ferret is often secondary to adrenal disease and androgenic stimulation of the periurethral prostatic tissue Enlargement of the periurethral prostatic tissue can lead to compression of the urethra and subsequent obstruction of urine flow Clinical signs of urethral obstruction may include stranguria, pollakiuria, alopecia and/or pruritis (secondary to adrenal disease), or anuria if the condition progresses to urethral obstructioniii. Physical examination may reveal a mass dorsal to the bladder, which is often the hypertrophied or cystic prostatic or periurethral tissueiii,iv.

Diagnostic testing for the ferret with suspected urethral obstruction should include a urinalysis, urine culture and sensitivity testing (collected by cystocentesis), and abdominal ultrasound to evaluate the urinary tract, paraurethral region, and adrenal glands If cystic areas are visible involving the prostatic tissue, a fine needle aspirate may be obtained of the fluid material via ultrasound guidance. A complete blood cell count and chemistry profile will provide important information to include blood urea nitrogen (BUN), creatinine (Cr) and phosphorus. Creatinine is a more sensitive indicator of renal function in the ferret than BUN and even a mild elevation in creatinine can be a concern.

Treatment of urethral obstruction involves alleviating the immediate obstruction and then treating and correcting the condition leading to the development of the obstructionUrethral catheterization can be performed in ferrets but can be quite difficult due to the small size and location of the urethral opening. The patient should be anesthetized using Isoflurane or other gas anesthesia. There are several options of materials to use for urethral catheterization in the ferret. A red rubber catheter (3.5 Fr), 20-22 gauge 8" jugular catheter, or a specialized ferret urethral catheter (Slippery Sam® , Cook Veterinary Products). A magnifying loupe will help to facilitate visualization of the urethral opening. The urethral opening in ferrets is several mm. proximal to the tip of the penis. Once the catheter is placed it can be sutured and a bandage should be placed around the abdomen to stabilize it. Ferrets are very adept at removing indwelling urinary catheters. A small neck collar may be necessary to prevent removal of the catheter by the ferret. The catheter may be difficult to pass if the prostate is compressing the urethra. In some of these cases, a cystotomy may be required and catheter placement can then be made through the abdominal wall.

If adrenal disease is diagnosed, medical therapy can be initiated. Leuprolide acetate for depot suspension (Lupron® , TAP Pharmaceuticals Inc., Lake Forest, IL) can be administered Because the effect of the leuprolide acetate treatment is not going to be immediate, the ferret will need to managed to alleviate the urethral obstruction. Surgical therapy is often required in cases of urethral obstruction. Prostatic marsupialization can be performed to alleviate the pressure on the urethra and allow drainage of the prostatic fluid directly out of the body through the surgically created stomav . In ferrets with adrenal enlargement, surgical resection or biopsy of the affected adrenal gland can be performed during the abdominal exploratory to address the prostatic enlargement. Recurrent obstruction due to cystic calculi or active urinary sediment may require a prescrotal urethrostomy. Urine production should be monitored and the urinary catheter should be maintained for at least 2-3 days after surgery to measure urine production. A broad-spectrum antibiotic should be started pending urine/prostatic fluid bacterial culture and sensitivity results.

Pancreatic Islet Cell Tumors (Insulinoma)

Hypoglycemia is a common clinical condition in pet ferrets in the United States. Pancreatic islet cell neoplasia (insulinoma) is the most frequent cause of hypoglycemia in the ferret Other differential diagnoses for hypoglycemia include sepsis, neoplasia, anorexia or starvation, hepatopathy or other metabolic disease.

Ferrets in the age range of two to seven years are most commonly affected. Hypoglycemia related to pancreatic islet cell neoplasia is not common in young ferrets under the age of two years. The initial clinical signs may develop gradually and may not be clinically obvious to the ferret owner. The history may include rear leg weakness, general musculoskeletal weakness, episodes of collapse with hypersalivation, depression, gagging, pawing at the mouth or seizures. Seizures related to hypoglycemia, although quite common in the canine patient, are rare in ferrets. Clinical signs are often intermittent in nature and may not be evident at the time of initial evaluation and physical examination.

A blood glucose level should be measured on any ferret over two years of age presenting to the hospital with the above-mentioned clinical signs. Rapid blood glucose analysis can be performed with either glucose measurement strips or a digital glucometer. It is helpful to also submit part of that same blood sample for evaluation by a clinical pathology laboratory for verification. The normal fasted blood glucose level in the ferret is between 65 mg/dL to 112 mg/dL. A blood glucose level less than 65 mg/dL with accompanying signalment and clinical signs is suggestive of insulinoma. Ferrets with a blood glucose level less than 40 mg/dL may present lethargic, collapsed or comatose. Other blood parameters indicative of insulinoma include an elevated serum insulin concentration (using an assay that has been validated for ferrets) concurrent with hypoglycemia. The reference range for serum insulin concentrations in normal ferrets is 5- 35 µU/mL (36-251 pmol/L). In the past, the insulin/glucose, glucose/insulin, and amended insulin/glucose ratios were sometimes used for diagnosis. These ratios, however, are not specific and have a high incidence of false-positive results. The use of these tests is no longer recommended. A definitive diagnosis of insulinoma can only be obtained from histopathological analysis of a surgical pancreatic biopsyv

In cases of hypoglycemic collapse, administer a slow intravenous (IV) bolus of diluted 50% dextrose (0.5 to 2 mL, diluted) to response. The immediate goal of treatment is stabilization and not the complete reversal of the hypoglycemia. Administration of the IV dextrose too rapidly has the potential to stimulate the pancreatic tumor to release large amounts of insulin, resulting in rebound hypoglycemia. After initial stabilization, an intravenous catheter should be placed for fluid support. A constant rate infusion of fluids supplemented with 2.5-5% dextrose should be started. Diazepam can be administered for control of seizures if necessary. Prednisone at a dose of 0.5 to 2 mg/kg PO every 12 hours should be started. The prednisone acts to inhibit peripheral tissue uptake of glucose and stimulate gluconeogenesis . It is best to start with the lowest dose possible to maintain adequate blood glucose level above 70 mg/dL. The dextrose supplementation in the fluids can be adjusted based on regular blood glucose monitoring during hospitalization.

Diazoxide (Proglycem® ) is a medication that can also be utilized to treat hypoglycemia secondary to insulin oversecretion. Diazoxide exhibits hyperglycemic activity by directly inhibiting pancreatic insulin secretion. This action may be a result of the drug's capability to decrease the intracellular release of ionized calcium, thereby preventing the release of insulin from the insulin granules. Diazoxide also enhances hyperglycemia by stimulating the beta-adrenergic system, stimulating epinephrine release and inhibiting the uptake of glucose by cells. Diazoxide can be administered to ferrets orally at a dose of 5 to 30 mg/kg PO every 12 hours2 . Once clinical signs have resolved, the IV dextrose supplementation can be gradually discontinued. Blood glucose level will need to be monitored after cessation of dextrose supplementation. It is best to keep the ferret hospitalized, if possible, for glucose monitoring at least 24 hours after discontinuation of fluid support. Often, the prednisone dose can be lowered with concurrent administration of diazoxide. Nutritional management is important and should include a high-protein, meat-based ferret or feline diet. Foods high in sugar or carbohydrate content (including treat foods such as raisins) should be avoided. The intake of sugar or carbohydrate based food items could cause an exacerbation of clinical signs by initially causing an increase in blood glucose level and subsequent rebound hypoglycemia.

A small number of ferret patients with seizure activity may be refractory to medical treatment alone. Ferrets unable to maintain normal blood glucose level once dextrose supplementation is discontinued may require surgical intervention. These ferrets, once stabilized, may require surgical debulking of the pancreatic tumors. Debulking may assist with management of this disease, but is not curative. Many ferrets, however, may not have visible pancreatic nodules. There is potential for microscopic disease in the pancreatic tissue. The average life expectancy with medical and/or surgical therapy after the development of persistent hypoglycemia is approximately 8-12 months. Post-surgical follow-up for these patients should include checking the blood glucose concentration 7-14 days after surgery and every 2-3 months thereafter. Recheck measurement of the serum insulin concentration can also be helpful, if pre-surgical levels were obtained.

Diabetes Mellitus

Diabetes mellitus is uncommon in the ferret patient. Iatragenic diabetes can develop secondary to aggressive pancreatectomy to debulk beta cell tumor nodules. Clinical signs of this disease in ferrets is similar to other mammals. Diagnosis is usually made through evaluation of serial blood glucose concentrations. Treatment can include insulin therapy if the blood glucose concentration is higher than 300 mg/dL on repeated measurements. Neutral protamine Hagedorn insulin is recommended in ferrets. Dosage information can be found in the literature.

Pheochromocytomas

Pheochromocytomas originate from the adrenal medulla and produce excessive amounts of catecholamines. These tumors rarely occur in ferrets. Clinical signs in ferrets with this disease would be similar to other mammals and could include tachycardia, dyspnea, and cardiovascular collapse. These symptoms are the effect of the catecholamines produced by the tumor on the cardiovascular system. Surgical excision is the treatment of choice and the prognosis is poor in ferrets with pheochromoctyomas.

Thyroid Disease

Clinical hypothyroidism or hyperthyroidism have not been described in ferrets.