Ferret insulinoma: State of the union (Proceedings)

Pancreatic islet beta cell tumors, more commonly known as insulinomas, have been well recognized and well documented in ferrets over the last 20 years. Insulinoma nodules within the pancreas secrete high levels of insulin and cause hypoglycemia. Clinical signs include lethargy, weight loss, weakness, ptyalism, bruxism, seizures, and death. Treatment modalities include medical therapy, chemotherapy, surgery, and dietary changes. The underlying etiology of insulinoma is unknown, however a nutritional hypothesis has recently been offered along with a prevention strategy based upon feeding a more natural, archetypal diet.

Epidemiology

Insulinoma is by far the most common neoplasm in middle-aged to older ferrets, with a reported incidence of 21.7% to 25% of neoplasms diagnosed. Most ferrets begin exhibiting clinical signs around 4-6 years of age, although it has been reported in ferrets as young as 2 weeks of age. It is likely that islet cell tumors exist subclinically for months or years before symptoms occur.

Insulinomas appear to occur regionally; most have been reported in North America, where the majority of ferrets are fed dry kibble, and many are fed treats that contain sugar. Insulinomas are uncommon in Europe, New Zealand and Australia, where ferrets are fed a low-carbohydrate diet of meat scraps, poultry scraps, and/or fish scraps, and sugary treats are generally not provided. The typical ferret diet in the US contains 22-42% protein, 15-28% fat, 10-45% carbohydrate, and 1.5-3.5% fiber. Such high levels of carbohydrate are unnatural and may have negative consequences for the ferret. Finkler hypothesizes that excessive carbohydrate intake stimulates excessive insulin production by the pancreas and results in compensatory hyperplasia. He postulates that lifelong stimulation of pancreatic beta cells leads to a hyperinsulinemic "preinsulinoma" state and eventually to the development of beta cell neoplasia.

Domestic pet ferrets in the U.S. are supplied by a small number of breeders, thus limiting their genetic diversity, and suggesting that the development of insulinomas may have a genetic component. Finally, it is thought that keeping ferrets indoors the U.S. (versus outdoors in other countries) may contribute to the propensity of endocrinopathies in ferrets in the United States.

Pathophysiology

The pancreas plays a major role in glucose, lipid, and protein metabolism through the balance of its two major hormones, insulin and glucagon. Insulin, a polypeptide produced by beta islet cells, is released when levels of glucose, amino acids, and free fatty acids are increased in the blood. In the case of a sudden increase in the blood glucose level, the plasma insulin level can increase almost 10 fold within minutes. Insulin then causes a rapid uptake of glucose into peripheral tissues and promotes the storage of glucose in the muscle and liver. Additionally, insulin inhibits hepatic gluconeogenesis and glycogenolysis, and promotes the conversion of excess glucose into fatty acids. The net effect of all these processes is a decrease in blood glucose levels. Glucagon is secreted by alpha cells in response to decreasing glucose levels and is involved in effects that are exactly opposite to those of insulin, namely, an increase in the blood glucose level.

Insulinomas produce their effects through the overproduction of insulin. Theses tumors secrete insulin indiscriminately and are not responsive to inhibitory stimuli such as hypoglycemia or hyperinsulinemia. Additionally, a rapidly increasing blood glucose level, even in the presence of a low blood glucose concentration, can stimulate excessive insulin release from these tumors, causing a profound rebound hypoglycemia. Although local tumor recurrence is common, metastasis to other organs is not. This finding is in contrast to insulinomas found in dogs, which are usually malignant and metastatic. When insulinoma metastasis does occur in a ferret, the regional lymph nodes, liver and spleen are the organs most commonly involved.

Clinical signs

Onset of symptoms may be gradual or sudden. Appetite may be normal or decreased, and weight loss may be noted. Advanced insulinomas result in hypoglycemia, causing weakness, anorexia, lethargy, stupor, and seizures. Owners may report that the ferret's eyes appear "glazed" during episodes. Hypersalivation and pawing at the mouth (presumably due to nausea, numbness, or tingling) also occur. Owners may present the ferret with concern that the patient has swallowed something noxious or has something stuck in its mouth. Affected ferrets may present with hind limb paresis or ataxia, as if nerve damage has occurred. Corticosteroid injection, which raises blood glucose levels, may improve symptoms, leading the practitioner to believe the problem is spinal trauma or disk disease when, in fact, hind limb paresis in the ferret is a nonspecific indication of weakness.

Diagnosis

In patients were insulinoma is suspected but blood glucose is within normal limits (80-120 mg/dL), a carefully monitored 3- to 4-hour fast may be required to confirm hypoglycemia. A presumptive diagnosis is made when ferrets demonstrate a fasting blood glucose of less than 60 mg/dL in the presence of clinical signs of insulinoma, and these signs cease after a feeding or intravenous administration of glucose (Whipple's triad).

Although a fasting blood glucose of less than 60 to 70 mg/dL is suggestive of an insulinoma, other causes of hypoglycemia, such as sepsis, starvation, hepatic disease, and lab artifact, should be ruled out. Immediate evaluation of freshly drawn blood provides a quick relative assessment of blood glucose status. Glucose levels will artifactually decrease by approximately 7% per hour at room temperature due to red cell metabolism if red cells are left in contact with serum or plasma. Additionally, handheld glucometers intended for use in humans give readings 10-20 mg/dL lower than blood chemistry analyzers designed for use in companion animals.

Plasma or serum obtained during periods of hypoglycemia can also be submitted for insulin level. Normal insulin level for ferrets is 4.88-34.84 µU/ml (35-250 pmol/L). Elevated insulin level with concurrent hypoglycemia is consistent with hyperinsulinism and supports the diagnosis of insulinoma. However, a low or normal insulin level does not necessarily rule out the presence of insulinoma, and could indicate erratic insulin production.

Various insulin-to-glucose ratios have been used in the past to diagnose the presence of insulinoma, but their use is no longer recommended due to the high incidence of false-positive results. Fructosamine and glycosylated hemoglobin (GHb) have not been validated in ferrets yet. Other blood tests are usually unremarkable, but may indicate concurrent disease. Likewise, radiographs and ultrasound are usually unremarkable due to the small size of tumors.

Histopathology acquired through surgical biopsy is required for definitive diagnosis. Tumors may be described as hyperplasia, adenomas, or carcinomas, and a specific tumor may have a combination of any of these processes. Immunohistochemistry has been used to further characterize pancreatic islet cell tumors and their metastasis in distant organs.

Treatment

Surgery

Surgical resection of pancreatic nodules or partial pancreatectomy is considered the treatment of choice for greater clinical resolution and longer survival times. An intravenous catheter should be placed prior to surgery, and 5% dextrose should be administered perioperatively to prevent a hypoglycemic crisis. Careful visualization with gentle palpation of the pancreas is performed to locate pancreatic nodules. These may be removed individually or, in the case of multiple nodules, a partial pancreatectomy can be performed. In one study, ferrets with partial pancreatectomy had longer survival times than those with nodulectomies. This is probably because microscopic tumors can be missed through nodulectomy alone. A full abdominal exploratory is recommended to evaluate for potential metastasis and concurrent conditions (e.g. adrenal disease). Biopsies of suspicious tissues should be collected for histologic evaluation.

The goal of surgery is to have patients normoglycemic following surgery, however some may remain hypoglycemic and many will have a recurrence of clinical signs within several months because of tumor metastasis. Case studies have demonstrated that as many as 52% of ferrets remain hypoglycemic following surgery, and reported disease-free intervals range from 0 to 23.5 months. Because of likely recurrence, owners should be advised that surgery is not curative but rather it may temporarily stop or slow the progression of disease and provide a longer disease-free interval than medical therapy alone. In one study, nodulectomy combined with partial pancreatectomy had a significantly longer median survival time (668 days), compared with nodulectomy alone (456 days) or medical treatment only (186 days).

Although some patients may need continued medical management of hypoglycemia postoperatively, clinical signs can usually be controlled on lower doses of medication than before surgery. In some patients, iatrogenic hyperglycemia may be exhibited after partial pancreatectomy, but this is usually transient and resolves within a few weeks without major treatment.

Symptomatic therapy

Glucocorticoids increase blood glucose levels by inhibiting cellular uptake, promoting hepatic gluconeogenesis, and inhibiting insulin binding to insulin receptors. Prednisolone (Pediapred Liquid) 0.5-2 mg/kg q 12 hr PO can usually control mild to moderate clinical signs. Begin at lowest dosage and gradually increase as needed to control symptoms. Blood glucose is rechecked at regular intervals and the dose is adjusted as needed to achieve normoglycemia. Although ferrets appear to be relatively resistant to the immunosuppressive effects of prednisolone, long-term administration can result in abdominal weight gain and slow regrowth of hair in shaved areas.

Diazoxide, an insulin inhibitor, is added to the protocol when clinical signs cannot be controlled with prednisone alone. At the same time, the dosage of prednisone may be lowered. Diazoxide (Proglycem liquid) directly inhibits pancreatic insulin secretion, and stimulates the release of epinephrine, which, in turn, promotes hepatic gluconeogenesis and glycogenolysis, and decreases cellular insulin uptake. Begin diazoxide at 5-10 mg/kg q 12 hr PO; the dose can be increased gradually to 30 mg/kg q 12 hr if lower doses are inadequate.

Decreases in blood glucose in the ferret often lead to increases histamine release and stomach acid production. Famotidine (2.5 mg/kg PO q 24 hr) will help to alleviate the pain, nausea and inappetence associated with insulinoma (Johnson-Delaney). Note: this dose is 5-10X higher than commonly published elsewhere.

Chemotherapy

Doxorubicin chemotherapy for insulinoma has direct toxic effects on pancreatic beta cells. Pre-treatment workup should include CBC, blood chemistry, ECG, and chest radiographs. The patient is pretreated with diphenhydramine 5 mg IM, and doxorubicin is infused at 30 mg/m2 (approximately 1 mg/kg) IV. The regimen is repeated q 3 weeks for 4 doses. The drug has to be infused slowly IV, and reported side-effects include bone marrow suppression, gastroenteritis, nephrotoxicity, and cardiac toxicity. The recommended cumulative dose for doxorubicin is less than 240 mg/m2.

Diet modification

Dietary changes are equally important in the management of insulinomas in ferrets. Owners should discontinue all high-sugar treats such as raisins, yogurt drops, peanut butter, or corn syrup-based supplements (i.e. Nutrical). The rapid increase in blood glucose from the ingestion of these simple sugars can induce a rebound insulin release and trigger a hypoglycemic episode. Changing the diet to a high-protein, low-carbohydrate diet is recommended, however the owner needs to be certain the ferret accepts the new diet; ferrets tend to be picky about new food items and may experience hypoglycemia from inadequate food intake. Food should be available at all times; it may need to be placed in multiple areas to ensure easy access. Offering food to ferrets (and hand feeding them, when necessary) every 4 hours, especially right before playing, will help to prevent hypoglycemic episodes.

Management of a hypoglycemic episode

If clinical signs are noted, the ferret should immediately be fed a high-protein, easily digestible diet (Oxbow Carnivore Care) to abate symptoms. If the ferret presents comatose or exhibiting seizures, corn syrup or sugar solution can be applied to the oral mucous membranes to provide temporary relief. Blood glucose level should be quickly assessed for hypoglycemia, and an intravenous catheter should be placed immediately for a slow bolus of 50% dextrose (0.25-2 mL), titrated to effect. Once seizures have ceased, the patient should be placed on maintenance fluids with 5% dextrose. If the ferret continues to seizure despite IV glucose, diazepam (1 mg/kg IV) may be required to stop the seizures.

Prevention

Ferrets are obligate carnivores. A growing number of experts are recommending that ferrets be fed a diet that more closely mimics natural diet: raw meat and bone. Finkler advocates a nutritional approach to insulinoma prevention, and recommends a diet low in carbohydrates, and high in fat and protein. Simple sugars should be completely avoided. He recommends a diet containing 42-55% protein, 18-30% fat, only 8-15% carbohydrates, and 1-3% fiber.

Wild polecats consume whole, small prey such as rodents, lagomorphs, and birds. Their natural diet is high in proteins and fat and low in carbohydrates and fiber. Some advocate the feeding of prey items such as mice and chicks. The nutrient analysis of a rat carcass, for example, is 55% protein, 38.1% fat, 1.2% carbohydrate, and 0.55% fiber. Commercially available archetypal diets that have been designed to mimic the nutrient profile of whole prey include Ferret Archetypal (Wysong), Natural Gold (Pretty Pets), and Evo Ferret Diet (Innova). Ancestral diets may some day be found to aid in insulinoma prevention.

References

Quesenberry K, Carpenter J. Ferrets, Rabbits, and Rodents: Clinical Medicine and Surgery, 2nd Ed. St. Louis: Saunders, 2004.

Rosenthal, KL. Basic Ferret Husbandry and Medicine, North Carolina Veterinary Conference Proceedings 2000: 363-366

Oglesbee, BL. The 5-Minute Veterinary Consult: Ferret and Rabbit, Ames, Iowa: Blackwell Publishing, 2006.

Lewington JH, ed. Ferret Husbandry, Medicine and Surgery, 2nd Ed. Philadelphia: Saunders, 2007.

Church RR. Ferret nutrition and dental disease. Proceedings of the North American Veterinary Conference 2007; 20:1633-1635.

Finkler MR. A nutritional approach to the prevention of insulinomas in the pet ferret, Journal of Exotic Mammal Medicine and Surgery 2004; 2(2): 1-4,15.

Dutton MA. Case studies on doxorubicin for the treatment of ferret insulinoma (12 cases). Journal of Exotic Mammal Medicine and Surgery 2004; 2(1):1-7

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Johnson-Delaney C. Endocrine system and diseases of exotic companion mammals, Proceedings of the ABVP Practitioner's Symposium 2009 (available on www.VIN.com ).