Endocrine emergencies (Proceedings)

Endocrine emergencies are clinical presentations in which immediate recognition and treatment of the endocrine disorder is required to decrease patient morbidity and prevent mortality. Endocrine disorders that require this immediate recognition and treatment are adrenal insufficiency, pheochromocytoma, diabetic ketoacidosis, hyperosmolar diabetes mellitus, insulinoma, hypoparathyroidism, and myxedema coma in severe hypothyroidism.

Hypoadrenocorticism

Hypoadrenocorticism occurs as a result of a deficiency in glucocorticoids and, in most cases, mineralocorticoids as a result of progressive destruction of the cortex. Mineralocorticoids and glucocorticoids are important in maintaining vascular tone and water balance. A deficiency in these hormones could result in circulatory failure and hypovolemic shock.

Clinical Findings

This is a disease of young to middle aged dogs with a predisposition for females and certain breeds. The classic history is of waxing and waning lethargy, inappetence, vomiting, and diarrhea that often responds to symptomatic treatment. Weakness, polyuria, polydipsia, muscle wasting, and regurgitation can occur. More critical patients present with a history of anorexia, vomiting, diarrhea, melena, and collapse. These dogs may be in hypovolemic shock, laterally recumbent, with pale tacky mucous membranes, increased capillary refill time, poor pulse quality, bradycardia, and hypothermia. A key identifier of this condition is a dog presenting in hypovolemic shock with bradycardia as opposed to tachycardia.

Laboratory Findings

Routine laboratory evaluation might reveal a mild non-regenerative anemia, the absence of a stress leukogram, prerenal azotemia, increased ALT, hypoalbuminemia, hypocholesterolemia, hypoglycemia, increased potassium, decreased sodium, and decreased chloride. Diagnosis is made with clinical signs and the ACTH stimulation test.

Treatment

In hypovolemic shock it is important to address hypotension and hypovolemia. Typically this is done with shock rates (80 – 90 ml/kg/hr) of crystalloids until signs of shock resolve. After correcting hypovolemia, fluid rates are adjusted to correct deficits, maintain hydration and replace losses. Sodium chloride (0.9%) is used initially in dogs with evidence of mineralocorticoid deficiency because of its higher sodium content. If bradycardia and moderate to severe hyperkalemia (> 8.0 mEq/L) are present then 10% calcium gluconate can be administered to help maintain a normal membrane potential. Dextrose (± regular insulin) or sodium bicarbonate should also be given to move potassium into cells. Fluid diuresis will aid in elimination of potassium through the kidneys and, in animals with mild to moderate hyperkalemia, may be all that is required.

Parenteral glucocorticoids should be given as soon as possible. Glucocorticoids most commonly used are dexamethasone, dexamethasone sodium phosphate, prednisolone sodium succinate, and hydrocortisone hemisuccinate. If considering glucocorticoids prior to or during the ACTH stimulation test, dexamethasone-containing formulations and hydrocortisone hemisuccinate are recommended because they reportedly will not interfere with measuring cortisol during the ACTH stimulation test. Parenteral glucocorticoids are given until the dog is no longer vomiting, eating and drinking regularly. At this time dogs can be switched to oral prednisone then tapered to lowest dose necessary once at home and feeling well.

Mineralocorticoids are not necessary in an acute crisis but should be given as soon as a mineralocorticoid deficiency is diagnosed. Desoxycorticosterone pivalate (DOCP) is a more suitable mineralocorticoid for critical cases because it is an injectable formulation. Glucocorticoids need to be supplemented with DOCP because of its lack of glucocorticoid activity. Fludrocortisone is an alternative in a dog that can take oral medications. Fludrocortisone can occasionally be administered without glucocorticoids but in both instances glucocorticoids should be given initially and then tapered to the lowest dose necessary to maintain appetite and normal activity levels while minimizing signs of glucocorticoid excess. Treatment is life long and the goals of therapy are to normalize potassium and control clinical signs. Mild hyponatremia is well tolerated.

Prognosis

With prompt recognition and treatment these dogs should do well short and long term.

Pheochromocytoma

Pheochromocytomas are neuroendocrine tumors that arise from chromaffin cells in the adrenal medulla. Approximately 50% of these tumors exhibit malignant behavior through local extension, vascular invasion and distant metastases. The adrenal medulla produces catecholamines including epinephrine, norepinephrine and dopamine. Some effects of catecholamines include vasoconstriction, increased heart rate and force of contraction, and increased renin release. Emergent presentations with pheochromocytomas are due to arrhythmias, hypertension and hemorrhage.

Clinical Findings

This is a disease more common in older dogs. Signs may be present for weeks to months and are often intermittent. They are non-specific and include lethargy, weight loss, anorexia, panting, polydispia, and polyuria. More critical patients present with signs related to arrhythmias, vasoconstriction and hemorrhage such as collapse, tachycardia, pale mucous membranes, and occasional abdominal distention. This should be a differential for any dog presenting with collapse, tachyarrhythmias and hypertension.

Laboratory Findings

Routine laboratory abnormalities are uncommon but may include a non-regenerative anemia of chronic disease, regenerative anemia (if hemorrhage), hyperglycemia, and elevated liver enzymes. Proteinuria and variable concentration might be found on urinalysis. A presumptive diagnosis is often made in dogs and cats with adrenal masses that display clinical signs consistent with a pheochromocytoma after ruling out a corticosteroid producing tumor. Currently, definitive diagnosis is often made with tumor removal and immunohistochemical staining.

Treatment

Adrenalectomy is the treatment of choice. Surgery is performed immediately in cases of hemorrhage. In the absence of hemorrhage,medical management is instituted prior to surgery. The most common pre-surgical concerns are hypertension and tachyarrhythmias. Anesthesia and surgical manipulation of the tumor can promote arrhythmias and abnormalities in blood pressure. For animals with hypertension the non-specific alpha antagonist, phenoxybenzamine, is given until 14 to 21 days of normal blood pressure has occurred prior to surgery. If tachycardia is present a beta blocker, such as atenolol or propanolol, is also given. It is important to start the beta blocker several days after the phenoxybenzamine in order to avoid severe hypertension that can result from unopposed stimulation of alpha adrenergic receptors. Phenoxybenzamine and beta blockers can also be given as needed when complete resection is not possible or if surgery is declined for whatever reason.

Prognosis

The prognosis with complete resection is good. Even with incomplete resection survival times of several years have been reported.

Diabeic ketoacidosis & hyperosmolar diabetes mellitus

Diabetic ketoacidosis occurs as a result of insulin insufficiency, increased production of counterregulatory hormones, generation of ketones, worsening hyperglycemia, and insulin resistance. Ketones not utilized for energy production will be excreted in the urine and contribute to polyuria. Ketones are negatively charged so will pull positively charged ions (Ca++, Mg++, Na+, K+) into the urine exacerbating electrolyte abnormalities. Hydrogen ions are produced with ketones in the liver. These H+ are buffered with HCO3 - and there is no buffer left for the ketones. Excess H+, lower HCO3 - and increased ketoacids produce a metabolic acidosis. Vomiting and diarrhea may contribute to electrolyte abnormalities and water loss. Hypovolemia leads to decreased GFR, a decrease in loss of glucose and decrease loss of ketones worsening hyperglycemia and acidosis. Cellular dehydration can occur in the brain leading to altered mentation and coma.

Hyperosmolar diabetes mellitus is an unusual variant in which ketones are not present but severe dehydration leads to a serum osmolality > 350 mOsm/kg (N = 280 – 300 mOsm/kg. Glucose is the greatest contributor and may exceed 1000 mg/dl (800 – 1600 mg/dl) in the blood. In these animals it is likely that extreme dehydration has led to extracellular dehydration and dramatic decreases in GFR so glucose elimination via the kidneys is impaired and hyperglycemia worsens. Ketosis does not occur because there is enough insulin produced by the pancreas to prevent lipolysis and thus ketone precursors.

Clinical Findings

In both syndromes more classic signs of diabetes mellitus will be present. Patients with DKA present acutely for anorexia, vomiting, diarrhea, lethargy, and depression. Change in mentation is a reason for animals with DKA and hypersomolar diabetes mellitus to present. Any animal that is a previously diagnosed diabetic, or with recent signs consistent with diabetes mellitus, that have developed lethargy, gastrointestinal signs and change in mentation should arouse suspicion of these conditions.

Laboratory Findings

The CBC is typically normal. Electrolyte abnormalities are common in DKA and include decreased sodium, chloride, potassium, phosphorus, and magnesium. Sodium may be increased with hypersomolar diabetes. In DKA or hyperosmolar diabetes a prerenal or renal azotemia may occur. Liver enzymes may be mildly to moderately elevated. Cholesterol and triglycerides are increased. The urine is variably concentrated. Glucosuria, ketonuria (DKA) and proteinuria may be found as well as findings suggestive of a urinary tract infection. Venous (or arterial) blood gas analysis reveals anion gap metabolic acidosis occurs. Diabetic ketoacidosis is diagnosed by identifying hyperglycemia, glucosuria, ketonuria, and metabolic acidosis. Hyperosmolar non-ketotic diabetes mellitus is diagnosed by identifying severe hyperglycemia and glucosuria in the absence of ketones.

Treatment

Goals of treatment are resolution of ketoacidosis and hypersomolality. Fluid therapy is recommended to treat dehydration, make-up for on-going losses, normalize electrolytes, treat acidosis, and improve renal elimination of glucose. Rate depends on hydration status but some animals may require shock therapy. In hyperosmolar patients it is important to try not to correct osmolality (either glucose or sodium) too quickly because this can lead to movement of water into the cells of the brain and neurologic deterioration.

Electrolyte abnormalities are common with DKA. Fluid and insulin therapy can exacerbate abnormalities. Potassium and phosphorus often need supplementation. The potassium needed is most often determined by the severity of hypokalemia. Phosphorus is usually supplemented when it measures < 2 mg/dl (normal 4 to 5.2 mg/dl). Hypomagnesemia is common with DKA. Hypomagnesemia can lead to lethargy, anorexia and weakness. Refractory hypokalemia and hypophosphatemia may be secondary to hypomagnesemia because of potassium and phosphorus dependence on magnesium for renal tubular resorption. Electrolytes are monitored one to four times a day in animals with DKA and hyperosmolar diabetes due to rapid changes that can occur.

Metabolic acidosis is often addressed with fluid therapy. In most cases of metabolic acidosis the acidosis improves with fluid therapy alone so addition of bicarbonate is not necessary.

Regular insulin is used most commonly because of short onset and duration of action. Regular is started after 4 to 6 hours of fluid therapy IV, as a CRI, or IM every 1 to 2 hrs. The goal is to lower the glucose by < 50 mg/dl/hr to 250 mg/dl. Once glucose is at 250 mg/dl or lower, dextrose is administered in the fluids. The goal is to keep the glucose 75 – 250 mg/dl by adjusting insulin and dextrose-containing fluids. Once the animal is rehydrated and glucose is < 250 mg/dl, insulin can be switched to IM (if CRI) or SC administration. Once the animal is rehydrated and eating, maintenance insulin can be initiated.

Prognosis

It is important to remember that many animals with DKA or non-ketotic hyperosmolar DM have concurrent disorders so it is important to identify and treat them if present. Many animals are put on antibiotics due to concerns about bacterial translocation from a poorly perfused intestinal tract in an immunocompromised patient. Antacids (H2 receptor antagonists, sucralfate) are commonly used when ulceration is suspected. Antiemetics are used in the face of vomiting. Dogs and cats with DKA and hyperosmolar DM may require hospitalization for days to weeks. The prognosis is guarded and dependent on underlying disease as well as complications that develop with the disease such as pancreatitis and acute renal failure.

Insulinomas

Insulinomas are tumors that arise from the beta cells of the Islets of Langerhans. Most tumors display malignant behavior rather histologically benign or malignant. In fact, some dogs with tumors initially classified as adenomas have gone on to develop metastases at a later date. These tumors have a high metastatic rate of approximately 50% at the time of diagnosis. Metastases occur to the liver, lymph nodes, spleen and mesentery. This disorder should be suspected in a relatively 'healthy' dog with signs of hypoglycemia.

Clinical Findings

This is a disease of older dogs. Clinical signs are intermittent, may be present days to years and are related to hypoglycemia. Signs include restlessness, behavioral changes, trembling, generalized weakness, ataxia, stumbling, collapse, and seizures. Some signs are due to neuroglycopenia (e.g. weakness, lethargy, collapse, seizure, coma) while others are related to activation of the autonomic system in an attempt to increase blood glucose (e.g. restlessness, trembling, hunger). These animals are often able to tolerate remarkably low glucose levels and may not show signs until their glucose is below 30 mg/dl.

Laboratory Findings

The CBC, chemistry panel and urinalysis are often normal in these animals except for hypoglycemia. Mild to moderate elevations in liver enzymes may occur. The diagnosis is most often made by observing fasting concurrent hypoglycemia (preferably < 60 mg/dl) and normal to increased insulin levels (> 10 µU/ml).

Treatment

Definitive diagnosis is dependent on exploratory laparotomy and histologic identification of neoplastic cells. Surgery is beneficial even in the presence of metastatic disease. Complications associated with surgery include pancreatitis and post-operative hyperglycemia.

Medical management may be indicated preoperatively to stabilize glucose in symptomatic animals, when surgery is declined or contraindicated, if widespread metastases are present, when hypoglycemia persists post operatively, and if hypoglycemia and signs recurs. Relatively stable dogs may only require frequent feeding of small meals that are moderate in fat and protein but low in highly digestible carbohydrates. Actively seizuring dogs require intravenous dextrose boluses and infusions. Boluses can be given but should be minimized because of stimulation of the tumor cells and more pronounced hypoglycemia. It is important to remember that the goal is not a normal glucose but an asymptomatic animal. Glucocorticoids are given when dietary management isn't enough. They are used because of antagonism of insulin effects on cells, increased gluconeogenesis, increased production of substrates for glucose production, and decreased muscle uptake of glucose. Diazoxide is a benzothiadiazide antihypertensive that increases circulating glucose by directly inhibiting insulin secretion, promoting glycogenolysis and inhibiting glucose uptake by cells. Diazoxide is typically given in patients with persistent hypoglycemia that does not respond to glucocorticoids. Less commonly used therapeutics are the somatostatin analogue ocreotide, intravenous glucagon and the chemotherapeutic streptozocin.

Prognosis

Dogs can live several months to years even with metastatic disease. Surgery has been shown to improve survival times over medical management alone.

Hypoparathyroidism

Hypoparathyroidism most commonly occurs following surgical parathyroidectomy for primary hyperparathyroidism or following surgical bilateral thyroidectomy in cats for hyperthyroidism. Naturally-occurring primary hypoparathyroidism is much less common and due to progressive destruction of the parathyroid glands.

The signs of hypoparathyroidism are due to hypocalcemia. Calcium is involved in many cellular and extracellular processes that include neuromuscular transmission and muscle contraction/tone.

Clinical Findings

Neuromuscular signs may be acute as a result of parathyroidectomy or more chronic with naturally-occurring primary hypoparathyroidism. Signs may be exacerbated by stress or exercise, are often episodic and non-specific including anxiety, lethargy, behavioral changes and excessive grooming. Additional less common signs include panting, tachyarrhythmias, bradyarrhythmias, ataxia, anorexia, vomiting, lethargy, diarrhea, weight loss, and cataracts. More suggestive of hypocalcemia are facial rubbing, muscle twitching/spasms, rigid gait, collapse, and seizures (focal to diffuse).

Laboratory Findings

Diagnosis of iatrogenic hypoparathyroidism is made by a history of thyroid or parathyroid surgery and concurrent hypocalcemia. Diagnosis if naturally-occurring primary hypoparathyroidism is made by documenting hypocalcemia, hyperphosphatemia and decreased or low normal parathyroid hormone levels.

Treatment

Obviously dogs and cats with low ionized calcium and clinical signs of tetany require emergent, aggressive treatment. For tetany the goal is not necessarily normal calcium levels but to keep the total calcium above 7 mg/dl and the ionized above 0.7 mmol/L, levels in which clinical signs are uncommon. For tetany, 10% calcium gluconate is given as a bolus over 15 minutes with ECG monitoring. Seizures will stop within a few minutes but anxiety, nervousness and panting may take longer to resolve due to a lag between serum and csf concentrations. Once tetany is controlled, diluted calcium gluconate QID. Every 48 hours of stable calcium the dose frequency is reduced (QID → TID → BID → daily). Alternatively to intermittent SC calcium, a CRI can be given. As soon as dogs are eating they are given oral calcium. Parenteral calcium is tapered with administration of oral calcium. Vitamin D is also given for long term maintenance of calcium. Supplemental calcium can often be tapered and monotherapy with vitamin D is often all that is required in animals with permanent hypoparathyroidism.

Prognosis

Therapy is usually necessary lifelong for naturally-occurring primary hypoparathyroidism but the prognosis is good with treatment. Hypocalcemia secondary to parathyroidectomy and thyroidectomy may be transient due to return of function to atrophied or damaged glands.

Hypothyroidism

Myxedema coma is a rare complication seen in dogs with severe hypothyroidism. Primary hypothyroidism is the most common form of hypothyroidism. Primary hypothyroidism is due to lymphocytic thyroiditis or idiopathic atrophy with rare cases secondary to thyroid neoplasia (mixed tumor, medullary thyroid carcinoma). Thyroid hormones influence all body systems. Thyroid hormones are involved in the nervous, musculoskeletal and cardiovascular systems as well as the regulation of other hormone and enzyme systems and red blood cell synthesis.

Clinical Findings

The most commonly observed clinical signs with hypothyroidism are lethargy, exercise intolerance, mental dullness, cold intolerance, weight gain, and dermatologic abnormalities. Central and peripheral nervous system signs may also be seen. Myxedema is the result of the accumulation of mucopolysaccharides within the tissues that draw water. This may occur in the skin of the head, causing the tragic facial expression commonly described, as well as the extremities. With myxedema coma profound weakness, stupor, coma, hypothermia, bradycardia, hypotension, and hypoventilation may be seen is an uncommon finding in severe cases of hypothyroidism. A dog that presents with altered mentation, non-pitting edema of the head, bradycardia and hypothermia should arouse suspicion of this condition.

Laboratory Findings

The most common laboratory abnormalities include non-regenerative anemia, hypercholesterolemia and hyperlipidemia. In addition with myxedema coma hyponatremia and hypoglycemia may be seen. The diagnosis of hypothyroidism is dependent on clinical signs and serum thyroxine (TT4), FT4(ED), and endogenous TSH.

Treatment

Supportive care consists of intravenous fluids, warming, ventilatory, and enteral support. Injectable levothyroxine sodium is used because of the inability to take or absorb medications via the intestinal tract. Once the dog is stable and able to take oral medications oral synthetic levothyroxine can be given.

Prognosis

The prognosis is guarded with central nervous system manifestations of myxedema. Failure to recognize this syndrome is likely responsible for high mortality rates.

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Herrara MA, Mehl ML, et al. Predictive factors and the effect of phenoxybenzamine on outcome in dogs undergoing adrenalectomy for pheochromocytoma. J Vet Int Med 2008 Nov-Dec;22(6):1333-9.

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