Felipedia

Hypoglycemia in cats

Maintenance of a euglycaemic state requires a constant balance of biochemical processes (gluconeogenesis, glycogenolysis, glycogen synthesis) and the availability of gluconeogenic substrates (amino acids, fatty acids and glycerol) mediated by the interaction of hormones (insulin, glucagon, cortisol and growth hormone) and the autonomic nervous system (epinephrine, norepinephrine). Hypoglycaemia can develop with dysregulation of any one of these homeostatic mechanisms. Hypoglycaemia may result from increased glucose utilisation, decreased glucose production, deficiency in diabetogenic hormones, inadequate diet of glucose precursors, or some combination of these mechanisms. Hypoglycaemia is defined as a blood glucose concentration less than 60 mg/dL. Blood glucose concentrations of less than 40 mg/dL may result in seizure, coma or death.

Insulin-producing islet cell tumours and non-islet cell tumours may cause hypoglycaemia. Insulin-producing islet cell tumours cause hypoglycaemia by unregulated production of insulin. Non-islet cell tumours may cause hypoglycaemia through one of several proposed mechanisms, including increased glucose utilisation by tumours of large volumes; decreased liver function (diminished gluconeogenesis, glycogenolysis or glycogen synthesis); production of insulin-like polypeptides such as polypeptide growth factors including insulin-like growth factor I and II (IGF-I and IGF-II), somatomedin A, and somatomedin C; and failure of counterregulatory mechanisms such as depression of counterregulatory hormones, for example, glucagon, adrenocorticotrophic hormone, glucocorticoids, and growth hormone. Peripherally, upregulation of insulin receptors also is proposed to be a cause of hypoglycaemia.

Pathophysiology

Hypoglycaemia affects the nervous system most dramatically. Glucose is the most important energy substrate for the brain. Glucose metabolism and oxygen consumption in the brain are closely linked. With decrements in blood glucose are commensurate reductions in cerebral oxygen consumption. Within the brain are regional differences in glucose metabolism and therefore differing susceptibilities to the adverse effects of hypoglycaemia. As the brain is deprived of glucose, rostral-to-caudal progression of signs occurs because higher brain centres are more sensitive to the insult.

The risk of prolonged or permanent neurological injury is related to the severity and duration of the hypoglycaemia. In situations of severe, prolonged hypoglycaemia, neurological deficits may persist for days or weeks despite correction of hypoglycaemia. Hypoglycaemia causes cortical lesions, especially in the temporal lobes, and injured middle layers of the cerebral cortex and hippocampus while sparing the brain stem and spinal cord. Chronic, recurrent hypoglycaemia may result in a predominantly motor-sensorimotor peripheral neuropathy. Prolonged hypoglycaemia can cause focal necrosis of the cerebral cortex, resulting in acquired seizure disorder. Irreversible lesions may result from long-term severe hypoglycaemia and the subsequent hypoxia, which predisposes to the development of cerebral oedema.

Clinical signs

Clinical signs of hypoglycaemia are attributable to neuroglycopenia and activation of the autonomic nervous system. Clinical signs caused by increased sympathetic tone are the adrenergic signs of mydriasis, tachycardia, tremors, irritability, nervousness and vocalisation. Clinical signs caused by the neuroglycopenia develop initially in higher brain centres, with cortical signs such as dullness, confusion, and seizures being most common. Progression to include lower brain areas results in signs such as bradycardia, hypothermia, miosis and decerebrate rigidity. Vestibular signs such as nystagmus also may be present. As clinical signs progress, tendon reflexes are lost as motor neurones are affected.

Differential diagnosis

Artifactual changes in blood glucose are an important differential diagnosis for hypoglycaemia. Serum or plasma must be separated from cellular components of blood within 30 minutes after collection to minimise consumption of glucose by cells. At 22°C, the glucose concentration decreases approximately 10 per cent every 30 to 60 minutes. Glucose concentration may decrease more rapidly in the presence of large concentrations of metabolically active cells as with leukocytosis or leukemia.

In cats, pathological causes of hypoglycaemia include neoplasia, sepsis, pathological increases in blood cells (polycythaemia or leukemia), and liver failure. Insulin-producing islet cell tumours ( insulinomas) and lymphoma have been reported to cause hypoglycaemia in cats. Non-islet cell tumours that have been reported to result in hypoglycaemia in other species include fibrosarcoma, leiomyoma, rhabdomyosarcoma, liposarcoma, mesothelioma, hepatoma, hepatocellular carcinoma, hemangiosarcoma, oral malignant melanoma, plasma cell tumour, multiple myeloma and salivary gland tumours.

Diagnosis

A number of diagnostic tests should be evaluated to determine the cause of hypoglycaemia. Routine blood count, serum chemistries and urinalysis can be used to assess overall health status of the cat and to investigate potential causes of hypoglycaemia, including liver disease, increased blood counts and sepsis. If sepsis is strongly suspected, urine and blood cultures should be considered. Thoracic and abdominal sonography can be used to screen for neoplasia. Insulinomas are detected uncommonly by these techniques. However, these diagnostic tests can be important to rule out other tumour types and to avoid surgery in those patients with grossly detectable, widespread metastases. Abdominal sonography also may demonstrate evidence of metastatic beta cell tumours in the liver or regional abdominal lymph nodes.

Confirmation of insulin-secreting neoplasia requires documentation of inappropriate insulin secretion despite hypoglycaemia. Serum insulin and glucose levels should be evaluated concurrently. If the blood glucose concentration is less than 60 mg/dL and the serum insulin concentration is increased (i.e. more than 20 μU/mL) or in the high normal range (i.e. 10-20 20 μU/mL), the presence of an insulin-secreting neoplasm is likely.

The amended insulin glucose ratio has been recommended to investigate the relationship of insulin to glucose. The formula for calculation of the amended insulin glucose ratio is extrapolated from the human literature, and assumptions made by the formula may not be directly applicable to veterinary species. The amended insulin glucose ratio has been found to have a higher percentage of false-positive results than comparison of absolute serum insulin to glucose during hypoglycaemia, so use of this ratio is not recommended to diagnose insulin-secreting tumours. Current diagnostic recommendations include evaluating the history, physical examination, findings, clinicopathological data, abdominal sonography, and comparison of absolute serum insulin and glucose during an episode of hypoglycaemia.

Provocative testing (glucose tolerance test, glucagon tolerance test, and tolbutamide tolerance testing) has not proven to be more reliable than the amended insulin glucose ratio and is not recommended. With advancement in nuclear diagnostic techniques, nuclear scintigraphy using radiolabelled octreotide may become available at veterinary diagnostic centres in the future. Octreoscan scintigraphy is reported to have 75-86% sensitivity in diagnosing beta cell tumours in humans. Somatostatin receptor scintigraphy has been used successfully to diagnose insulin-secreting tumours in a small number of dogs. Non-invasive diagnosis of insulinoma can be challenging in some instances and leaves abdominal exploratory as a final diagnostic test, and hopefully, therapeutic option.

Treatment

For best long-term results, primary treatment of the underlying cause of hypoglycaemia is recommended. For most tumours, surgical excision is recommended, with the exception of lymphoma. In those instances in which surgical management is not possible or fails to resolve hypoglycaemia, other medical therapies can be administered. The most common medical therapy used to treat hypoglycaemia is glucocorticoids, which are insulin antagonists and have a stimulatory impact on hepatic glycogenolysis (directly) and gluconeogenesis (indirectly). Prednisolone (0.25 - 1.0 mg/kg PO q12hrs) is administered at the lowest effective dose. Over time, dose escalation may be required. Dietary manipulation also can play an important role in managing hypoglycaemia medically. Frequent feedings of a diet that is high in protein, fat and complex carbohydrates have been recommended. Other recommended medical therapies include diazoxide (5-20 mg/kg PO q12hrs), octreotide (1-2 μg/kg SQ q8-12hrs) and propanolol (0.2-1.0 mg/kg PO q8hrs). These therapies generally are used if hypoglycaemia is not controlled adequately with glucocorticoids and dietary management.