METABOLICALLY ACTIVE TUMORS

Tumors that arise from cells within the endocrine glands may secrete normal hormones in abnormal amounts. These cells derive from neural crest, neural ectoderm, or placodal ectodermal tissue that secrete monoamine (e.g., serotonin) or polypeptide (e.g., insulin) substances. These tumors are referred to as APUDomas (i.e., amine precursor uptake and decarboxylation) or neurocrinopathies. Tumor types include islet cell tumors, medullary carcinoma from the thyroid C cells, pheochromocytomas from adrenal chromaffin cells, and carcinoid tumors from Kulschitsky or enterochromaffin cells found in almost every organ of the body.

Carcinoid tumors are the most common of the APUDomas. They occur most frequently in the ileum and bronchus and have a high incidence of synchronous and metachronous neoplasms, whether carcinoid or other types of neoplasms. The active tumors secrete serotonin, although other substances (e.g., histamine, dopamine, substance P) have been suggested. The carcinoid syndrome includes flushing, diarrhea, cardiac valve disease, and occasionally wheezing. The mainstay of diagnosis is the 24-hour urinalysis for 5-HIAA, the major metabolite of serotonin. Treatment is surgical removal or pharmacotherapy to control the diarrhea and flushing using serotonin antagonists (e.g., cyproheptadine, methasergide), parachlorophenylalanine, or natural or synthetic somatostatin.

Pheochromocytomas are associated with “spells” and hypertension, either episodic (50%) or sustained (50%), which is difficult to differentiate from essential hypertension. The spells include a variety of symptoms, such as headache and acute anxiety or panic attacks with sweating. The rule of 10s applies: 10% are malignant, 10% occur bilaterally, and 10% are extraadrenal, occurring anywhere along the sympathetic chain from the skull base to the gonads. These types of tumors are usually called paragangliomas. Active tumors secrete norepinephrine alone (i.e., paragangliomas) or norepinephrine combined with epinephrine (i.e., adrenal tumors).

Tumors are diagnosed using 24-hour urinalysis for vanillylmandelic acid, computed tomography, 131I-metaiodobenzylguanadine, or ultrasound. All patients must be prepared for surgical excision with 7 to 14 days of a-adrenergic blockers. Phenoxyabenzamine is used orally beginning at a dose of 10 mg given four times each day and gradually increased to 300 mg daily until postural hypotension develops. A b-adrenergic blocker may be added 48 hours before surgery if the patient has tachycardia or arrhythmia or if the catecholamine profile shows excess epinephrine secretion. Propranolol is given in doses of 10 mg four times a day. Both medications are given the morning of surgery, and large amounts of intravenous fluid are used intraoperatively after tumor removal to counteract the marked increase in intravascular capacity, which can cause an acute fall in blood pressure. This occurs because the adrenergic stimulation is precipitously removed as the secreting tumor is removed.

Multiple Endocrine Neoplasia Syndromes

Several neoplastic syndromes involving multiple endocrine glands have been described. Currently, the favored nomenclature for the most well-established yndromes and their most commonly encountered neoplasias are listed. These syndromes are typically inherited in an autosomal dominant pattern; however, penetrance is variable.

MEN I is characterized by parathyroid, pancreatic, and pituitary neoplasias. The most common parathyroid neoplasia is multiglandular hyperplasia. Gastrin-producing islet cell tumors account for over half of the pancreatic tumors in MEN I and become the greatest source of morbidity in affected individuals. The most frequent pituitary neoplasm is a prolactinoma. Other endocrine tumors are unusual in patients with MEN I but may occur. The genetic mutation responsible for the syndrome occurs in the tumor suppressor gene, menin, and has been mapped to chromosome 11.

The distinguishing features of MEN IIa are medullary thyroid carcinoma (MTC), pheochromocytomas, and parathyroid tumors. MTC develops in hyperplastic C cells of the thyroid and is nearly universal in MEN IIa. Treatment consists of total thyroidectomy in all known cases and in unaffected carriers identified through prospective screening. Pheochromocytomas occur in over half of individuals and are typically bilateral and multicentric. They typically develop much later than MTC; however, when both are present, the pheochromocytoma should be removed first. Parathyroid hyperplasia is less frequent compared with MEN I, occurring in 10% to 35%. The genetic abnormality responsible for MEN IIa is a mutation of the RET proto-oncogene on chromosome 10. There is a 100% correlation between the presence of the RET mutation and MEN II and hereditary MTC. Thus, suspected carriers and family members are now being screened based on polymerase chain reaction techniques to identify carriers of the mutated RET proto-oncogene .

MEN IIb is characterized by MTC, pheochromocytomas, and mucosal neuromas. The mucosal neuromas are universal and predominantly involve the oral cavity and can involve other sites of the gastrointestinal tract and the conjunctiva, cornea, and eyelid. MTC in these patients is more aggressive than in MEN IIa, with metastatic disease developing in some children before age 1. The incidence of pheochromocytomas and their clinical course is similar to that of MEN IIa. Hyperplasia of the parathyroid glands is rare. The genetic mutation is also found in the RET proto-oncogene on chromosome 10; however, the specific point mutation is distinct from that causing MEN IIa.

Endocrine Emergencies

Hypercalcemic Crisis

Severe hypercalcemia, or hypercalcemic crisis, predominantly occurs in patients with advanced previously diagnosed malignancy. Serum calcium levels are typically elevated at least to 3.5 mmol/L (14 mg/dL); however, symptom severity also correlates with the rapidity of the calcium elevation. Ionized calcium levels are preferred for diagnosis and follow-up, as this is the physiologically active fraction. Clinical findings in emergent cases include hypovolemia, mental status changes, and gastrointestinal symptoms. Cardiac arrhythmias and renal dysfunction may also complicate the initial course.

Two separate mechanisms for malignancy-associated hypercalcemia are currently accepted. First, many solid tumors secrete a PTH-related protein (PTHrP) that has similar activity to PTH, although its production is unregulated. Squamous cell carcinoma of the lung, head and neck, cervix, esophagus, vulva, and skin, in addition to breast cancer, renal cell, and bladder cancer, are most commonly found to secrete PTHrP. Second, metastatic and hematogenous tumors produce local intercellular mediators that stimulate osteoclast activity. These cytokines (tumor necrosis factor beta, interleukin-6, etc.), once secreted by the tumor cells, act on the local osteoclast population to mediate bone resorption and calcium liberation.

Regardless of the underlying etiology, acute symptomatic hypercalcemia requires aggressive treatment. Initial efforts focus on rehydration. Volume contraction is universal and results from the osmotic diuresis and decreased glomerular filtration rate, which accompany uncontrolled hypercalcemia. Fluid replacement with isotonic saline should be started at 2 to 4 L/day. The use of loop diuretics to stimulate calciuresis is not performed routinely. Bisphosphonates (e.g., pamidronate) are osteoclast inhibitors and are considered first-line therapies for hypercalcemic crisis. Volume expansion and bisphosphonate therapy can normalize most patients’ serum levels. However, the rate of response with the bisphosphonates is 3 to 6 days for calcium normalization. In the critically ill patient, a more rapid response is desired. Calcitonin reduces calcium levels within hours by direct osteoclast inhibition, and its ability enhances renal calcium excretion. Its main drawback is its short-lived effectiveness. Gallium nitrate and plicamycin are no longer considered first-line therapy because the bisphosphonates have significantly better toxicity profiles. Glucocorticoids and dialysis are indicated in specific circumstances.

Hypocalcemia

Acute or emergent hypocalcemia is uncommon. The typical presentation centers around the neuromuscular irritability that predominates the clinical picture. Numbness, paresthesias, cramps, tetany, and seizures are often seen. Laryngeal tetany and cardiac arrhythmias can result in mortality if not treated immediately. When complicated or emergent hypocalcemia is suspected, intravenous elemental calcium should be administered until clinical improvement is observed. Preferably, 100 to 300 mg of calcium gluconate is given over 10 minutes. Ionized calcium levels should be obtained and followed until normalization occurs. Ideally, the underlying etiology will be identified and treated. The most common etiology in the practice of otolaryngology is hypocalcemia from sudden PTH deficiency, seen after parathyroid or thyroid surgery. Intravascular ionized calcium levels typically reach their lowest 24 to 48 hours after surgery. Additional causes of hypocalcemia include rapid intravascular protein binding, vitamin D deficiency, and PTH resistance. Several anions may also complex with ionized calcium to decrease the concentration precipitously, such as citrate, bicarbonate, and phosphate. One other scenario is the hungry bone syndrome most commonly seen after removal of larger adenomas in elderly patients.

Once the acute situation has been temporized, long-term calcium supplementation is instituted and may be enhanced with vitamin D, depending on the underlying etiology and the initial response to oral calcium therapy. Difficult cases may benefit from evaluation of serum phosphate and magnesium levels, because abnormal levels will complicate the diagnosis and treatment of hypocalcemia.

Thyroid Storm

Thyrotoxic crisis is an uncommon complication of thyrotoxicosis. It has become a rare complication in the surgical patient, and most commonly occurs in medical patients with known Grave’s disease and a precipitating event that leads to an acceleration or decompensation of their hyperthyroid state. Clinically, patients present in a severe hypermetabolic state. Fever, tachycardia, and sweating are nearly universal. Arrhythmias are common, and heart failure and shock may ensue. Motor restlessness and mental status changes are common. If unrecognized or untreated, stupor, coma, and hypotension develop, and the course ends in fatality.

Common precipitating events include other acute illnesses, infections, trauma, and emergent surgeries. Others include radioiodine therapy, parturition, toxemia of pregnancy, and diabetic ketoacidosis. Not all cases have identifiable precipitating events; however, they must be sought to properly treat the patient and avoid additional morbidity.

Diagnosis is based on the history and clinical presentation. Once the diagnosis is anticipated, treatment should begin before confirmation with laboratory testing. A scoring system has been devised for grading patients on the severity of their crisis.

There are three goals of therapy. First, treatment must focus on controlling the hyperthyroid state. Propylthiouracil is used first to prevent further synthesis of thyroid hormone and to limit the peripheral conversion of T4 to the more physiologically active T3. Iodide is used to block the release of preformed hormone stores from the thyroid gland. Lithium may be used in cases where iodide is contraindicated. Glucocorticoids are used routinely and are associated with improved survival. Definitive treatment of the hyperthyroidism occurs after reaching an euthyroid state with either radioactive 131I ablation or surgical excision. The second object of therapy is reestablishing a normal homeostatic state. Many of the acute manifestations can be controlled with b-adrenergic blocking agents. Propranolol has been used most extensively, but B1-selective agents have theoretic advantages in certain patients (e.g., heart failure, asthma, etc.). Other measures include volume reexpansion, electrolyte normalization, glucose monitoring, and treating the hyperthermia. Salicylates should be avoided because they increase the basic metabolic rate and displace bound thyroid hormone, thereby increasing serum levels. Cardiac arrhythmias may require pharmacotherapy and anticoagulation. The final goal of therapy is identifying and treating the precipitating trigger. Mortality from thyroid storm is still significant (15% to 20%), despite earlier diagnosis and aggressive treatment.

Myxedema Coma

Myxedema coma is the end result of chronic untreated hypothyroidism. It is typically seen in elderly women during the winter months. Most cases are initiated by a precipitating event such as an infection (35%), medications (e.g., sedatives), cold exposure, or an exacerbation of another chronic illness. Patients develop symptoms insidiously, and diagnosis may be delayed. Major clinical findings include hypothermia, altered mental status, and respiratory suppression. Typical skin changes include periorbital edema, peripheral edema, dry skin, and signs of anemia. Bradycardia is common. Progressive depression of the sensorium may result in coma. Early diagnosis is essential to limit morbidity and mortality. Once the diagnosis is suspected, treatment should begin. Confirmation with laboratory testing will reveal depressed T4 levels and elevated TSH.

Initial treatment may require respiratory assistance with mechanical ventilation. In addition, underlying illnesses need attention (pneumonia, heart failure, urinary tract infection, etc.). Thyroid replacement begins with an intravenous T4 bolus, followed by daily maintenance doses. Glucocorticoids are given routinely to prevent the potential complication of adrenal crisis. Passive measures are used to rewarm the patient, thereby avoiding rapid vasodilation and possible vascular collapse, which may accompany aggressive warming measures. Typically, a hyponatremia similar to SIADH is present and should be treated with free water restriction. Volume expansion should be accomplished with isotonic crystalloids or whole blood. Response to therapy occurs within the initial 24 hours and is evident by improvement of hypothermia, bradycardia, and mental status. Prolonged respiratory assistance is not uncommon. Mortality rates have improved to approximately 15% to 20% with aggressive treatment.

Diabetic Emergencies

Many of the complications of diabetes are true medical emergencies, including diabetic ketoacidosis, nonketotic hyperglycemic–hyperosmolar coma, and hypoglycemia. Additional characterization and therapeutic protocols for these conditions is beyond the scope of this chapter, and the reader is directed to the chapter on perioperative management issues.