Pancreatic Beta Cell Tumors in the Ferret

Understanding insulinoma in the ferret

Pancreatic beta cell tumor or insulinoma is among the most commonly diagnosed neoplasms of ferrets.^2,13,23  This condition is frequently seen in middle-aged to older pet ferrets (mean age 5 years, range 2-7 yrs) in the United States, Japan, Italy, and the Netherlands. ^{1,2,5,10,19,25} This condition is also sporadically reported in the United Kingdom and Australia.² Gender predilections are not obvious clinically ²³, however three case series have reported that males are more commonly affected.^5,10,13,26

Presentation

Affected ferrets can exhibit intermittent, acute onset episodes of hypoglycemia or clinical signs can develop slowly and insidiously. Signs are often exacerbated by exercise or fasting.¹⁷ Signs of hypoglycemia frequently include altered mentation, a dazed or glazed appearance in the eyes (star gazing), posterior paresis and ataxia, as well as ptyalism or copious drooling, pawing at the mouth (sometimes to the point of facial excoriation), and vomiting (Fig 1 and Fig 2).²² If hypoglycemia becomes severe enough the ferret may collapse or exhibit seizure activity.

 

 

Clinical signs of insulinoma in the ferret can include

• Altered mentation
• Star gazing
• Rear limb weakness and ataxia
• Ptyalism
• Pawing at the mouth
• Weight loss
• Collapse
• Seizures
• Coma

Until proven otherwise, a ferret with persistent hypoglycemia almost invariably has insulinoma.  Other, less frequent causes of hypoglycemia in the ferret include severe liver disease, neoplasia, sepsis, malnutrition or starvation, and heatstroke.²³

 

 

Urgent care tips

Diagnosis of insulinoma generally relies on history, clinical findings, and persistent hypoglycemia.²²

• Normal fasting blood glucose levels range from 80 to 120 mg/dL.
• Fasting blood glucose less than 90 mg/dL is suspicious for insulinoma.
• Blood glucose less than 70 mg/dL is strongly suggestive.

If insulinoma is suspected, it is not necessary to fast the ferret. If fasting is performed, do so for no more than 2 to 4 hours and carefully monitor the patient during this time.¹⁶

It should be noted that portable blood glucose meters designed for humans significantly underestimate blood glucose (by approximately 30 mg/dL) in ferrets as compared to laboratory analyzers.²⁰ Knowing this, veterinarians can avoid treating potentially normoglycemic ferrets presumptively for insulinoma without further workup. Portable blood glucose meters designed for veterinary use (AlphaTrak Abbott Laboratories, Abbott Park, IL) have much better agreement with laboratory analyzers.²⁰ Ideally, diagnosis of hypoglycemia would be made with a point of care chemistry analyzer using a hexokinase method (VetScan, Abaxis, Union City, CA).²⁰

Mild to moderate hypoglycemic episodes

These patients can often be managed on an outpatient basis. If the ferret is alert enough to swallow, feed an easily digestible, animal protein-based food source, such as EmerAid Intensive Care Carnivore ²⁰, chicken baby food, Hill’s prescription diet a/d, or Iam’s Maximum-Calorie Plus.

Severe hypoglycemic episodes

Hypoglycemia that does not improve following feeding or hypoglycemic episodes that involve collapse and/or seizures are considered severe. Advise clients over the phone to put Nutri-Cal (Vetoquinol, USA), dextrose, corn syrup, or honey on the gums of any collapsed or seizing ferret as hypoglycemia is the most common cause of seizures in this species.^8,23 Carbohydrates alone will cause further insulin release, and should be followed by a high-protein meal if the ferret becomes alert and responsive. All ferrets experiencing these clinical signs should be seen emergently, although it is preferable to control seizures with buccal application of sugar solutions prior to transport.⁸

If the ferret is still recumbent or seizing when it arrives at the hospital, place an intravenous (IV) catheter in the cephalic vein preferably, although the saphenous and jugular veins work as well.⁷ A blood glucose level can be acquired using the blood from the catheter with a portable veterinary blood glucometer (AlphaTrak Abbott Laboratories, Abbott Park, IL). Administer 0.25-0.5 ml (2-3 ml, if seizing) of 50% dextrose slow bolus IV over at least 10 to 15 minutes.^8,21 Dilute 50% dextrose in a 1:1 concentration with saline or sterile water. Some clinicians will also give dexamethasone sodium phosphate (0.1mg/kg IV) to promote cellular uptake of glucose.⁸ This dextrose bolus can be given until effect. When the ferret becomes alert and responsive, it can then be given a high protein meal. After profound hypoglycemia, even patients that eat a high protein meal may require a constant rate infusion (CRI) of 2.5-5% dextrose.

CAUTION: If IV dextrose is administered too rapidly, the functional beta cell tumor will be stimulated to secrete more insulin. This can lead to an ever-worsening cycle of hypoglycemia, dextrose administration, and subsequent insulin secretion.²¹ Additionally, when a ferret with insulinoma is maintained on intravenous fluids, it is essential that infusion truly be continuous. Starting and stopping fluids containing dextrose will only stimulate insulin secretion and potentially worsen the patient’s condition.²¹

In rare instances, anticonvulsants may also be indicated in seizing ferrets that do not respond to dextrose infusion alone. Diazepam (0.5-1.0 mg/kg) or midazolam (0.25-0.5 mg/kg) can be given rectally or IV.¹⁴ If IV or intraosseous access is not readily available, intranasal or intramuscular midazolam can be administered.⁶ Double the dose for rectal or nasal administration.¹⁴

Although unlikely to be available in most hospitals, a glucagon CRI (15 ng/kg/min) was used to successfully control clinical signs prior to surgery in a single case report of a ferret with insulinoma refractory to glucocorticoid therapy.⁴

 

 

Diagnosis

Case management

If insulinoma is suspected, provide frequent breaks during diagnostic and therapeutic procedures. Feed an easily digestible, highly palatable animal protein source, such as EmerAid Carnivore or chicken baby food, during breaks. Close, careful monitoring is also required since changes in clinical status can occur quickly.

Diagnosis of insulinoma generally relies on history, clinical findings, and persistent symptomatic hypoglycemia that resolves with the administration of glucose. One of the most important historical questions to ask the owner is whether the signs wax and wane with the provision of food.²²

Physical examination

Physical examination is often unremarkable except for evidence of generalized weakness such as posterior paresis, ataxia, or collapse, and possible weight loss (Fig 3). Signs of concurrent illness are common in middle-aged to older ferrets, particularly signs of adrenocortical disease.

 

Labwork

The hallmark of insulinoma is persistent hypoglycemia. Blood glucose concentrations lower than 60 mg/dL (<3.3 mmol/L), after withholding food for 4 hours, are highly suggestive of an insulinoma.²² Other causes of hypoglycemia, such as liver disease or sepsis, should be ruled out.² The remainder of the biochemistry panel is usually normal in ferrets with insulinoma. Liver enzyme elevation can occur with secondary hepatic lipidosis, or much less commonly, metastasis of the beta cell tumor to the liver.¹⁶

Unlike pancreatic beta cell tumors in the dog, measurement of insulin levels or insulin to glucose ratios is rarely necessary or particularly helpful in the ferret.

Imaging

Survey whole body radiographs are usually unremarkable, although incidental splenomegaly can be observed.

Abdominal ultrasound can be a useful, if not particularly sensitive, method of identifying pancreatic nodules in ferrets. In one study of histology-confirmed pancreatic islet cell tumors, abdominal ultrasound detected pancreatic nodules in 22% of ferrets.⁵ These nodules are typically hypoechoic and are evenly distributed between right and left lobes of the liver.²⁷ Although sensitivity in detecting pancreatic nodules is suboptimal, abdominal ultrasound is still recommended prior to surgery to assess for metastasis (uncommon) or concurrent disease (very common) that may also warrant surgery, such as adrenocortical disease.

 

 

Treatment

Management often relies upon a combination of medical and surgical treatment.

Surgery

Although only a palliative measure, surgical removal of nodules or portions of the pancreas is the long-term treatment of choice.¹⁶  Surgery offers the possibility of a disease-free interval or cessation of clinical signs while medical management does not. In one study, the left lobe was most commonly affected ^5,26, however disseminated lesions are also common.¹³ To remove as much undetectable islet cell tumor as possible and increase post-operative disease-free time to 1 year, a partial pancreatectomy has been recommended over pancreatic nodulectomy.^23,26 Recurrence of clinical signs is typically due to the development of new insulinomas in the ferret and not by metastases of the original tumor.²³ Detailed descriptions of surgical procedures can be found elsewhere.^3,15 Fewer complications are usually noted when compared to dogs, although case reports of post-surgical pancreatitis exist.^5,25 If too much of the pancreas is removed via partial pancreatectomy, diabetes mellitus can also occur.²³

Histologic examination of pancreatic islet lesions are classified as hyperplasia, adenoma, and adenocarcinoma.^2,5,13,23 Most insulinomas are well circumscribed, but infiltration into surrounding tissues can occur.²³

The stress of surgery can often trigger recrudescent Helicobacter mustelae infection. These clinical signs include anorexia, melena as well as ptyalism and pawing at the face as seen with insulinomas. It is often prudent to treat these patients prophylactically using gastroprotectants, such as sucralfate.¹²

Medical management

The goal of medical management is not euglycemia, but rather control of clinical signs of hypoglycemia.²² Prednisone or prednisolone and diazoxide are most commonly used for management of insulinoma.²²²

• Administer prednisone or prednisolone solution or syrup  at 0.5-2.0 mg/kg PO q12 to 24 hours. Begin at the low end of the dose range and gradually increase the amount of prednisone/prednisolone given based on the clinical response. Select an alcohol-free formulation since alcohol lowers blood glucose and is poorly tolerated by ferrets. Ferrets are fortunate in that they are fairly refractory to developing side effects caused by glucocorticoids, however, excessive abdominal weight gain and a thinning haircoat has been reported in ferrets that have received glucocorticoids for prolonged periods of time.⁷
• Administer diazoxide (Proglycem, Schering) at 5 mg/kg PO q12 initially. Diazoxide is generally well tolerated in ferrets, compared to dogs, and doses can increase to more than 15 to 20 mg/kg.²³ If diazoxide is used in conjunction with oral prednisone/prednisolone, then the corticosteroid dose should be started at the low end of the dose range. After which the patient’s blood glucose level should be regularly monitored to modify the dosages of both diazoxide and prednisone/prednisolone. Diazoxide is generally not used in emergency situations unless the ferret continues to be unresponsive to treatment since adverse effects can include nausea and vomiting.
• Somatostatins or octreotide, a synthetic long-acting analogue of somatostatin, have shown only equivocal efficacy and are therefore not recommended.²²
• If the ferret continues to suffer from persistent and severe hypoglycemia, then constant rate infusion of glucagon may prove helpful (see Urgent Care above).¹⁰
• Chemotherapy is rarely reported, however the use of doxorubicin in 12 ferrets with suspected insulinoma was associated with clinical improvement in eight animals.^9,13
• The tyrosine kinase inhibitor, toceranib phosphate (Palladia; Zoetis) may hold promise in the future. Toceranib appeared to provide a clinical benefit in dogs diagnosed with insulinoma and other solid tumors, including one dog with metastatic insulinoma.^11,18,24

Some ferrets with severe signs of insulinoma will not respond to medical management and will require surgical debulkment of the pancreas for clinical signs to resolve. Preoperatively, these patients should be maintained on a 2.5-5% dextrose CRI. After surgery, ferrets may have a transient hyperglycemia, be normoglycemic, and in some cases remain hypoglycemic if not all insulinomas were removed.

Client education

Client education is crucial for owners of affected ferrets. Teach owners to recognize signs of hypoglycemia and to prevent hypoglycemic episodes from occurring. Owners (and clinicians) should recognize situations that can precipitate a hypoglycemic crisis, such as stress, travel, and exercise. Minimize stressors whenever possible and ensure that the ferret eats after any stressful event. Other important preventive measures include feeding high-protein, meat-based foods frequently, having food sources accessible at all times, and avoiding foods and treats containing simple sugars and carbohydrates.

Download LafeberVet’s client education handout “Insulinoma in the Ferret” for assistance.

 

 

Prognosis

Survival times vary widely, but a longer duration of clinical signs prior to diagnosis is a negative prognostic indicator.^10,22 Medical management alone may be effective in controlling signs for 6 months to 1.5 years, although shorter survival times are often seen.²² Surgical and medical therapy combined seem to result in longer median survival times when compared with medical management alone.²² There is no cure for insulinoma. Eventually the disease will progress to a point where clinical signs cannot be controlled, and euthanasia will be needed to address quality of life issues.

 

 

References