Logical approach to diagnosis and management of hypoglycemia (Proceedings)

In the normal dog fasting does not usually result in hypoglycemia. Therefore a serum glucose concentration < 60 mg/dl is almost always due to either organic disease or to laboratory error. In an animal with normal glucose homeostasis, insulin secretion is stimulated when the blood glucose is > 110 mg/dl; insulin secretion is depressed and secretion of hormones that oppose insulin (epinephrine, glucagon, cortisol, growth hormone) is stimulated when the blood glucose falls below < 60 mg/dl.

Insulin acts by decreasing the rate of glycogenolysis and gluconeogenesis by the liver and increasing the rate of uptake of glucose by insulin sensitive tissues. In the presence of an insulinoma, neoplastic pancreatic ß cells continue to release insulin despite the presence of hypoglycemia. Clinical signs are dependent on the degree of hypoglycemia and the rate at which it develops.

Effect of hypoglycemia on CNS

Glucose entrance into neurons is not insulin dependent (apart from the satiety and appetite centers in the hypothalamus). Decreased neuronal glucose concentrations causes inadequate ATP concentrations within the cell, resulting in increased vascular permeability, vasospasm, vascular dilatation and edema. This causes neuronal death from anoxia. Histopathologic changes are most marked in the cerebral cortex, basal ganglion, hippocampus, and vasomotor cortex.

Differential diagnosis hypoglycemia

A wide range of disorders may result in hypoglycemia. The mechanisms causing hypoglycemia in these disorders is diverse, and may influence approach to treatment. Differential diagnosis of hypoglycemia in dogs and cats is shown in the table below.

Diagnosis hypoglycemia

Diagnostic tests that are indicated to determine the cause of hypoglycemia include review of sample handling, and if necessary a repeat measurement to confirm the finding. A CBC is useful to evaluate for the presence of polycythemia, or leukocytosis, and may reflect evidence of sepsis. A serum biochemical panel may exhibit abnormalities consistent with hepatic disease or hypoadrenocorticism. Abdominal and thoracic radiographs may give support for neoplastic disease, while abdominal ultrasound is a useful screen for hepatic disease and smooth muscle tumors. Unfortunately insulinomas are only detected via ultrasound in approximately 35% of dogs. Liver failure is evaluated by a liver function test such as measurement of bile acids, and hypoadrenocorticism is confirmed by a lack of an adequate cortisol response to ACTH administration. Diagnosis of insulinoma relies on paired measurement of serum insulin and glucose concentrations (see below).

Emergency treatment hypoglycemia

Emergency management of hypoglycemia in the hospital setting relies predominantly on the intravenous administration of dextrose either as a bolus or constant rate infusion. A constant rate infusion of glucagon has also been shown to be useful in the emergency management of dogs with insulin-induced hypoglycemia. The appropriate starting dose for glucagon is 5-10 ng/kg/minute. This is particularly effective in dogs with iatrogenic insulin overdose and in dogs with insulinoma.

Insulinoma

Insulinomas are most common in middle-aged to older dogs. They have also been reported in aged cats. There is no sex predilection and a wide variety of breeds are affected. The clinical signs are typically episodic, since the effects of insulin on blood glucose are partially opposed by the action of diabetogenic hormones such as glucagon, cortisol, epinephrine and growth hormone. Clinical signs are often precipitated by fasting, eating, exercise, or excitement, and include seizures, ataxia, weakness, collapse, muscle fasciculations, bizarre behavior, depression, nervousness, polyphagia and weight gain. Blood work is usually normal apart from hypoglycemia and increases in hepatic enzymes, which may be indicative of hepatic metastasis. The diagnosis relies on the measurement of normal or high serum insulin in the presence of a blood glucose concentration less than 60 mg/dl (Normal 5 - 20 IU/ml). If the serum insulin is below detectable limits when the dog is hypoglycemic, the presence of an insulinoma is unlikely. If a borderline result is obtained a repeat measurement should be made. A number of ratios have been utilized to aid in the diagnosis of an insulinoma (eg. Insulin:glucose ratio, amended insulin:glucose ratio). The most commonly utilized index is the amended insulin;glucose ratio which is calculated by the following equation:

Amended insulin:glucose ratio = plasma.insulin(µU/ml)/(plasma glucose (mg/dl) -30)x 100

The use of any insulin:glucose ratio is no longer recommended however, because of a lack of specificity. In the case of non-diagnostic results, detection of an insulin peak is more likely if at least four glucose and insulin measurements are made during a 24-hour period.

Other provocative tests for diagnosis of insulinoma in dogs have also been evaluated (e.g. glucagon, glucose, tolbutamide tolerance tests; epinephrine stimulation test). Unfortunately these tests are no more sensitive for making a diagnosis than concurrent measurement of insulin and glucose, and may potentiate hypoglycemia. Ultrasound may be useful in identifying the presence of a pancreatic mass; however the sensitivity of ultrasound for diagnosis of insulinoma is only about 35% because tumors are often small or even microscopic. For this reason a normal ultrasound examination does not rule out insulinoma. Presurgical or intraoperative localization of insulinomas is important for effective surgical treatment. Because of their small size, insulinomas may be difficult to identify grossly or by palpation at surgery. The right and left lobes are involved with equal frequency and occult insulinomas are most common in the pancreatic body, therefore random partial pancreatectomy is controversial. Techniques for pre-surgical or intraoperative localization of insulinomas include administration of intravenous methylene blue, intraoperative ultrasound and scintigraphic techniques. Computed tomography, magnetic resonance imaging, and endoscopic ultrasound are additional techniques commonly used in humans for preoperative localization. CT has some utility in detection of small pancreatic tumors but has poor specificity for detection of metastatic disease in dogs with suspected insulinoma. Somatostatin receptor imaging may also be a useful adjunctive diangositc test for detection of insulinoma.

Surgical resection of tumor

Insulinomas in dogs and cats are malignant tumors and have a high predisposition to metastasize particularly to the lymph nodes, liver, and omentum. Metastatic disease is detected grossly in 30-50% cases at the time of surgery, and occult metastasis is present in most dogs. For this reason a cure is unlikely even in cases in which a single lesion is detected grossly. Removal of all gross tumor however, may allow clinical improvement and a good short –term prognosis. Long term control of disease is only achieved in a small percentage of dogs. The goals of surgery for patients with insulinoma should be to confirm the disease, obtain tissue for histopathology, surgically remove all detectable gross disease if possible, and perform a complete exploratory laparotomy to detect evidence of metastasis. If suspected metastatic lesions are detected they should either be removed or a sample collected for histopathologic evaluation. In the approximately 20% of dogs in which the lesion is not grossly visible, one of the techniques for localization discussed above should be considered.

Complications after surgery include pancreatitis, diabetes mellitus, persistent hypoglycemia, and exocrine pancreatic insufficiency.

Medical management of insulinoma

Indications for medical management of insulinoma include stabilization of a patient prior to exploratory surgery, patients with obvious metastatic disease, and patients which have undergone surgery in which complete surgical removal of the tumor or metastases was not possible. In some cases frequent feeding of a diet high in fat, protein, and complex carbohydrates, but low in simple sugars will control clinical signs for a period of time. In addition stress should be minimized and exercise limited. Once frequent feeding fails to control clinical signs, treatment with glucocorticoids is necessary. The starting dose for prednisone is 0.25 mg/kg q 12 hours. The dose should be titrated upward in order to control clinical signs as necessary. There is little benefit to increasing the dose above 3 mg/kg/dose. The drug diazoxide inhibits insulin secretion from the pancreas, stimulates gluconeogenesis and glycogenolysis, and has a direct inhibitory effect on cellular uptake of glucose. The recommended dose is 5-30 mg/kg q 12 hours. Again the recommendation is to start with the lowest dose and titrate upwards to effect. Side effects that have been reported include anorexia, vomiting, diarrhea, tachycardia, bone marrow suppression, and pancreatitis. Thiazide diuretics potentiate the effects of diazoxide. The recommended starting dose for hydrochlorothiazide is 2-4 mg/kg/day. In some cases routine medical therapy is not adequate to stabilize a patient adequately prior to surgery. In these cases intravenous glucagon infusion should be considered for short-term management of hypoglycemia. The somatostatin analogue, Octreotide, has also been used in a small number of dogs with insulinoma. The drug works by stimulating somatostatin receptors in the pancreas which inhibit insulin synthesis and secretion. Octreotide at a dose of 10-40 µg SC q 8-12 hours is effective in approximately 50% of dogs, however the drug is expensive and most dogs became refractory over time. Chemotherapeutic agents such as alloxan and streptozotocin have direct toxicity for the beta cells of the pancreas. Use of these drugs in dogs with insulinoma has been reported to cause partial or complete remission in 30-50% of dogs; however nephrotoxicity of these drugs is high. In a recent study of 17 dogs with insulinoma treated with streptozocin and a diuresis protocol however, azotemia was only reported in one dog. Median duration of normoglycemia was 163 days. Two dogs had rapid resolution of paraneoplastic peripheral neuropathy and two others had measurable reductions in tumor size. Two dogs developed diabetes mellitus.

The long-term prognosis for insulinoma is poor. Survival times are generally longer for those dogs treated surgically. In one study, median survival for dogs treated surgically was 381 days (range 20-1758), while survival for those dogs treated medically was 74 days (range 8-508). However, dogs in the medical group tended to receive less aggressive therapy overall. The long-term prognosis for dogs with detectable metastatic disease is generally considered poor, however long survival times after aggressive surgical debulking of primary and metastatic nodules has been reported. In one study of 28 dogs with insulinoma median survival time was 785 days. Nineteen of the dogs were treated with partial pancreatectomy and medical treatment with prednisone and diazoxide was initiated in those dogs that relapsed after surgery.

Treatment other causes hypoglycemia

In most other causes of hypoglycemia, treatment relies on short term IV infusion of dextrose in addition to treatment of the underlying disease or condition. Glucagon infusion may be useful in dogs with insulin overdose. In cases of artefactual hypoglycemia specific treatment of hypoglycemia is unnecessary.

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