In the developed world, hypercalcemia is typically discovered incidentally by routine chemistry panels. Many patients are asymptomatic or have mild symptoms that may be elicited only upon questioning. Parathyroid adenomas are usually so small and deeply located in the neck that they are almost never palpable; when a mass is palpated, it usually turns out to be an incidental thyroid nodule.
Symptomatic patients are said to have problems with “bones, stones, abdominal groans, psychic moans, with fatigue overtones.”
1. Skeletal manifestations
Low bone density is typically most prominent at the distal one-third of the radius, a site of mostly cortical bone. Lumbar (trabecular) spine bone density is often spared and is higher compared to the distal radius. Hip bones are a mixture of trabecular and cortical bone, and femur bone density tends to be midway between the lumbar spine and distal radius. Postmenopausal women are prone to asymptomatic vertebral fractures, but severe bone demineralization is uncommon in mild hyperparathyroidism. More commonly, patients experience arthralgias and bone pain, particularly involving the legs. Severe chronic hyperparathyroidism can cause osteitis fibrosa cystica, which is the replacement of calcified bone matrix with fibrous tissue forming cystic brown tumors of bone that can be palpable in the jaw. The skeleton becomes weaker with bowing of the long bones and pathologic fractures. Osteitis fibrosa cystica is now a presenting manifestation in under 2% of hyperparathyroidism patients in the United States, Canada, and Europe. However, it remains common in other parts of the world (eFigure 26–16, eFigure 26–17).
Osteitis fibrosa cystica with resorption of the distal phalanges. (Used, with permission, from C Grunfeld, MD.)
Radiographs of index finger of a patient before (left) and after (right) plasma phosphate was reduced to normal with aluminum hydroxide gel and 6 months of dialysis against a bath of 8 mg/dL calcium. (Reproduced, with permission, from Vosik WM et al. Successful medical management of osteitis fibrosa due to tertiary hyperparathyroidism. Mayo Clin Proc. 1972:47:110.)
2. Hypercalcemia manifestations
Mild hypercalcemia may be asymptomatic. However, hypercalcemia of hyperparathyroidism usually causes a variety of manifestations whose severity is not entirely predictable by the level of serum calcium or PTH. In fact, patients with mild hypercalcemia can have significant symptoms, particularly depression, constipation, and bone and joint pain. Neuromuscular manifestations include paresthesias, muscle cramps and weakness, and diminished deep tendon reflexes. Neuropsychiatric manifestations include malaise, headache, fatigue, intellectual weariness, insomnia, irritability, and depression. Patients may have cognitive impairment that can vary from intellectual weariness to more severe disorientation, psychosis, or stupor. Cardiovascular manifestations include hypertension, palpitations, prolonged P-R interval, shortened Q-T interval, bradyarrhythmias, heart block, asystole, and sensitivity to digitalis. Overall cardiovascular mortality is increased in patients with chronic moderate to severe hypercalcemia. Renal manifestations include polyuria and polydipsia, caused by hypercalcemia-induced nephrogenic diabetes insipidus. Among all patients with newly discovered hyperparathyroidism, calcium-containing renal calculi have occurred or are detectable in about 18%. Patients with asymptomatic hyperparathyroidism have a 5% incidence of asymptomatic calcium nephrolithiasis, compared to 1.6% incidence in age-matched controls. Gastrointestinal symptoms include anorexia, nausea, heartburn, vomiting, abdominal pain, weight loss, constipation, and obstipation. Pancreatitis occurs in 3%. Dermatologic symptoms may include pruritus. Calcium may precipitate in the corneas (“band keratopathy”), in extravascular tissues (calcinosis), and in small arteries, causing small vessel thrombosis and skin necrosis (calciphylaxis).
3. Normocalcemic primary hyperparathyroidism
Patients with normocalcemic primary hyperparathyroidism generally have few symptoms. However, on average, such patients have a slightly more atherogenic lipid panel and higher blood pressures (systolic blood pressure 10 mm Hg higher and diastolic blood pressure 7 mm Hg higher) than controls. Also, affected patients can have very subtle symptoms, such as mild fatigue, that may not be appreciated as abnormal.
4. Hyperparathyroidism during pregnancy
Pregnant women having mild hyperparathyroidism with a serum calcium below 11.0 mg/dL (less than 2.75 mmol/L) generally tolerate pregnancy well with normal outcomes. However, the majority of women with more severe hypercalcemia during pregnancy experience complications such as nephrolithiasis, hyperemesis, pancreatitis, muscle weakness, and cognitive changes. About 30% of affected women experience preeclampsia and two-thirds of eclamptic women have preterm delivery. Hypercalcemic crisis may occur, especially postpartum. About 80% of fetuses experience complications of maternal hyperparathyroidism, including fetal demise, preterm delivery, and low birth weight. Newborns have hypoparathyroidism that can be permanent. Hypocalcemia in the infant can present with tetany even 2–3 months after delivery.
Hyperparathyroidism with a large neck mass, or vocal fold paralysis from recurrent laryngeal nerve palsy, raises concern for parathyroid carcinoma. FNA biopsy is not recommended because it may seed the biopsy tract with tumor and cytologic distinction between benign and malignant tumors is problematic. Parathyroid carcinoma is more frequent in patients with hyperparathyroidism–jaw tumor syndrome as well as patients with MEN 1 and MEN 2A. Therefore, patients should have genetic testing.
The hallmark of primary hyperparathyroidism is hypercalcemia, with the serum adjusted total calcium greater than 10.5 mg/dL (2.6 mmol/L) (eFigure 26–18). The adjusted total calcium = measured serum calcium in mg/dL + [0.8 × (4.0 – patient’s serum albumin in g/dL)]. Serum ionized calcium levels are elevated (above 1.36 mmol/L).
Parathyroid hormone and calcium nomogram. Relationship between serum intact parathyroid hormone (PTH) and serum calcium levels in patients with hypoparathyroidism, pseudohypoparathyroidism, nonparathyroid hypercalcemia, primary hyperparathyroidism (HPT), and secondary hyperparathyroidism. (Used with permission from GJ Strewler, MD.) Note: A multivariate model that adds clinical and demographic information may perform better than the nomogram alone. (See O’Neill SS et al. Multivariate analysis of clinical, demographic, and laboratory data for classification of disorders of calcium homeostasis. Am J Clin Pathol. 2011 Jan;135(1):100–7. [PMID: 21173131])
To confirm the diagnosis of hyperparathyroidism, an assessment of urinary calcium excretion is recommended, particularly for patients with mild hyperthyroidism. In primary hyperparathyroidism, the urine calcium excretion may be normal (100–300 mg/day [25–75 mmol/day]) or high. However, low urine calcium excretions (below 100 mg/day [25 mmol/day]) in the absence of thiazide diuretics occur in only 4% of cases of primary hyperthyroidism and raise the differential diagnosis of familial hypocalciuric hypercalcemia.
The serum phosphate is often less than 2.5 mg/dL (0.8 mmol/L). In primary hyperparathyroidism, there is an excessive loss of phosphate in the urine in the presence of hypophosphatemia (25% of cases). A serum calcium:phosphate (Ca/P) ratio above 2.5 (mg/dL) or above 2.17 (mmol/L) helps confirm the diagnosis of primary hyperparathyroidism. The alkaline phosphatase is elevated only if bone disease is present. The plasma chloride and uric acid levels may be elevated. Vitamin D deficiency is common in patients with hyperparathyroidism, and it is prudent to screen for vitamin D deficiency with a serum 25-OH vitamin D determination. Serum 25-OH vitamin D levels below 20 mcg/L (50 nmol/L) can aggravate hyperparathyroidism and its bone manifestations.
Elevated serum levels of intact PTH confirm the diagnosis of hyperparathyroidism. Parathyroid carcinoma must always be suspected in patients with a serum calcium of 14.0 mcg/dL (3.5 mmol/L) or more and a serum PTH 5 or more times the upper limit of normal.
Patients with low bone density who have an elevated serum PTH but a normal serum calcium must be evaluated for causes of secondary hyperparathyroidism (eg, vitamin D or calcium deficiency, hyperphosphatemia, chronic kidney disease). In the absence of secondary hyperparathyroidism, patients with an elevated serum PTH but normal serum calcium are determined to have normocalcemic hyperparathyroidism. Such individuals require monitoring, since hypercalcemia develops in about 19% of patients over 3 years of follow-up.
Genetic testing is recommended for patients with documented primary hyperparathyroidism who are younger than age 40 or who have multiglandular disease or a family history of hyperparathyroidism.
Parathyroid imaging is not necessary for the diagnosis of hyperparathyroidism. Imaging is performed for most patients prior to parathyroid surgery and is particularly important for patients who have had prior neck surgery. The visualization of an apparent parathyroid adenoma helps secure the diagnosis when there is occasional diagnostic difficulty and often allows for minimally invasive surgery.
Ultrasound of the neck should be performed with a high-resolution transducer (5–15 MHz) and should scan the neck from the mandible to the superior mediastinum in an effort to locate ectopic parathyroid adenomas. Ultrasound has a sensitivity of 79% for single adenomas but only 35% for multiglandular disease. Enlarged parathyroids appear as ovoid, homogeneous, hypoechoic structures that are 0.8–1.5 cm in length and less compressible than surrounding tissue. Doppler imaging assists in distinguishing parathyroid adenomas from other structures.
Sestamibi scintigraphy with 99mTc-sestamibi and single-photon emission computed tomography (SPECT) is most useful for localizing parathyroid adenomas. However, false-positive scans are common, caused by thyroid nodules, thyroiditis, or cervical lymphadenopathy. Sestamibi-SPECT imaging improves sensitivity for single parathyroid adenomas. Dual-phase imaging at 10–15 minutes, in addition to the usual imaging at 90–180 minutes, can identify the occasional parathyroid adenoma with rapid sestamibi washout that is not visible with later imaging. Sestamibi-iodine subtraction scanning and neck ultrasonography can locate parathyroid adenomas preoperatively in an effort to improve the outcome and limit the invasiveness of neck surgery. However, preoperative imaging has been used with only modest success. (See Surgery.) Small benign thyroid nodules are discovered incidentally in nearly 50% of patients with hyperparathyroidism who have imaging with ultrasound or MRI.
18F-flurocholine PET/MRI is a useful scan for patients with primary hyperparathyroidism and negative or discordant localization imaging on neck ultrasound and sestamibi scanning. In a small study, the sensitivity of this scan was 90%, with a 100% positive predictive value.
Conventional CT and MRI imaging are not usually required prior to a first neck surgery for hyperparathyroidism. However, a four-dimensional CT (4D-CT), with the fourth dimension referring to time, captures the rapid uptake and washout of contrast from parathyroid adenomas; it is particularly useful for preoperative imaging when ultrasonography and sestamibi scans are negative. It can also be helpful for patients who have had prior neck surgery and for those with ectopic glands. In such patients, 4D-CT has a sensitivity of 88%, versus 54% for sestamibi SPECT and 21% for ultrasound. However, 4D-CT delivers more radiation to the thyroid and so is used mostly for older patients. MRI may also be useful for repeat neck operations and when ectopic parathyroid glands are suspected. MRI shows better soft tissue contrast than CT.
Noncontrast-enhanced CT scanning of the kidneys in patients with hyperparathyroidism can determine whether calcium-containing stones are present. However, for patients with mild and apparently asymptomatic hyperparathyroidism, only about 5% are found to have unsuspected nephrolithiasis.
Bone density measurements by dual energy x-ray absorptiometry (DXA) are helpful in determining the amount of bone loss in patients with hyperparathyroidism. Bone loss occurs mostly in long bones, and DXA should ideally include three areas: lumbar vertebrae, hip, and distal radius. Vertebral bone density is usually not diminished in hyperparathyroidism.
Bone radiographs are usually normal and are not required to make the diagnosis of hyperparathyroidism. There may be demineralization, subperiosteal resorption of bone (especially in the radial aspects of the fingers) (eFigure 26–19), or loss of the lamina dura of the teeth. There may be cysts throughout the skeleton, mottling of the skull (“salt-and-pepper appearance”), or pathologic fractures. Articular cartilage calcification (chondrocalcinosis) is sometimes found.
A: Magnified radiograph of index finger on the fine-grain industrial film showing classic subperiosteal resorption in a patient with severe primary hyperparathyroidism. Note the left (radial) surface of the distal phalanx, where the cortex is almost completely resorbed, leaving only fine wisps of cortical bone. B: Skull radiograph from a patient with severe secondary hyperparathyroidism due to prolonged end-stage renal disease. Extensive areas of demineralization alternate with areas of increased bone density, resulting in an exaggerated picture of the "salt and pepper" skull radiograph, which used to be a classic finding in primary hyperparathyroidism. This is rarely seen now and cannot be visualized easily in radiographic reproductions. Although it is difficult to appreciate at this magnification, the dental lamina dura is absent—another classic radiographic finding in severe hyperparathyroidism. (Both films used, with permission, from H Genant, MD.)
Patients with renal osteodystrophy may have ectopic calcifications around joints or in soft tissue. Such patients may exhibit radiographic changes of osteopenia, osteitis fibrosa cystica, or osteosclerosis, alone or in combination. Osteosclerosis of the vertebral bodies is known as “rugger jersey spine.”