Diseases of the Endocrine System

Etiology

The many causes of hypercalcemia can be grouped pathophysiologically into six broad categories ( Fig 13-2 ). Excessive PTH production is seen in (1) primary hyperparathyroidism, caused by adenoma, hyperplasia, or rarely carcinoma; (2) tertiary hyperparathyroidism, caused by long-term stimulation of PTH secretion in renal insufficiency; (3) ectopic PTH secretion (rare); (4) inactivation mutations at the calcium sensor receptor (CaSR), as seen in familial hypocalciuric hypercalcemia (FHH); and (5) alteration in CaSR function, as seen with lithium therapy.

Parathyroid hyperplasia, usually involving all four parathyroid glands, may be a major cause of the hyperparathyroid syndrome. Carcinoma of the parathyroid glands is extremely rare. All adenomas might begin as hyperplasia; therefore, for the individual patient, where surgery occurs in the natural history of the disease may determine whether hyperplasia or an adenoma is found. Hypercalcemia can also be seen in solid malignancies caused by overproduction of PTH-related peptide (PTHrP) or lytic skeletal metastases, as seen in myeloma or breast cancer. Excessive 1,25(OH) ₂ D ₃ production can also cause hypercalcemia. This is typically observed with lymphomas, granulomatous diseases, or vitamin D intoxication. Primary increase in bone resorption, as seen with immobilization, Paget's disease, and hyperthyroidism, can also lead to hypercalcemia. Excessive calcium intake, which can occur with total parenteral nutrition (TPN) and milk-alkali syndrome, can also cause hypercalcemia. Hypercalcemia also results from other endocrine disorders (e.g., adrenal insufficiency, pheochromocytoma, VIPomas) and medications (e.g., antiestrogens, vitamin A, thiazides). Thiazides increase renal tubular reabsorption of calcium and may even enhance the PTH effects on the renal tubule. Most patients with significant hypercalcemia associated with thiazide diuretics have hyperparathyroidism.

Clinical Presentation

Patients with hypercalcemia present with a variety of symptoms. The level of blood calcium is frequently related to the degree and severity of symptoms. Mild hypercalcemia (up to 11-11.5 mg/dL) is usually asymptomatic and detected on routine calcium measurement. Patients may have vague complaints of depression, poor concentration, and personality changes. Other patients may present with nephrolithiasis or peptic ulcer disease. Nephrolithiasis occurs in 60% to 70% of patients with hyperparathyroidism. Sustained hypercalcemia can result in tubular and glomerular disorders. Polyuria and polydipsia are common complaints. Patients with calcium levels above 12 to 13 mg/dL, especially developing acutely, have anorexia, nausea, vomiting, abdominal pain, constipation, polyuria, tachycardia, and dehydration.

Hypercalcemia can also result in significant echocardiographic (ECG) changes, including bradycardia, atrioventricular block, and short QT interval. Psychosis and obtundation are usually the end results of severe and prolonged hypercalcemia. Band keratopathy is a most unusual physical finding. Bone disease in hyperparathyroidism, such as subperiosteal resorption, can also be seen in radiographs of the teeth and hands in patients with prolonged hypercalcemia. Severe bone disease in hyperparathyroidism, such as osteitis fibrosa cystica, is only rarely seen and usually in older patients with long-standing disease (up to 20 years). The older patient with severe osteopenia, and perhaps vertebral compression fractures, should prompt suspicion of hyperparathyroidism.

Patients with hyperparathyroidism have elevated calcium and low serum phosphate levels. Very mild hyperchloremic acidosis may be present. The PTH level is usually elevated, particularly with respect to the level of calcium concentration, and PTH reduction is the hallmark of successful surgery. The only two situations in which hypercalcemia would be associated with a high PTH level are hyperparathyroidism and the ectopic PTH syndrome (usually secondary to a tumor of the lung or kidney that produces a biologically active fragment of PTH). All other causes of hypercalcemia are associated with either “normal” or, more appropriately, low levels of PTH. When a patient presents with an extremely high blood calcium level (> 14 mg/dL), the patient likely has a distant cancer rather than hyperparathyroidism. Overall, about 50% of all cases of hypercalcemia are caused by cancer invading bone. In these patients, prognosis is poor; more than 50% die within 6 months. Treating hypercalcemia does not prolong survival but usually improves quality of life.

Evaluation for bony metastases includes a technetium diphosphonate bone scan, which is positive in a large percentage of cancers that have metastasized. In addition to serum calcium and phosphate, the bony fraction of alkaline phosphatase, creatinine, electrolyte, and urinary calcium levels are obtained, as well as the appropriate skeletal radiographs and isotope bone scan (by endocrinologist) to aid diagnosis.

Management

Severe symptomatic hypercalcemia, especially levels greater than 14 mg/dL, constitutes a medical emergency, and often treatment must be begun before the diagnosis is complete. The signs and symptoms in any one patient cannot be related to serum calcium level. One patient with total calcium of 14 mg/dL may be almost asymptomatic, whereas another may have severe polyuria, tachycardia, dehydration, and even psychosis. Age seems to be a factor; that is, for any given calcium level, the older patient is more likely to be symptomatic than younger patients.

The first step in the management of hypercalcemia is hydration. Infusion of 4 to 6 L of intravenous (IV) saline may be required in the first 24 hours. Loop diuretics may be required to enhance sodium and calcium excretion. Complications of these interventions include hypomagnesemia and hypokalemia. Extreme care must be exercised in the use of digitalis derivatives for patients with hypercalcemia. Digitalis intoxication occurs quite readily in the presence of hypercalcemia, and dysrhythmias from digitalis toxicity are common ( Box 13-1 ).

If there is increased calcium mobilization from bone, as in malignancy or severe hyperparathyroidism, drugs that inhibit bone resorption should be considered. Zoledronic acid (e.g., 4 mg intravenously [IV] over 30 minutes), pamidronate (e.g., 60–90 mg IV over 2-4 hours), and etidronate (e.g., 7.5 mg/kg/day for 3-7 consecutive days) can be used in the treatment of hypercalcemia of malignancy in adults. Onset of action is within 1 to 3 days, with normalization of serum calcium levels occurring in 60% to 90% of patients. Because of their effectiveness, bisphosphonates have replaced calcitonin and plicamycin, which are rarely used in current practice for the management of hypercalcemia. In rare cases, dialysis may be necessary. Finally, although IV phosphate chelates calcium and decreases serum calcium levels, this therapy can be toxic because calcium-phosphate complexes may deposit in tissues and cause extensive organ damage.

In patients with 1,25(OH) ₂ D ₃ -mediated hypercalcemia, glucocorticoids are the preferred therapy because they decrease 1,25(OH) ₂ D ₃ production. IV hydrocortisone (100-300 mg daily) or oral prednisone (40-60 mg daily) for 3 to 7 days are used most often. Other drugs, such as ketoconazole, chloroquine, and hydroxychloroquine, may also decrease 1,25(OH) ₂ D ₃ production and are used occasionally.

Preoperative Considerations

Patients with moderate hypercalcemia who have normal renal and cardiovascular function present no special preoperative problems. ECG findings can be examined preoperatively and intraoperatively for shortened PR or QT interval. Because severe hypercalcemia can result in hypovolemia, normal intravascular volume and electrolyte status should be restored before anesthesia for elective surgery. Aspiration precautions must be taken because the hypercalcemic patient with altered mental status may have a full stomach or may be unable to protect the airway. Radiographs of the cervical spine should be taken to rule out lytic lesions when hypercalcemia results from cancer. Laryngoscopy in a patient with an unstable cervical spine may result in quadriplegia.

Intraoperative and Postoperative Considerations

There have been significant advances in parathyroid surgery. With newer imaging and radionuclide techniques and rapid intraoperative PTH assay, it is no longer necessary to remove all four parathyroid glands. Unilateral removal of the glands is now possible with less invasive techniques. Surgery can be performed under general, regional, or local anesthesia based on institutional approach. Although no controlled study has demonstrated clinical advantages of one anesthetic over another, if rapid intraoperative PTH assessment is contemplated (to determine the effectiveness of resection), propofol use is discouraged. If propofol is used, it should be stopped at least 5 minutes before the assay is drawn.

Maintenance of anesthesia usually presents little difficulty. No special intraoperative monitoring for hyperparathyroid patients is required. Because of the proximity of surgical retraction to the face, however, meticulous care is taken to protect the eyes. The possibility of lytic or pathologic fractures warrants careful positioning. Response to neuromuscular blocking agents may be unpredictable when calcium levels are elevated; reversal of the effects may be difficult. Failure to remove all the parathyroid adenomas may necessitate single or multiple reoperations. Sestamibi scanning and venous sampling of PTH levels in thyroidal venous beds may provide useful information to the surgeon at reoperation. Unusual sites of parathyroid adenoma include areas behind the esophagus, in the mediastinum, and within the thyroid.

Of the many possible postoperative complications (nerve injuries, bleeding, metabolic abnormalities), bilateral recurrent nerve trauma and hypocalcemic tetany are most serious. Bilateral recurrent laryngeal nerve injury (from trauma or edema) causes stridor and laryngeal obstruction as a result of unopposed adduction of the vocal cords and closure of the glottic aperture. Immediate endotracheal intubation is required in these patients, usually followed by tracheostomy to ensure an adequate airway. This rare complication of bilateral recurrent nerve injury occurred only once in more than 30,000 operations at the Lahey Clinic (Tufts University School of Medicine, Burlington, Mass). Unilateral recurrent laryngeal nerve injury often goes unnoticed because of compensatory overadduction of the uninvolved cord. Because bilateral injury is rare and clinically obvious, laryngoscopy after thyroid or parathyroid surgery need not be performed routinely; however, the clinician can easily test vocal cord function after surgery by asking the patient to say “e” or “moon.” Unilateral nerve injury is characterized by hoarseness, and bilateral nerve injury is characterized by aphonia. Selective injury of adductor fibers of both recurrent laryngeal nerves leaves the abductor muscles relatively unopposed, and pulmonary aspiration is a risk. Selective injury of abductor fibers, on the other hand, leaves the adductor muscles relatively unopposed, and airway obstruction can occur.

Bullous glottic edema is edema of the glottis and pharynx, which occasionally follows parathyroid surgery. This is an additional cause of postoperative respiratory compromise; it has no specific origin, and there is no known preventive measure.

Unintended hypocalcemia during surgery for parathyroid disease occurs in rare cases, usually from the lingering effect of vigorous preoperative treatment. This effect is especially important for patients with advanced osteitis because of the calcium affinity of their bones. After parathyroidectomy, magnesium or calcium ions may be redistributed internally (into “hungry bones”), thus causing hypomagnesemia, hypocalcemia, or both. Risk factors for the development of hypocalcemia (and hypocalcemic tetany) after parathydroidectomy include subtotal or 3½-gland parathyroidectomy, bilateral neck exploration, removal of the parathyroids together with thyroid glands, or history of previous neck dissection. In high-risk situations, management after parathyroid surgery should include serial determinations of serum calcium, inorganic phosphate, magnesium, and PTH levels. Serum calcium levels fall by several milligrams per deciliter in the first 24 hours. The lowest level usually is reached within 4 or 5 days. In some patients, hypocalcemia may be a postoperative problem. Causes include insufficient residual parathyroid tissue, surgical trauma or ischemia, postoperative hypomagnesemia, and delayed recovery of function of normal parathyroid gland tissue. It is particularly important to correct hypomagnesemia in patients with hypocalcemia because PTH secretion is diminished in the presence of hypomagnesemia. Potentially lethal complications of severe hypocalcemia include laryngeal spasm and hypocalcemic seizures.

In addition to monitoring total serum calcium or ionized calcium postoperatively, the clinician can test for Chvostek and Trousseau signs. Because Chvostek sign is present in 10% to 20% of individuals who do not have hypocalcemia, an attempt should be made to elicit this sign preoperatively. Chvostek sign is a contracture of the facial muscles produced by tapping the ipsilateral facial nerves at the angle of the jaw. Trousseau sign is elicited by application of a blood pressure (BP) cuff at a level slightly above the systolic pressure for a few minutes. The resulting carpopedal spasm, with contractions of the fingers and inability to open the hand, stems from the increased muscle irritability in hypocalcemic states, which is aggravated by ischemia produced by the inflated BP cuff. Because a postoperative hematoma can compromise the airway, the neck and wound dressings should be examined for evidence of bleeding before a patient is discharged from the recovery room.

Hypophosphatemia may also occur postoperatively. It is particularly important to correct this deficiency in patients with congestive heart failure (CHF). In a group of patients with severe hypophosphatemia, correction of serum phosphate concentration from 1.0 to 2.9 mg/dL led to significant improvement in left ventricular contractility at the same preload. Other complications of hypophosphatemia include hemolysis, platelet dysfunction, leukocyte dysfunction (depression of chemotaxis, phagocytosis, and bactericidal activity), paresthesias, muscular weakness, and rhabdomyolysis. In patients with both hypocalcemia and hypomagnesemia, correction of the hypomagnesemia may cause greatly increased PTH secretion, resulting in dramatic hypophosphatemia. Serum phosphate levels should be monitored closely in such patients.

Hypomagnesemia may occur postoperatively. Clinical sequelae of magnesium deficiency include cardiac dysrhythmias (principally ventricular tachydysrhythmias), hypocalcemic tetany, and neuromuscular irritability independent of hypocalcemia (tremors, twitching, asterixis, seizures). Both hypomagnesemia and hypokalemia augment the neuromuscular effects of hypocalcemia. Often, just restoring the magnesium deficit corrects the hypocalcemia. It is preferable to use oral calcium (1 or 2 g of calcium gluconate four times daily) when the patient is able to take oral fluids.

During the first week or 10 days after surgery, vitamin D derivatives are avoided to allow the suppressed parathyroid tissue (if present) to function. Vitamin D derivatives are always started if the patient has significant hypocalcemia 2 weeks after surgery. The management of hypoparathyroidism is not easy, and careful follow-up of patients is mandatory. Oral calcium and vitamin D analogs are used for long-term management.

Etiology

Probably the most common cause of hypocalcemia is hypoalbuminemia, followed by surgical removal of the parathyroids. However, causes of hypocalcemia can be differentiated based on high or low PTH levels. Low PTH levels (hypoparathyroidism) are associated with (1) parathyroid agenesis (DiGeorge syndrome); (2) parathyroid gland destruction from surgery, radiation, autoimmune disease, or infiltration by metastatic or inflammatory diseases; and (3) reduced parathyroid function caused by hypomagnesemia or activating calcium sensor receptor mutations ( Fig. 13-3 ).

Hypocalcemia can lead to a compensatory increase in PTH levels (secondary hyperparathyroidism). The causes for hypocalcemia in patients with high PTH level include the following:

• 1.

  Vitamin D deficiency or impaired 1,25(OH) ₂ D ₃ production or action, as seen in nutritional deficiency, renal insufficiency with impaired 1,25(OH) ₂ D ₃ production, or resistance to vitamin D, including receptor defects.

• 2.

  Parathyroid hormone resistance syndromes, including PTH receptor mutations and G-protein mutations (pseudohypoparathyroidism).

• 3.

  Drugs such as calcium chelators, inhibitors of bone resorption, and agents that alter vitamin D metabolism (e.g., phenytoin, ketoconazole).

• 4.

  Acute pancreatitis, acute rhabdomyolysis, “hungry bone” syndrome after parathyroidectomy, or osteoblastic metastases with marked stimulation of the bone (prostate cancer).

In DiGeorge syndrome, thymic hypoplasia is associated with hypoparathyroidism. Pseudohypoparathyroidism is an unusual entity associated with short stature, round facies, and short metacarpals, as well as parathyroid hyperplasia. It represents in part as end-organ resistance to the action of PTH resulting from G-protein defects. 1,25(OH) ₂ D ₃ levels are low in pseudohypoparathyroidism, and replacement of this vitamin D derivative can partially reverse the end-organ resistance.

Hypomagnesemia impairs PTH release and thus can cause profound hypocalcemia. Hypomagnesemia is common in patients with alcoholism, malnutrition, or chronic severe malabsorption states. The calcium level may be restored by replacing magnesium. The vitamin D deficiency of the malabsorption syndrome, osteomalacia (adults) and rickets (children), is associated with a low serum phosphorus concentration. In all other causes of hypocalcemia, serum phosphorus tends to be elevated. It is disproportionately elevated in chronic renal failure. Cataracts and basal ganglion calcification are seen in both hypoparathyroidism and pseudohypoparathyroidism. Subperiosteal resorption, the hallmark of excessive PTH secretion, is seen mainly in chronic renal failure associated with secondary hyperparathyroidism and in some forms of pseudohypoparathyroidism.

Clinical Presentation

Most of the clinical manifestations of hypoparathyroidism are attributable to hypocalcemia. Hypocalcemia occurs because of a fall in the equilibrium level of the blood-bone calcium relationship, in association with a reduction in renal tubular reabsorption and GI absorption of calcium. PTH inhibits renal tubular reabsorption of phosphate and bicarbonate; thus, serum phosphate and bicarbonate levels are elevated in patients with hypoparathyroidism.

The manifestations of acute hypoparathyroidism are discussed earlier in the context of the postoperative management of hypercalcemia. A nerve exposed to low calcium concentration has a reduced threshold of excitation, responds repetitively to a single stimulus, and has impaired accommodation and continuous activity. Tetany usually begins with paresthesias of the face and extremities, which increase in severity. Spasms of the muscles in the face and extremities follow. Pain in the contracting muscle may be severe. Patients often hyperventilate, and the resulting hypocapnia worsens the tetany. Spasm of laryngeal muscles can cause the vocal cords to be fixed at the midline, leading to stridor and cyanosis. Chvostek and Trousseau signs are classic signals of latent tetany, and manifestations of spasm distal to the inflated BP cuff should occur within 2 minutes (see earlier discussion).

Hypocalcemia delays ventricular repolarization, thus increasing the QTc interval (normal, 0.35-0.44). With electrical systole thus prolonged, the ventricles may fail to respond to the next electrical impulse from the sinoatrial (SA) node, causing 2:1 heart block. Prolongation of the QT interval is a moderately reliable ECG sign of hypocalcemia, not for the population as a whole but for individual patients. Thus, following the QT interval as corrected for heart rate is a useful but not always accurate means of monitoring hypocalcemia. CHF may also occur with hypocalcemia, but this is rare. Heart failure in patients with coexisting heart disease can be improved when calcium and magnesium ion levels are restored to normal, and these levels should be normal before surgery. Sudden decreases in blood levels of ionized calcium (as with chelation therapy) can result in severe hypotension.

Patients with hypocalcemia may have seizures. These may be focal, jacksonian, petit mal, or grand mal in appearance, indistinguishable from those that occur in the absence of hypocalcemia. Patients may also have a type of seizure called cerebral tetany, which consists of generalized tetany followed by tonic spasms. Therapy with standard anticonvulsants is ineffective. In long-standing hypoparathyroidism, calcifications may appear above the sella, representing deposits of calcium in and around small blood vessels of the basal ganglia, and may be associated with various extrapyramidal syndromes.

Other common clinical signs of hypocalcemia include clumsiness, depression, muscle stiffness, paresthesias, dry scaly skin, brittle nails, coarse hair, and soft tissue calcifications. Patients with long-standing hypoparathyroidism sometimes adapt to the condition well enough to be asymptomatic.

The symptoms related to tetany seem to correlate best with the level of the ionized calcium. If alkalosis is present, the total calcium level may be normal, but the ionized calcium may be low. This can result in symptoms of neuromuscular irritability (i.e., hyperventilation syndrome). With slowly developing chronic hypocalcemia, the symptoms may be very mild despite severe hypocalcemia, which may partly result from adaptive changes in the level of the ionized calcium. Even with calcium levels of 6 to 7 mg/dL, minor muscle cramps, fatigue, and mild depression may be the only symptoms. Many patients with a calcium level of 6 to 6.5 mg/dL are asymptomatic aside from some mild depression of intellectual function.

Management

The approach to treatment of patient with hypocalcemia depends on the rate of decline and clinical presentation. For example, seizure and laryngospasm require acute treatment. Acute, symptomatic hypocalcemia is initially managed with calcium gluconate, 10 mL 10% wt/vol (90 mg or 2.2 mmol) IV, diluted in 50 mL of 5% dextrose or 0.9% sodium chloride, IV over 5 minutes. Continuing hypocalcemia often requires a constant IV infusion (typically 10 ampules of calcium gluconate or 900 mg of calcium in 1 L of 5% dextrose or 0.9% NaCl administered over 24 hours). Accompanying hypomagnesemia, if present, should be treated with appropriate magnesium supplementation ( Box 13-2 ).

Chronic hypocalcemia from hypoparathyroidism is treated with calcium supplements (1000-1500 mg/day of elemental calcium in divided doses) and either vitamin D ₂ or vitamin D ₃ (25,000-100,000 U daily) or calcitriol (1,25[OH] ₂ D ₃ , 0.25-2 μg/day). Other vitamin D metabolites (dihydrotachysterol, alfacalcidiol) are now used less frequently. Vitamin D deficiency, however, is best treated using vitamin D supplementation, with the dose depending on the severity of the deficit and the underlying cause. Thus, nutritional vitamin D deficiency generally responds to relatively low doses of vitamin D, 50,000 U two or three times per week for several months, whereas vitamin D deficiency caused by malabsorption may require much higher doses (≥ 100,000 U/day). The treatment goal is to bring serum calcium into the low-normal range and to avoid hypercalciuria, which may lead to nephrolithiasis.

Patients with Hypoparathyroidism

Because treatment of hypoparathyroidism is not surgical, hypoparathyroid patients require surgery for an unrelated condition. Their calcium, phosphate, and magnesium levels should be measured both preoperatively and postoperatively. Patients with symptomatic hypocalcemia should be treated with IV calcium gluconate before surgery, as previously detailed. Initially, 10 to 20 mL of 10% calcium gluconate may be given at a rate of 10 mL/min. The effect on serum calcium levels is of short duration, but a continuous infusion with 10 mL of 10% calcium gluconate in 500 mL of solution over 6 hours may help to maintain adequate serum calcium levels.

The objective of therapy is to have symptoms under control before surgery and anesthesia. In patients with chronic hypoparathyroidism, the objective is to maintain the serum calcium level in at least the lower half of the normal range. A preoperative electrocardiogram (ECG) can be obtained and the QTc interval calculated. The QTc value may be used as a guide to the serum calcium level if a rapid laboratory assessment is not possible. The choice of anesthetic agents or techniques does not appear to influence outcome, with the exception of avoidance of respiratory alkalosis, because this tends to decrease ionized calcium levels further.

Patients with DiGeorge Syndrome

These patients can have congenital thymic hypoplasia and hypoparathyroidism; associated anomalies are usually vascular, such as tetralogy of Fallot, persistent truncus arteriosus, or right aortic arch. Furthermore, airway abnormality and compression of the trachea by abnormal vessels are possibilities. Thorough preoperative workup to rule out lower airway abnormalities and cardiovascular anomalies is warranted before elective surgery. These patients are also prone to sepsis caused by depressed cellular immunity, so leukocyte-depleted, irradiated blood is indicated for such patients.