ESSENTIALS OF DIAGNOSIS
Increased fatigue, weakness, arthralgias, nausea, vomiting, dyspepsia, constipation, polydipsia, polyuria, nocturia, psychiatric disturbances, renal colic, bone pain, and joint pain (“stones, bones, abdominal groans, psychic moans, and fatigue overtones”). Some patients are asymptomatic
Nephrolithiasis and nephrocalcinosis, osteopenia, osteoporosis, osteitis fibrosa cystica, peptic ulcer disease, renal dysfunction, gout, pseudogout, chondrocalcinosis, pancreatitis
Hypertension, band keratopathy, neck masses
Serum calcium, PTH, chloride, usually increased; serum phosphate low or normal; uric acid and alkaline phosphatase sometimes increased; urine calcium increased, normal, or, rarely, decreased; urine phosphate increased; tubular reabsorption of phosphate decreased, osteocalcin and deoxypyridinoline cross-links increased
X-rays: subperiosteal resorption of phalanges, demineralization of the skeleton (osteopenia or osteoporosis), bone cysts, and nephrocalcinosis or nephrolithiasis
Primary hyperparathyroidism is due to excess or nonsuppressed PTH secretion from a single parathyroid adenoma (83%), multiple adenomas (6%), hyperplasia (10%), or carcinoma (1%). Once thought to be rare, primary hyperparathyroidism is now found in 0.1%-0.3% of the general population and is the most common cause of hypercalcemia in unselected patients. It is uncommon before puberty; its peak incidence is between the third and fifth decades, and it is two to three times more common in women than in men.
Overproduction of PTH in spite of upper normal or elevated serum levels of calcium results in mobilization of calcium from bone and inhibition of the renal reabsorption of phosphate, thereby producing hypercalcemia and hypophosphatemia. This causes a wasting of calcium and phosphorus, with osseous mineral loss and osteopenia or osteoporosis. Other associated or related conditions that offer clues to the diagnosis of hyperparathyroidism are nephrolithiasis, nephrocalcinosis, osteitis fibrosa cystica, peptic ulcer, pancreatitis, hypertension, and gout or pseudogout. Hyperparathyroidism also occurs in both MEN1, known as Wermer syndrome, and MEN2, known as Sipple syndrome (Table 16–3). The former is characterized by tumors of the parathyroid, pituitary, and pancreas (hyperparathyroidism, pituitary tumors, and functioning or nonfunctioning islet cell pancreatic tumors) that may cause Zollinger-Ellison syndrome (gastrinoma), hypoglycemia (insulinoma), glucagonoma, somatostatinoma, and pancreatic polypeptide tumors (PPomas). Other tumors in MEN1 syndrome include adrenocortical tumors, carcinoid tumors, multiple lipomas, and cutaneous angiomas. MEN2A consists of hyperparathyroidism (20%) in association with medullary carcinoma of the thyroid (98%), pheochromocytoma (50%), and lichen planus amyloidosis. MEN2B patients have a marfanoid habitus, multiple neuromas, and pheochromocytomas but rarely have hyperparathyroidism. Familial hyperparathyroidism can also occur alone or in the presence of jaw tumor syndrome.
Parathyroid adenomas range in weight from 65 mg to over 35 g, and the size usually parallels the degree of hypercalcemia. Microscopically, these tumors may be of chief cell, water cell, or, rarely, oxyphil cell type.
Primary parathyroid hyperplasia involves all of the parathyroid glands. Microscopically, there are two types: chief cell hyperplasia and water-clear cell (wasserhelle) hyperplasia. Hyperplastic glands vary considerably in size but are usually larger than normal (65 mg).
Parathyroid carcinoma is rare but is more common in patients with profound hypercalcemia and in patients with familial hyperparathyroidism and jaw tumor syndrome. Parathyroid cancers are palpable in half the patients and should be suspected in patients at operation when the parathyroid gland is hard, has a whitish or irregular capsule, or is invasive. Parathyromatosis is a rare condition causing hypercalcemia due to multiple embryologic rests or, more commonly, due to seeding when a parathyroid tumor has ruptured or the tumor capsule has been disrupted.
Historically, the clinical manifestations of hyperparathyroidism have changed. Forty years ago, the diagnosis was based on bone pain and deformity (osteitis fibrosa cystica), and in later years on the renal complications (nephrolithiasis and nephrocalcinosis). At present, over two-thirds of patients are detected by routine screening, or because of osteopenia or osteoporosis, and some are asymptomatic. Patients with even mild primary hyperparathyroidism are predisposed to cardiovascular events and fractures. After successful surgical treatment, many patients thought to be asymptomatic become aware of improvement in unrecognized preoperative symptoms such as fatigue, mild depression, weakness, constipation, polydipsia and polyuria, and bone and joint pain. Hyperparathyroidism should be suspected in all patients with hypercalcemia and the above symptoms, especially if associated with nephrolithiasis, nephrocalcinosis, hypertension, left ventricular hypertrophy, peptic ulcer, pancreatitis, or gout. Patients with primary hyperparathyroidism appear to have a shortened life expectancy that improves after successful parathyroidectomy. Younger patients and those with less severe hypercalcemia after parathyroidectomy have the best prognosis.
B. Laboratory Findings, Imaging Studies, and Differential Diagnosis (Approach to the Hypercalcemic Patient)
Together, hyperparathyroidism and humoral hypercalcemia of malignancy (nonparathyroid cancer) are responsible for about 90% of all cases of hypercalcemia. Hyperparathyroidism is the most common cause of hypercalcemia detected by undirected methods such as routine screening, whereas cancer is the most common cause of hypercalcemia in hospitalized patients. Other causes of hypercalcemia are listed in Table 16–4. In many patients the diagnosis is obvious, while in others it may be difficult. At times, more than one reason for hypercalcemia may exist in the same patient, such as cancer or sarcoidosis plus hyperparathyroidism. A careful history must be obtained documenting: (1) the duration of any symptoms possibly related to hypercalcemia; (2) symptoms related to malignant disease; (3) conditions associated with hyperparathyroidism, such as renal colic, peptic ulcer disease, pancreatitis, hypertension, or gout; and (4) possible excess use of milk products, antacids, baking soda, or vitamins. In patients with a recent cough, wheeze, or hemoptysis, epidermoid carcinoma of the lung should be considered. Hematuria might suggest hypernephroma, bladder tumor, or renal lithiasis. A long history of renal stones or peptic ulcer disease suggests that hyperparathyroidism is likely.
Table 16–4.Causes of hypercalcemia. ||Download (.pdf) Table 16–4. Causes of hypercalcemia.
| ||Approximate Frequency |
|Cancer ||Common |
| Metastatic breast cancer || |
| PTH-related peptide secreting (lung, kidney) || |
| Multiple myeloma || |
| Leukemia || |
| Other metastatic cancer || |
|Endocrine Disorders ||Common |
| Hyperparathyroidism || |
| Hyperthyroidism || |
| Addison disease, pheochromocytoma || |
| Hypothyroidism, VIPoma || |
|Increased Calcium or Vitamin Intake and Drugs ||Uncommon |
| Milk-alkali syndrome || |
| Vitamin D and A overdosage || |
| Thiazide diuretics, lithium || |
|Granulomatous Diseases ||Uncommon |
| Sarcoidosis || |
| Tuberculosis || |
|Benign Familial Hypocalciuric Hypercalcemia and Other Disorders ||Rare |
| Paget disease || |
| Immobilization || |
| Idiopathic hypercalcemia of infancy || |
| Aluminum intoxication || |
| Dysproteinemias || |
| Rhabdomyolysis || |
The most important tests for the evaluation of hypercalcemia are, in order of importance, serum calcium, PTH, phosphate, chloride, alkaline phosphatase, creatinine; uric acid and urea nitrogen; urinary calcium; blood hematocrit and pH; serum magnesium; and erythrocyte sedimentation rate (Table 16–5). Measurement of 25-hydroxy and 1,25-hydroxy vitamin D levels, and serum protein electrophoresis are helpful in selected patients when other tests are equivocal.
Table 16–5.Laboratory evaluation of hypercalcemia. ||Download (.pdf) Table 16–5. Laboratory evaluation of hypercalcemia.
|Essential ||Selective |
|Blood Tests |
|Calcium ||Creatine and BUN |
|Phosphate ||Chloride |
|PTH (intact or two-site assay) ||Uric acid |
|Alkaline phosphatase ||pH |
| ||Protein electrophoresis or albumin: globulin ratio |
| ||25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D |
|Radiographic or Nuclear Medicine Procedures |
|Chest x-ray ||Sestamibi scan of neck and ultrasound of neck |
|Abdominal plain films || |
|Ultrasound of kidneys || |
|Bone density (hip, lumbar spine, wrist) || |
|Urine Tests |
|24-hour urinary calcium1 ||Urinalysis |
| ||Deoxypyridinoline cross-links |
| ||Osteocalcin |
A high serum calcium and a low serum phosphate suggest hyperparathyroidism, but about half of patients with hyperparathyroidism have normal serum phosphate concentrations. Patients with vitamin D intoxication, sarcoidosis, malignant disease without metastasis, and hyperthyroidism may also be hypophosphatemic, but patients with breast cancer and hypercalcemia are only rarely so. In fact, if hypophosphatemia and hypercalcemia are present in association with breast cancer, concomitant hyperparathyroidism is probable. Measurement of serum PTH has its greatest value in this situation, since the PTH level is low or nil in patients with hypercalcemia due to all causes other than primary hyperparathyroidism or familial hypocalciuric hypercalcemia. In general, serum PTH levels should be measured in all patients with persistent hypercalcemia without an obvious cause and in normocalcemic patients who are suspected of having hyperparathyroidism. Determination of intact serum PTH levels is sensitive and is not influenced by tumors that secrete parathyroid-related peptide. Nonparathyroid tumors that secrete pure PTH are extremely rare.
An elevated serum chloride concentration is a useful diagnostic clue found in about 40% of hyperparathyroid patients. PTH acts directly on the proximal renal tubule to decrease the resorption of bicarbonate, which leads to increased resorption of chloride and mild hyperchloremic renal tubular acidosis. An increased serum chloride is not found in other causes of hypercalcemia. Calculation of the serum chloride to phosphate ratio takes advantage of slight increases in serum chloride and slight decreases in serum phosphate concentrations. A ratio above 33 suggests hyperparathyroidism; this was a more clinically useful observation before the availability of rapid and accurate PTH measurement.
A 24-hour urine calcium level is helpful for diagnosing hypercalcemic patients who have low urinary calcium levels resulting from benign familial hypocalciuric hypercalcemia (BFHH) and for patients with marked hypercalciuria (> 400 mg/24 h). Patients with BFHH do not benefit from parathyroidectomy.
Serum protein electrophoretic patterns are helpful for diagnosis of multiple myeloma and sarcoidosis. Hypergammaglobulinemia is rare in hyperparathyroidism but is not uncommon in patients with multiple myeloma and sarcoidosis. Roentgenograms of the skull or site of bone pain in patients with elevated alkaline phosphatase levels will often reveal typical “punched-out” bony lesions, and the diagnosis of myeloma can be firmly established by bone marrow examination. Sarcoidosis can be difficult to diagnose, because it may exist for years with limited clinical findings. A chest x-ray revealing a diffuse fibronodular infiltrate and prominent hilar adenopathy is suggestive, and the demonstration of noncaseating granuloma in lymph nodes is diagnostic.
Serum alkaline phosphate levels are elevated in about 10% of patients with primary hyperparathyroidism and may also be increased in patients with Paget disease and cancer. When the serum alkaline phosphatase level is elevated, serum 5′-nucleotidase, which parallels liver alkaline phosphatase, should be measured to determine if the increase is from bone, which suggests parathyroid disease, or liver.
Bone densitometry and radiographic examination of bone frequently reveals osteopenia (1 standard deviation below normal density) or osteoporosis (2.5 standard deviations below normal), but overt skeletal changes such as subperiosteal resorption or brown tumor are found in less than 10% of patients with hyperparathyroidism. Dual photon bone density studies of the femur, lumbar spine, and radius help document osteopenia that occurs in about 70% of women with hyperparathyroidism. Bone changes of osteitis fibrosa cystica are rare on x-ray unless the serum alkaline phosphatase concentration is increased. Primary and secondary hyperparathyroidism can produce subperiosteal resorption of the phalanges and bone cysts (Figure 16–3). A ground-glass appearance of the skull with loss of definition of the tables and demineralization of the outer aspects of the clavicles are less frequently seen. In patients with markedly elevated serum alkaline phosphatase levels without subperiosteal resorption on x-ray, Paget disease or cancer must be suspected. A 24-hour urine test for deoxypyridinoline cross-link assay or osteocalcin detects increased bone loss.
3. Differential Diagnosis
The differentiation between hyperparathyroidism because of primary parathyroid disease and that due to humoral hypercalcemia of malignancy can now almost always be determined by measuring intact PTH, which is increased in primary hyperparathyroidism but suppressed in humoral hypercalcemia of malignancy. The most common tumors causing humoral hypercalcemia of malignancy are squamous cell carcinoma of the lung, renal cell carcinoma, and bladder cancer. Less commonly it is due to hepatoma or to cancer of the ovary, stomach, pancreas, parotid gland, or colon. Recent onset of symptoms, increased sedimentation rate, anemia, serum calcium greater than 14 mg/dL, and increased alkaline phosphatase activity without osteitis fibrosa cystica suggest humoral hypercalcemia of malignancy; mild hypercalcemia with a long history of nephrolithiasis or peptic ulcer suggests primary hyperthyroidism. Documented hypercalcemia of 6 months or longer essentially rules out malignancy-associated hypercalcemia.
In milk-alkali syndrome, a history of excessive ingestion of milk products, calcium-containing antacids, and baking soda is often obtained. These patients become normocalcemic after discontinuing these habits. Patients with milk-alkali syndrome usually have renal insufficiency and low urinary calcium concentrations and are usually alkalotic rather than acidotic. Because of the high incidence of ulcer disease in hyperparathyroidism, milk-alkali syndrome may occasionally coexist with that disorder. This is very infrequent now that acid-suppressing medications, such as proton pump inhibitors, are available to manage peptic ulcer disease.
Hyperthyroidism, another cause of hypercalcemia and hypercalciuria, can usually be differentiated because manifestations of thyrotoxicosis rather than hypercalcemia bring the patient to the physician. Occasionally, an elderly patient with apathetic hyperthyroidism may be hypercalcemic. A sensitive TSH test should be evaluated in hypercalcemic patients whose PTH levels are not increased. Treatment of hyperthyroidism with antithyroid medications causes serum calcium to return to normal levels within 8 weeks.
Normal subjects taking thiazide diuretics may develop a transient increase in serum calcium levels, usually less than 1 mg/dL. Larger rises in serum calcium induced by thiazides have been reported in patients with primary hyperparathyroidism and idiopathic juvenile osteoporosis. Most patients who have hypercalcemia while taking thiazides have another reason for the increase. The best way to evaluate these patients is to switch them to a nonthiazide antihypertensive agent or diuretic and to measure the PTH level. Thiazide-induced hypercalcemia is not associated with increased serum PTH in patients without hyperparathyroidism.
Benign familial hypocalciuric hypercalcemia is one of the few conditions that causes chronic hypercalcemia and mildly elevated PTH levels. It can be difficult to distinguish from mild primary hyperparathyroidism. The best way to diagnose this disorder is to document a low urinary calcium and a family history of hypercalcemia, especially in children.
Other miscellaneous causes of hypercalcemia are Paget disease, immobilization (especially in Paget disease or in young patients), dysproteinemias, idiopathic hypercalcemia of infancy, aluminum intoxication, and rhabdomyolysis (Table 16–4).
C. Approach to the Normocalcemic Patient With Possible Hyperparathyroidism
Renal failure, hypoalbuminemia, pancreatitis, deficiency of vitamin D or magnesium, and excess phosphate intake may cause serum calcium levels to be normal in hyperparathyroidism. Correction of these disorders results in hypercalcemia if hyperparathyroidism is present. The incidence of normocalcemic hyperparathyroidism in patients with hypercalciuria and recurrent nephrolithiasis (idiopathic hypercalciuria) is not known. Because the serum calcium concentration may fluctuate, it should be measured on more than three separate occasions. Determination of serum ionized calcium is also sometimes revealing, since it may be increased in patients with normal total serum calcium levels.
If a patient has elevated serum levels of ionized calcium and PTH, the diagnosis of normocalcemic hyperparathyroidism has been confirmed. There are three major causes of hypercalciuria and nephrolithiasis: (1) increased absorption of calcium from the gastrointestinal tract (absorptive hypercalciuria), (2) increased renal leakage of calcium (renal hypercalciuria) and (3) primary hyperparathyroidism. Patients with absorptive hypercalcemia absorb too much calcium from the gastrointestinal tract and therefore have low serum PTH levels. Patients with renal hypercalciuria lose calcium from leaky renal tubules and have increased PTH levels. They can be distinguished from patients with normocalcemic hyperparathyroidism by their response to treatment with thiazides. In renal leak hypercalcemia, serum PTH levels become normal because thiazides correct the excessive loss of calcium, whereas in primary hyperparathyroidism increased serum PTH levels persist and the patient often becomes hypercalcemic.
Natural History of Untreated & Treated Hyperparathyroidism
Patients with untreated hyperparathyroidism have an increased risk of dying prematurely, mainly from cardiovascular and malignant disease. There is decreased respiratory muscular capacity and increased frequency of hypertrophic cardiomyopathy with left ventricular hypertrophy and decreased vascular compliance even in hyperparathyroid patients without hypertension. Hyperparathyroid patients have more hypertension, nephrolithiasis, osteopenia, peptic ulcer disease, gout, renal dysfunction, and pancreatitis. After successful parathyroidectomy, previously hyperparathyroid patients still have an increased risk of premature death, however, younger patients and those with less severe disease return to a normal survival curve sooner than do older patients or those with more severe hyperparathyroidism. Most patients with hyperparathyroidism—even those with normocalcemic hyperparathyroidism—have symptoms and associated conditions. In 80% of patients, these clinical manifestations improve or disappear after parathyroidectomy.
The only curative treatment of primary hyperparathyroidism is parathyroidectomy. There are no convincing data to support a plan of medical observation, and considerable data support a surgical approach. Once associated conditions such as hypertension and renal dysfunction become well established, they seem to progress despite correction of the primary hyperparathyroidism. Thus, it appears to be better to intervene early while it is still possible to correct these problems. In all patients, however, the diagnosis should be established, and short delays to clarify the diagnosis are justified. The criteria for intervention in asymptomatic patients have been revised several times over two decades (Table 16–6), but have always also included the option for correction of the abnormality based on individual patient and physician judgments.
Table 16–6.Indications for parathyroidectomy in asymptomatic primary hyperparathyroidism. ||Download (.pdf) Table 16–6. Indications for parathyroidectomy in asymptomatic primary hyperparathyroidism.
|Criterion ||1990 ||2002 ||2008 |
|Hypercalcemia ||Serum calcium > 1.5 mg/dL above normal ||Serum calcium > 1 mg/dL above normal ||Serum calcium > 1 mg/dL above normal |
|Hypercalciuria ||24 h urine calcium > 400 mg ||24 h urine calcium > 400 mg ||Not included |
|Renal insufficiency ||Reduced by 30% ||Reduced by 30% ||GFR < 60 mL/min |
|Osteoporosis ||Z-score < 2 ||T-score < 2.5 ||T-score < 2.5 or h/o fragility fracture |
|Age ||< 50 y ||< 50 y ||< 50 y |
A. Marked Hypercalcemia (Hypercalcemic Crisis)
The initial treatment in patients with marked hypercalcemia and acute symptoms is hydration and correction of hypokalemia and hyponatremia. While the patient is being hydrated, assessment of the underlying problem is essential so that more specific therapy may be started. Milk and alkaline products, estrogens, thiazides, and vitamins A and D should be immediately discontinued. Furosemide is useful to increase calcium excretion in the rehydrated patient. Etidronate, plicamycin, and calcitonin are usually effective for short periods in treating hypercalcemia regardless of cause. Glucocorticoids are very effective in vitamin D intoxication, hyperthyroidism, and sarcoidosis and in many patients with cancer, including those with peptide-secreting tumors, but are less effective when there is extensive bone disease. As mentioned previously, hyperparathyroid patients only occasionally respond to glucocorticoid administration.
In patients with marked hypercalcemia, once the diagnosis of hyperparathyroidism is established, localization studies, cervical exploration, and parathyroidectomy should be performed in a vigorously hydrated patient, since this is the most rapid and effective method of normalizing the serum calcium.
Preoperative localization of parathyroid tumors can now be accomplished in about 80%-90% of patients with ultrasonography and sestamibi scans. These studies, however, are helpful in fewer patients with parathyroid hyperplasia (Figure 16–4). Localization studies are essential in patients with persistent or recurrent hyperparathyroidism and can direct a focused exploration in patients with primary hyperparathyroidism. An experienced surgeon can find the tumors in about 95% of patients who have not had previous parathyroid or thyroid surgery without preoperative tests, however preoperative knowledge of the location of the abnormal glands can simplify the operation.
Parathyroid adenomas. A: Sestamibi scan of right lower parathyroid adenoma. B: Longitudinal ultrasound scan of left lower parathyroid adenoma. C: Transverse ultrasound scan of left lower parathyroid adenoma.
For patients who have had prior neck operations, including thyroid and parathyroid procedures, preoperative localization is especially important. CT scan with specially timed contrast enhancement and selective venous catheterization with PTH immunoassay are often helpful. The surgeon must carefully evaluate these cases prior to exploration to optimize the opportunity for a successful operation. A frequently employed preference is that two concordant studies identify the site of the parathyroid abnormality prior to operating.
Three approaches are now acceptable for patients with sporadic primary hyperparathyroidism. A bilateral neck exploration (exposing all four parathyroid glands) is safe and does not depend upon preoperative tests or intraoperative PTH testing for success. A unilateral approach can be elected when one or more localization tests lateralize a solitary parathyroid tumor. At operation, a normal and abnormal parathyroid should be identified on the side of the localized tumor. A focal operation can be done in similar patients and the operation completed when the intraoperative PTH level decreases according to some planned criteria. When the sestamibi and ultrasound scans both independently identify the same tumor, a successful operation occurs in approximately 96% of patients. Videoscopic parathyroidectomy is recommended by a minority of surgeons.
In over 80% of cases, the parathyroid tumor is found attached to the posterior capsule of the thyroid gland. The parathyroid glands are usually symmetrically placed, and lower parathyroid glands are situated anterior to the recurrent laryngeal nerve, whereas the upper parathyroid glands lie posterior to the recurrent laryngeal nerve, where it enters the cricothyroid muscle. Parathyroid tumors may also lie cephalad to the superior pole of the thyroid gland, along the great vessels of the neck in the tracheoesophageal area, in thymic tissue, in the substance of the thyroid gland itself, or in the mediastinum. Care must be taken to avoid bleeding and not to traumatize the parathyroid gland or tumors, since color is useful in distinguishing them from surrounding thyroid, thymus, lymph node, and fat. Furthermore, rupture of the parathyroid gland may result in parathyromatosis (seeding of parathyroid tissue) and possible recurrent hyperparathyroidism. Two helpful maneuvers for localizing parathyroid tumors at operation are following the course of a branch of the inferior thyroid artery and looking for the fat that is usually associated with the parathyroid glands. One should attempt to identify four parathyroid glands when a bilateral approach is elected, though there may be more than four or fewer than four.
In a focused parathyroidectomy, if a probable parathyroid adenoma is found, it is removed and the diagnosis of adenoma confirmed by a decrease in PTH of greater than 50% from baseline and into the normal range. If the intraoperative PTH does not fall appropriately, then further exploration to identify additional abnormal parathyroid tissue should be undertaken during the same anesthetic. If normal glands are identified, they should be carefully documented. If two adenomas are found, both are removed, and both normal glands can be biopsied for confirmation but should not be removed.
The presence of a completely normal parathyroid gland at operation indicates that the tumor removed is adenomatous rather than hyperplastic, since in hyperplasia all the parathyroid glands are involved. However, the variation in the appearance of normal parathyroid glands, and the subtlety of hyperplastic glands can make this distinction complex.
When all parathyroid glands are hyperplastic, the most normal gland should be partially resected, leaving a 50 mg remnant, and confirmed to be well-vascularized prior to removal of the remaining glands. The upper thymus and perithymic tract should be removed in patients with hyperplasia, because a fifth parathyroid gland is present in 15% of cases.
If exploration fails to reveal a parathyroid tumor, a missing lower gland is often in the thymus (anterior mediastinum), whereas a missing upper gland is usually paraesophageal (or in the posterior mediastinum). One should therefore perform a careful and thorough exploration of the areas in which parathyroid tissue is likely to reside.
The recurrence rate of hyperparathyroidism after the removal of a single adenoma in patients with sporadic hyperparathyroidism is 2% or less. In patients with multiple endocrine neoplasia and familial hyperparathyroidism, recurrent hyperparathyroidism is expected as long as they have residual parathyroid tissue. Thus, the plan for management of these patients over their lifetime should be to limit both the complications from hyperparathyroidism, and the number and complexity of operations required to manage it.
Following removal of a parathyroid adenoma or hyperplastic glands, the serum calcium concentration falls to normal or below normal in 24-48 hours. Patients with severe skeletal depletion (“hungry bones”), long-standing hyperparathyroidism, vitamin D deficiency, or high preoperative serum calcium levels may develop profound hypocalcemia with paresthesias, carpopedal spasm, or even seizures. If the symptoms are mild and serum calcium falls slowly, oral supplementation with calcium is all that is required. When marked symptoms develop, it can be necessary to administer intravenous calcium gluconate. If the response is not rapid, the serum magnesium concentration should be determined and replenished. Treatment with calcitriol, 0.5 micrograms twice daily is sometimes required. (See section on Hypoparathyroidism.)
Treatment of persistent or recurrent hyperparathyroidism requires careful evaluation and planning. First the diagnosis must be reestablished, and the rationale for correcting the hyperparathyroidism must be specifically confirmed. If operation is planned, then preoperative localization is mandatory. Most surgeons perform noninvasive localization tests (ultrasound, sestamibi scan, CT scan) initially. If the localization is not clear, then invasive testing follows (selective venous catheterization with PTH measurement, rarely angiography). Most patients have a parathyroid tumor that can be removed through a cervical incision, making mediastinal exploration unnecessary. The success rate for patients requiring reoperation is about 90%, and the complication rate is higher depending upon the nature of the prior operation(s) and the location of the abnormal gland. The success rate is lower in patients with negative or equivocal localization tests and in patients with parathyromatosis and parathyroid cancer.
JP: Primary hyperparathyroidism. Endocr Prac. 2012;18:781.
et al.: Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab. 2009;94:335.
SECONDARY & TERTIARY HYPERPARATHYROIDISM
In secondary hyperparathyroidism, there is an increase in PTH secretion in response to low plasma concentrations of ionized calcium, usually due to renal disease or vitamin D deficiency, and malabsorption,. This results in chief cell hyperplasia. When secondary hyperparathyroidism occurs as a complication of renal disease, the serum phosphorus level is usually high, whereas in malabsorption, osteomalacia, or rickets it is frequently low or normal. Secondary hyperparathyroidism with renal osteodystrophy is a frequent complication of hemodialysis and peritoneal dialysis. Factors that play a role in renal osteodystrophy are: (1) phosphate retention secondary to a decrease in the number of nephrons; (2) failure of the diseased or absent kidneys to hydroxylate 25-dihydroxyvitamin D to the biologically active metabolite 1,25-dihydroxyvitamin D, with decreased intestinal absorption of calcium; (3) resistance of the bone to the action of PTH; and (4) increased serum calcitonin concentrations. The resulting skeletal changes are identical with those of primary hyperparathyroidism but are often more severe.
Most patients with secondary hyperparathyroidism are treated medically. Maintaining relatively normal serum concentrations of calcium and phosphorus during hemodialysis and treatment with calcitriol (orally or intravenously) have decreased the incidence of bone disease.
Indications for operation in patients with secondary hyperparathyroidism include: (1) a calcium × phosphate product > 70, (2) severe bone disease and pain, (3) pruritus, (4) extensive soft tissue calcification with tumoral calcinosis, and (5) calciphylaxis. Most patients with secondary hyperparathyroidism requiring parathyroidectomy have very high serum PTH levels. In the patient with secondary hyperparathyroidism in whom subtotal parathyroidectomy or total parathyroidectomy with autotransplantation is indicated, all but about 50 mg of the most normal parathyroid gland should be removed, or 15 (1-mm) slices of parathyroid tissue should be transplanted into individual muscle pockets in the forearm.
Following parathyroidectomy patients usually respond with dramatic relief of bone and joint pain and pruritus. Profound hypocalcemia frequently results following subtotal or total parathyroidectomy with autotransplantation for renal osteodystrophy, both because of “hungry bones” and because of decreased PTH secretion. Hypocalcemia due to hungry bones can be anticipated in patients with markedly elevated alkaline phosphatase levels and hand films documenting subperiosteal resorption.
Occasionally, a patient with secondary hyperparathyroidism develops relatively autonomous hyperplastic parathyroid glands. In most patients after successful renal transplantation, the serum calcium concentration returns to normal, and the hyperplastic parathyroid glands regress. In some patients, however, profound hypercalcemia develops (tertiary hyperparathyroidism). In general, surgical therapy for so-called tertiary hyperparathyroidism should be delayed until all medical approaches, including treatment with vitamin D, calcium supplementation, and phosphate binders, have been exhausted; if the condition persists beyond 1 year posttransplant, or if the hypercalcemia is severe, then operation for tertiary disease should be considered.
et al.: KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int. 2010 Feb;77(4):299–311.
Kidney disease: improving global outcomes (KDIGO) CKD-MBD work group: KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2009 Aug;(113):S1–S130.
et al.: Parathyroidectomy for the attainment of NKF-K/DOQI™ and KDIGO recommended values for bone and mineral metabolism in dialysis patients with uncontrollable secondary hyperparathyroidism. Langenbeck Arch Surg. 2012;397:413.
ESSENTIALS OF DIAGNOSIS
Paresthesias, muscle cramps, carpopedal spasm, laryngeal stridor, convulsions, malaise, muscle and abdominal cramps, tetany, urinary frequency, lethargy, anxiety, psychoneurosis, depression, and psychosis
Surgical neck scar. Positive Chvostek and Trousseau signs
Brittle and atrophied nails, defective teeth, cataracts
Hypocalcemia and hyperphosphatemia, low or absent urinary calcium, low or absent circulating parathyroid hormone
Calcification of basal ganglia, cartilage, and arteries as seen on x-ray
Hypoparathyroidism, although uncommon, occurs most often as a complication of thyroidectomy, especially when performed for carcinoma or recurrent goiter. Idiopathic hypoparathyroidism, an autoimmune process associated with autoimmune adrenocortical insufficiency, is also unusual, and hypoparathyroidism after 131I therapy for Graves disease is rare. Neonatal tetany may be associated with maternal hyperparathyroidism. Hypothyroidism as well as hypoparathyroidism may occur in patients with Riedel struma.
The manifestations of acute hypoparathyroidism are due to hypocalcemia. Low serum calcium levels precipitate tetany. Latent tetany may be indicated by mild or moderate paresthesias with a positive Chvostek or Trousseau sign. The initial manifestations are paresthesias, circumoral numbness, muscle cramps, irritability, carpopedal spasm, convulsions, opisthotonos, and marked anxiety. Chronically, dry skin, brittleness of the nails, and spotty alopecia including loss of the eyebrows are common. Since primary hypoparathyroidism is rare, a history of thyroidectomy is almost always present. Generally speaking, the sooner the clinical manifestations appear postoperatively, the more serious the prognosis. After many years, some patients become adapted to a low serum calcium concentration, so that tetany is no longer evident.
Hypocalcemia and hyperphosphatemia are demonstrable. The urine phosphate is low or absent, tubular resorption of phosphate is high, and the urine calcium is low.
In chronic hypoparathyroidism, x-rays may show calcification of the basal ganglia, arteries, and external ear.
A good history is most important in the differential diagnosis of hypocalcemic tetany. Occasionally, tetany occurs with alkalosis and hyperventilation. Symptomatic hypocalcemia occurring after thyroid or parathyroid surgery is due to parathyroid removal or injury, or is secondary to hungry bones. Other major causes of hypocalcemic tetany are intestinal malabsorption and renal insufficiency. These conditions may also be suggested by a history of diarrhea, pancreatitis, steatorrhea, or renal disease. Laboratory abnormalities include decreased concentrations of serum proteins, cholesterol, and carotene and increased concentrations of stool fat in malabsorption and an increased blood urea nitrogen and creatinine in renal failure.
Serum PTH concentrations are low in hypocalcemia secondary to idiopathic or iatrogenic hypoparathyroidism. In hypocalcemia secondary to malabsorption and renal failure, serum PTH concentrations are elevated and the serum alkaline phosphatase concentration is normal or increased.
The aim of treatment is to raise the serum calcium concentration, to bring the patient out of tetany, and to lower the serum phosphate level so as to prevent metastatic calcification. Most postoperative hypocalcemia is transient; if it persists longer than 2-3 weeks or if treatment with calcitriol (1,25-dihydroxyvitamin D) is required, the hypoparathyroidism may be permanent.
A. Acute Hypoparathyroid Tetany
Acute hypoparathyroid tetany requires emergency treatment. Make certain an adequate airway exists. Reassure the anxious patient to avoid hyperventilation and resulting alkalosis, which exacerbates the hypocalcemia. Calcium gluconate IV, 10-20 mL of 10% solution administered slowly resolves the tetany. Fifty milliliters of 10% calcium gluconate may then be added to 500 mL of 5% dextrose solution and administered by intravenous drip at a rate of 1 mL/kg/h. Adjust the rate of infusion so that hourly determinations of serum calcium are normal.
To make the transition to oral supplements to support the serum calcium level, calcitriol (1,25-dihydroxyvitamin D), 0.25-0.5 μg twice daily, is very helpful and takes effect within 48-72 hours. This enables the GI tract to absorb increased amounts of calcium. Calcitriol has a rapid onset of action compared to other vitamin D preparations. Oral calcium supplements of up to 6 g/d can then generally resolve the hypocalcemia even in patients with permanent, severe hypoparathyroidism. Hypomagnesemia is present in some cases of tetany not responding to calcium treatment. In such cases, magnesium (as magnesium sulfate) should be given in a dosage of 4-8 g/d intramuscularly or 2-4 g/d intravenously.
B. Chronic Hypoparathyroidism
Once tetany has responded to intravenous calcium, change to oral calcium (citrate, gluconate, lactate, or carbonate) three times daily or as necessary. The management of the hypoparathyroid patient is difficult, because the difference between the controlling and intoxicating dose of vitamin D may be quite small. Episodes of hypercalcemia in treated patients are often unpredictable and may occur in the absence of symptoms. Vitamin D intoxication may develop after months or years of good control on a given therapeutic regimen. Dihydrotachysterol is useful in the exceptional case to supplement treatment with calcium and 1,25-dihydroxyvitamin D, when the usual measures fail to control the hypocalcemia. Frequent serum calcium determinations are necessary to regulate the proper dosage of vitamin D and to avoid vitamin D intoxication. The dose of vitamin D required to correct hypocalcemia may vary from 25,000 to 200,000 IU/d. Phosphorus should also be limited in the diet; in most patients, simple elimination of dairy products is sufficient. In some patients, aluminum hydroxide gel may be necessary to bind phosphorus in the gut to increase fecal losses.
Exogenous PTH analogs may be helpful in the long-term management of bone disease in patients with hypoparathyroidism. The optimal strategies are under development.
et al.: The effect of PTH(1-84) on quality of life in hypoparathyroidism. J Clin Endocrinol Metab. 2013 Jun;98(6):2356–2361.
et al.: PTH (1-84) replacement therapy in hypoparathyroidism: a randomized controlled trial on pharmacokinetic and dynamic effects following 6 months of treatment. J Bone Miner Res. 2013 Oct;28(10):2232–2243.