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HYPERPARATHYROIDISM                                                                                             REF:  ACP PIER 2006 | UpToDate 2006

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Clinical Presentation of Hyperparathyroidism  

Patients with primary hyperparathyroidism may present in one of four ways:

  1. Asymptomatic hypercalcemia detected by routine biochemical screening
  2. Symptomatic hypercalcemia
  3. During evaluation for manifestations of hyperparathyroidism such as osteopenia, osteoporosis, bone pain, or nephrolithiasis, PUD, constipation, N/V, pancreatitis, fatigue, psych overtones.
  4. Rarely, hyperparathyroid bone disease (osteitis fibrosa cystica) or parathyroid crisis

Clinical Symptomatic Presentation of Hyperparathyroidism:  

  • Stones (renal) - about 1/2 of these pts have elevated urinary calcium excretion (>250 mg/d in women, and >300 mg/d in men) < and half of these patients develop renal stones.  The stone is usually calcium oxalate.    (due to prolonged PTH excess)
    - Nephrolithiasis occurs in approximately 15 - 20 % of patients with primarily hyperparathyroidism; conversely, about 5 percent of patients with nephrolithiasis have hyperparathyroidism.
  • Bones (osteoporosis) - loss of cortical bone (outermost compact bone rather than the trabecular or cancellous interior bone), esp. in the distal third of the forearm.   (due to prolonged PTH excess)
  • Groans (peptic ulcer, pancreatitis, constipation, fatigue, and psych overtones)   (due to hypercalcemia)

Osteitis fibrosa cystica
— The classic (and now rare) manifestations of primary hyperparathyroid bone disease are osteitis fibrosa cystica and brown tumors. Subperiosteal bone resorption on the radial aspect of the middle phalanges is the most sensitive radiologic sign of primary hyperparathyroidism. These findings are found only in patients with prolonged, severe disease, especially those with parathyroid carcinoma.
In a review of 97 cases of mild hyperparathyroidism, for example, conventional radiography revealed signs of bone disease in only one patient .

Rheumatologic manifestations
— have been described in patients with primary hyperparathyroidism. They include:

  • Hyperuricemia and gout.
  • Pseudogout with pyrophosphate crystals into the joint. Calcification of articular cartilage (chondrocalcinosis), most commonly affecting the wrists and knees, is a common finding in these patients.  

  
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PARATHYROID CRISIS
— A few patients with primary hyperparathyroidism develop parathyroid crisis, which is characterized by severe hypercalcemia, with the serum calcium concentration usually above 15 mg/dL (3.8 mmol/L), and marked symptoms of hypercalcemia, in particular, central nervous system dysfunction.
Clinical presentation — In a review of 48 cases of parathyroid crisis, the numbers of women and men were similar, the mean age was 55 years, and the mean serum calcium concentration was 17.5 mg/dL (4.4 mmol/L). Of the 38 patients for whom clinical information was available, the following characteristics were noted:
  • Changes in mental status were common; 20 patients were comatose and the remaining 18 were confused.
  • 69 percent had bone disease, as assessed by plain radiography or radionuclide bone scan.
  • 53 percent had nephrolithiasis, and 50 percent had both bone disease and nephrolithiasis.
  • Serum PTH concentrations were on average 20 times the upper limit of normal.
  • One-fourth of the patients were known to have had hypercalcemia at some time in the preceding 10 years.
  • Other clinical problems included severe abdominal pain, nausea, vomiting, peptic ulcer, and pancreatitis.

Treatment  of Parathyroid Crisis (Hypercalcemia)
— Patients with parathyroid crisis should be treated by rapid correction of volume depletion and hypercalcemia followed by surgical removal of the hyperfunctioning parathyroid tissue.
Increasing urinary calcium excretion is essential, by aggressive hydration with isotonic saline and, once the patient is euvolemic, administration of a loop diuretic such as furosemide. In addition, decreasing bone resorption, by administration of pamidronate, often lowers the serum calcium concentration substantially within 48 to 72 hours.  Zolendronate, a newer bisphosphonate which is FDA approved for the treatment of hypercalcemia of malignancy, could also be considered in this situation.

  
Screening for Primary Hyperparathyroidism

Screen only those patients with known hypercalcemia; history, symptoms, or signs suggestive of hypercalcemia; and medical conditions in which primary or secondary hyperparathyroidism is known to occur.   Specific recommendation:

* Use serum calcium and intact PTH levels to screen for primary hyperparathyroidism in patients with:

  • Nephrolithiasis
  • Reduced BMD (Bone Mass Density)/ Osteopenia or osteoporosis
  • Mental status changes or psychiatric disorders
  • Unexplained neuromuscular symptoms, constipation, and polyuria
  • Biochemical abnormalities, such as: + Elevated alkaline phosphatase, + Hypophosphatemia, + Hypercalciuria
  • Shortened QT interval on electrocardiogram
  • X-ray abnormalities, including: + Brown tumors, + Resorption of distal phalanges, + Resorption of distal clavicles, + “Salt and pepper” skull,
  • History of head and neck radiation
  • History of lithium use
  • Multiple endocrine neoplasia types 1 and 2A

* Use calcium, phosphorus, and PTH levels to screen for secondary and tertiary hyperparathyroidism in patients with:

  • Pseudohypoparathyroidism
  • Chronic renal insufficiency
  • Dietary deficiency or malabsorption of calcium 
  • Renal wasting of calcium
  • High oral phosphorus intake
  • Vitamin D deficiency or depletion 
  • Impaired vitamin D metabolism

   
Diagnosis of Primary Hyperparathyroidism with Hypercalcemia  
  • Inappropriately elevated serum PTH concentration associated with hypercalcemia.
  • 10-20% of patients with primary hyperparathyroidism have normal serum calcium concentrations. These patients typically come to medical attention in the setting of an evaluation for low bone mineral density. In some patients this may be due to concomitant vitamin D deficiency.
  • Other lab. findings:  low serum phosphorus, increased urin. calcium excretion, elevated serum 1,25-dihydroxyvitamin D, decreased tubular reabsorption of phosphorus, elevated urin. excretion of nephrogenous cAMP.

Use history to look for symptoms of hypercalcemia and conditions associated with hyperparathyroidism:
* Ask about: Bone pain o Calcium disorder o Constipation o Nausea or Vomiting o Depression or other psychiatric disorders o Fatigue o Head and neck radiation exposure o Kidney stones o Osteoporosis o Polyuria or nocturia
* Ask about Medications, including lithium, thiazide diuretics, or excess calcium o Personal or family history of MEN syndromes, familial hyperparathyroidism, and FBHH (familial benign hypocalciuric hypercalcemia) o Renal insufficiency o Vitamin D intake or abuse, or use of vitamin supplements

Use physical exam primarily to look for signs of hypercalcemia and diseases that underlie or are associated with hyperparathyroidism.
* Look for: o Arthritis suggestive of gout or pseudogout o Band keratopathy (calcium phosphate deposition in the medial and lateral limbic margins of the  cornea), only rarely seen with hypercalcemia o Facial angiofibromas and truncal collagenomas specific for MEN1 o Palpable neck mass o Pathologic fracture

Physical findings
— There are no specific physical findings of hyperparathyroidism. Parathyroid adenomas are rarely palpable although parathyroid carcinomas may be.  Band keratopathy (deposition of calcium phosphate in the exposed areas of the cornea) is rare, and occurs only when serum calcium and phosphate concentrations are both high.

Use the serum PTH level to differentiate between parathyroid- and nonparathyroid-mediated hypercalcemia.

  • * Obtain simultaneous intact PTH, serum calcium, and serum phosphorus levels.
  • * Perform a 24-hour urine collection for calcium and creatinine to exclude FBHH suggested by a calcium creatinine clearance ratio of <0.01.
  • * Assess renal function with a serum creatinine (or a creatinine clearance for a more accurate assessment in older patients with sarcopenia).
  • * Look for vitamin D deficiency by obtaining a 25-hydroxyvitamin D level: o In patients with osteoporosis o When the PTH level is significantly high but the calcium level is only minimally increased o In patients with a lower-than-expected, 24-hour urine calcium measurement
    Other lab tests: Serum bone alkaline phosphatase, 1,25-dihydroxyvitamin D (PTH stimulates conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D; thus, these levels tend to be high normal in the setting of primary hyperparathyroidism, but typically it is not necessary to measure), Serum chloride- Often >103 mEq/L in primary hyperparathyroidism, but not routinely helpful in the diagnosis  

Consider imaging studies to localize the origin of increased PTH secretion.

  • * Obtain either parathyroid nuclear scans or parathyroid ultrasounds depending on your radiology and surgical colleagues' preferences.
  • * Know your surgeon's preference on parathyroid imaging before parathyroid surgery; if they perform minimally invasive parathyroid surgery, obtain localization imaging.

         

Hypophosphatemia
— Serum phosphate concentrations are low in some patients with primary hyperparathyroidism because PTH inhibits the proximal tubular reabsorption of phosphate, leading to increased phosphate excretion.

Urinary 24-hour calcium excretion
— Measurement of 24-hour urine calcium excretion may be useful.  Approximately 40% of patients with primary hyperparathyroidism are hypercalciuric, and most of the remaining patients have normal values.  A high value, eg, more than 400 mg/day, is a reason to consider earlier surgical treatment for primary hyperparathyroidism, because it increases the risk of nephrolithiasis. If, however, calcium excretion is low, eg, less than 200 mg/day (5.0 mmol/day), familial hypocalciuric hypercalcemia (FHH) or hyperparathyroidism with concomitant vitamin D deficiency are possibilities; about 75 percent of affected persons with FHH excrete less than 100 mg of calcium in urine daily.

A Ca/Cr clearance ratio
—  which is equivalent to the fractional excretion of calcium, also may be helpful. This ratio is calculated from the following formula:  
Ca/Cr clearance ratio = [Urine Ca x plasma Cr] ÷ [Plasma Ca x Urine Cr]
A value below 0.01 is highly suggestive of FHH (familial hypocalciuric hypercalcemia) rather than hyperparathyroidism (ratio usually >0.02). In an analysis of five large studies combining 165 patients with FHH and 197 patients with primary hyperparathyroidism, a Ca/Cr clearance ratio <0.01 has a sensitivity for FHH of 85 percent, a specificity of 88 percent, and a positive predictive value of 85 percent; a value >0.02 essentially rules out FHH .
Patients with this FHH disorder have mild hypercalcemia, few if any symptoms, no evidence of end organ damage from their disease, and they do not benefit from parathyroidectomy.

Markers of bone turnover
— Biochemical markers of bone turnover (collagen crosslinks, osteocalcin, bone-specific alkaline phosphatase) are usually elevated in primary hyperparathyroidism.

In patients with primary hyperparathyroidism, parathyroidectomy results in the normalization of biochemical values and increased bone mineral density. Most asymptomatic patients who did not undergo surgery did not have progression of disease, but approximately one quarter of them did have some progression.  (N Engl J Med Oct.21, 1999;341:1249-55.- Shonni J. Silverberg)   See the Editorial  below.

  
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Causes of Hyperparathyroidism  

A. Primary hyperparathyroidism - Causes:

  1. Parathyroid benign single adenoma (73- 89%), multiple adenoma (1 -5%)
    Most adenomas consist of parathyroid chief cells. They are usually encapsulated and 50 percent are surrounded by normal parathyroid tissue. Some adenomas, however, are composed of oxyphil cells. These adenomas are usually larger than chief cell adenomas.
    PTH-secreting adenomas are occasionally located in the thymus gland. These tumors express a parathyroid-specific gene, GCMB, unlike normal human thymus, which expresses neither PTH nor GCMB. This observation suggests that these tumors are derived from parathyroid cells that migrated during embryogenesis.
  2. Parathyroid generalized hyperplasia (6 -17%)
    In this case, all four glands are enlarged, with the lower glands typically being larger than the upper ones. The glands are usually composed of chief cells. Clear cell hyperplasia is very rare, and is the only form in which the upper glands are larger than the lower ones.
  3. Parathyroid carcinoma (0.5 -2%) quite rare.
    The diagnosis of carcinoma requires at least one of the following: characteristic histopathologic changes (including fibrous trabeculae, mitotic figures, or capsular or vascular invasion); local invasion of contiguous structures; or lymph node or distant metastases.

B. Secondary hyperparathyroidism - Causes:

  1. Vit. D deficiency
  2. Primary decreased calcium absorption in elderly
  3. Increased urin. calcium loss idiopathic or renal tubular acidosis
  4. Increased phosphate in acute or chronic renal failure
  5. Target organ resistance pseudohypoparathyroidism

   

CONDITIONS ASSOCIATED WITH PRIMARY HYPERPARATHYROIDISM

  1. Familial Primary Hyperparathyroidism
    — Hereditary forms of hyperparathyroidism are rare. In contrast to sporadic hyperparathyroidism, the molecular basis of the various subtypes of hereditary hyperparathyroidism is well understood. Probably the most common cause of this rare form of hyperparathyroidism is as part of the MEN type 1 or 2 syndromes.  It can also occur as familial primary hyperparathyroidism not associated with any other endocrine disorder in the familial hyperparathyroidism-jaw tumor syndrome and familial cystic parathyroid adenomatosis.  FHH and neonatal severe hyperparathyroidism could be considered part of the familial hyperparathyroidism syndrome, but because of the dual defect in calcium-sensing at the parathyroid gland and kidney these syndromes are discussed separately.  Familial hyperparathyroidism often presents with severe hypercalcemia; in one series of 16 patients, almost one-half had severe hypercalcemia (>15 mg/dL [3.8 mmol/L]), one-third presented in parathyroid crisis, and 75 percent had multiple abnormal parathyroid glands.
  2. Thiazide therapy
    — Thiazide diuretics reduce urinary calcium excretion and therefore can cause mild hypercalcemia (up to 11.5 mg/dL [2.9 mmol/L]).
  3. Lithium therapy
    — 10-20% of patients taking lithium develop hypercalcemia and hypocalciuria, and a smaller percentage have high serum PTH concentrations .  Over the long term, however, the prevalence of hypercalcemia seems to fall.  In one study of 142 patients who had taken lithium for 15 years or more, only 3.6 percent had hypercalcemia.

   

Differential Diagnosis of Hyperparathyroidism/Hypercalcemia

  1. Primary hyperparathyroidism
    • Typically asymptomatic with an elevated calcium level
    • Most patients with primary hyperparathyroidism have an elevated PTH level, but approximately 20% of patients can have a normal PTH value, which is inappropriate in the setting of hypercalcemia
  2. Drug-induced hypercalcemia due to lithium or thiazide diuretics.
    • Typically asymptomatic ,taking lithium or a thiazide diuretic, with hypercalcemia.  Laboratory findings can be identical to those of patients with primary hyperparathyroidism.   Hypercalcemia in patients taking thiazide is generally mild and returns to normal by 3 months after discontinuation.
    • Long-term lithium use has been associated with adenomatous parathyroid disease
  3. FBHH -familial benign hypocalciuric hypercalcemia
    • Asymptomatic with incidentally noted mild hypercalcemia. FBHH is an autosomal dominant disorder; thus, there should be a family history of hypercalcemia.  Hypercalcemia is noted at a young age
    • Calcium creatinine clearance ratio should be <0.01.  Urinary calcium levels can be falsely lowered by several factors, including vitamin D deficiency, inadequate specimen collection, thiazide diuretics, lithium, restricted dietary calcium consumption, and renal insufficiency
  4. Chronic renal failure
    • Patients with longstanding renal insufficiency can develop secondary hyperparathyroidism due to hyperphosphatemia and reduced calcium absorption due to calcitriol deficiency. Long-standing secondary hyperparathyroidism can lead to adenomatous parathyroid disease and result in hypercalcemia Serum creatinine should be consistent with significant renal disease.
    • In elderly patients, CrCl may be a more reliable marker of renal function due to decreased muscle mass
  5. Calcium deficiency or malabsorption
    • Typically malabsorbing calcium and may have typical symptoms associated with malabsorption, such as weight loss and steatorrhea
    • Calcium and phosphorus levels are low or low normal in association with elevated serum PTH levels
  6. Hypercalciuria (renal wasting of calcium)
    • Typically asymptomatic, but may have a history of kidney stones or osteopenia.   
    • Serum calcium levels are normal, but PTH and 24-hour urine calcium levels are elevated. Treatment with a thiazide diuretic should improve both of these parameters
  7. Vitamin D deficiency
    • Subclinical vitamin D deficiency is estimated to be present in 50% of the elderly and up to 30% of college-age persons, and they are typically asymptomatic. Severe vitamin D deficiency can be seen in patients with malabsorption or significant nutritional deficiencies. Patients may present with bone pain, fractures, osteoporosis, proximal muscle weakness and weight loss
    • Calcium levels will be normal or low associated with low or normal phosphorus. Other nutritional deficiencies may be noted in severe cases
  8. Impaired vitamin D metabolism
  9. Several congential abnormalities of vitamin D metabolism can lead to a secondary hyperparathyroidism.
    These abnormalities are seen in childhood and are often associated with osteomalacia (rickets) This is a secondary elevation in PTH and should be associated with low serum calcium and phosphorus levels
  10. High oral phosphorus intake
    • Patients with hypophosphatemic disorders (tumor-induced osteomalacia, x-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets) requiring large doses of oral phosphorus can develop secondary hyperparathyroidism.
    • These patients typically have osteomalacia and muscle weakness related to low serum phosphorus levels Patients should have a normal calcium level and phosphorus may be low or normal depending on the adequacy of replacement phosphorus therapy
  11. MEN1 -multiple endocrine neoplasia 1
    • An autosomal dominant disorder consisting of hyperparathyroidism due to multi-gland disease, pituitary neoplasms, and pancreatic neuroendocrine tumors
    • Primary hyperparathyroidism is the most common manifestation of MEN1
  12. MEN2a - multiple endocrine neoplasia 2a
    • An autosomal dominant disorder consisting of medullary thyroid cancer (90%), pheochromocytoma (50%), and primary hyperparathyroidism (30%)
    • Less common than MEN1. Multiple gland involvement due to parathyroid hyperplasia
  13. Ectopic PTH secretion
    • A very rare cause of hyperparathyroidism due to ectopic secretion of PTH by nonparathyroid tumors
    • Case reports have included ovarian cancer, small-cell cancer, thymoma, neuroectodermal malignancy, squamous cell lung cancer, and papillary thyroid cancer 

Some patients with asymptomatic hyperparathyroidism, when carefully questioned, have nonspecific symptoms such as fatigue, weakness, anorexia, mild depression, and mild cognitive or neuromuscular dysfunction, osteopenia, or nephrolithiasis, and others simply miss work often. Among such patients, parathyroidectomy may improve overall well-being, although there are no findings that predict benefit. In a prospective cohort study, functional health status improved after parathyroidectomy independent of preoperative serum calcium concentrations.

Effects of concurrent vitamin D deficiency
— The diagnosis of mild primary hyperparathyroidism can be obscured by concurrent vitamin D deficiency (due to poor dietary intake of vitamin D or sunlight exposure).  Vitamin D deficiency can result in a further increase in parathyroid hormone (PTH) secretion and bone resorption, possibly leading to increased bone turnover.  Vitamin D replacement in such patients results in an increase in bone mineral density, in spite of the coexisting primary hyperparathyroidism.

  
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Surgical Treatment of Hyperparathyroidism  

Which patients need surgery?

The indications for surgical exploration (parathyroidectomy) in asymptomatic primary hyperparathyroidism patients with:   (Recommendation from NIH 2002 workshop)

  • Serum Ca > 11.5 mg/dL [1.0 mg/dL (0.25 mmol/L) or more above the upper limit of normal.]
  • DEXA bone density scan with T score < - 2.5 at any site
  • Renal stones or urinary caclium >400 mg/24hrs while on usual diet.
  • Age younger than 50 years
  • Patient who cannot be reliably monitored.

On the other hand, surgery can be delayed in patients aged 50 years and older who are asymptomatic or minimally symptomatic and who have serum calcium concentrations <1.0 mg/dL (0.2 mmol/L) above the upper limit of normal, and in patients who are medically unfit for surgery.

The standard surgical approach for most patients with primary hyperparathyroidism is bilateral neck exploration usually under general anesthesia .

ABLATION TECHNIQUES
— An occasional patient who needs treatment but is not a candidate for surgery, or who has an adenoma in the mediastinum, might be considered for angiographic ablation or ablation with ethanol injected with ultrasound guidance. Success rates of 66 percent at up to four years have been reported for angiographic ablation.

  

A.  THE CASE FOR SURGERY — Surgery is the only permanently effective therapy for patients with primary hyperparathyroidism. The arguments for surgery in patients with asymptomatic, or minimally symptomatic, hyperparathyroidism are outlined here.

  1. Control of symptoms — Although few patients with mild primary hyperparathyroidism have the classic symptoms of the disease (nephrolithiasis or bone disease), they may have nonspecific symptoms, presumably caused by hypercalcemia. These symptoms include fatigue, weakness, mild depression, vague abdominal pain, and constipation; their reversal after surgery in some patients suggests that they were caused by the hypercalcemia or the hypersecretion of parathyroid hormone (PTH).  There was significant improvement in the hyperparathyroidism symptom severity scores post-parathyroidectomy.
  2. Control of bone disease — Patients with asymptomatic hyperparathyroidism may have decreased bone mineral density, in particular at cortical sites (forearm and hip) as compared to the spine. Significant increments in bone mineral density post-parathyroidectomy have been consistent across studies.
  3. Low complication rate — Neck exploration and parathyroidectomy by an experienced surgeon take about two hours, and blood products rarely need to be given. In the hands of an experienced parathyroid surgeon the cure rate is 95 to 98 percent in patients undergoing bilateral neck exploration, and most patients are discharged from the hospital within two days.  Approximately 5 percent have perioperative complications (wound hematoma or infection, transient recurrent laryngeal nerve injury). Perioperative death is rare. Minimally invasive parathyroidectomy with intraoperative PTH monitoring is performed at some institutions, and appears to decrease both operating time and length of hospital stay. (See "Preoperative localization and surgical therapy of primary hyperparathyroidism").
  4. Possible improved survival — Nontraditional presentations of asymptomatic hyperparathyroidism include cardiovascular morbidity and increased mortality risk as demonstrated in several studies from Europe, but not in the only study from the United States.

B.  THE CASE AGAINST SURGERY — Those who recommend observation rather than surgery rely on the following observations:

  1. Lack of progressive bone loss — Most longitudinal data suggest that primary hyperparathyroidism is not associated with progressive loss of bone. While most patients have low bone density at the time of diagnosis, the reduction is usually small.  
  2. Little evidence of disease progression — Although controlled studies have not been performed (and would be nearly impossible), and some patients are lost to follow up, there is little evidence that hypercalcemia worsens or renal function deteriorates in patients followed for prolonged periods (up to 15 years). Among 52 patients followed for up to 10 years, as an example, there was no change in mean serum calcium and PTH concentrations and urinary calcium excretion (or bone mineral density), but one or more of these measures increased substantially in 14 (27 percent) of the patients.  Furthermore, some patients become spontaneously normocalcemic during long-term follow-up.
  3. Surgical risk in older patients — Many patients with asymptomatic hyperparathyroidism are elderly and have chronic cardiovascular or other chronic disease. They may therefore be at increased risk for complications of anesthesia and surgery.

  
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MEDICAL TREATMENT OF HYPERPARATHYROIDISM

ALTERNATIVES TO SURGERY
— The first decision to be made in a patient with asymptomatic primary hyperparathyroidism is whether to recommend surgery. If it is not recommended or the patient refuses, then it is appropriate to recommend only supportive-preventive measures with adequate monitoring. Treatment with antiresorptive agents may be indicated in patients with osteopenia or osteoporosis.

Preventive measures
— A number of measures should be recommended to patients who do not undergo surgery including the following:

  1. Avoid factors that can aggravate hypercalcemia, including thiazide diuretic and lithium carbonate therapy, volume depletion, prolonged bed rest or inactivity, and a high calcium diet (> 1000 mg/day).
  2. Encourage physical activity to minimize bone resorption.
  3. Encourage adequate hydration (at least six to eight glasses of water per day) to minimize the risk of nephrolithiasis.
  4. Maintain a moderate calcium intake (1000 mg/day). A low calcium diet may lead to increased PTH secretion and aggravate bone disease. On the other hand, a high calcium diet may exacerbate hypercalcemia or hypercalciuria, particularly in patients with high serum calcitriol concentrations. Moderate calcium restriction (eg, <800 mg/day) is probably warranted when the serum calcitriol concentration is high.
  5. Maintain moderate vitamin D intake (400 to 600 IU daily). Vitamin D deficiency stimulates PTH secretion and bone resorption, and therefore is deleterious in patients with primary hyperparathyroidism.

Monitoring
— Periodic monitoring should be performed with measurements of serum calcium every six months, and serum creatinine, and bone density (hip, spine, and forearm) every 12 months. While confirmation of the absence of silent nephrolithiasis at the time of the original evaluation is recommended, monitoring with serial ultrasounds is not.

  

Drug therapy for Hypercalcemia of Primary Hyperparathyroidism 

  • Consider drug therapy to control symptomatic or asymptomatic hypercalcemia for patients with primary hyperparathyroidism who do not undergo surgery, and use it as initial therapy in those with secondary hyperparathyroidism.
  • Treat patients with secondary or tertiary hyperparathyroidism with phosphate binders, vitamin D analogues, or calcimimetic therapy.
  1. Bisphosphonates — Bisphosphonates are potent inhibitors of bone resorption and may be useful in the long-term control of osteopenia in patients with untreated primary hyperparathyroidism. In four studies in which alendronate was given to patients with mild primary hyperparathyroidism for one to two years, bone density increased at the hip and lumbar spine (but not radius) as compared with untreated or placebo-treated patients. In two of the studies, there were small transient increases in serum PTH concentrations and small transient decreases in serum calcium concentrations and urinary calcium excretion in the first months of alendronate treatment, but the values then returned to baseline for the duration of the two-year period.  An oral bisphosphonate may become the drug treatment of choice for patients with primary hyperparathyroidism, particularly in those with osteopenia or osteoporosis, although documentation that the benefit is sustained, and accompanied by reduced fracture risk is needed.    
    Alendronate (Fosamax) 10 mg/d or 70 mg/wk PO
    Risedronate (Actonel)      5 mg/d or 35 mg/wk PO
    Pamidronate (Aredia)    typically 30-90 mg IV infusion over 2- 24h every week to month        
  2. Calcitonin (Miacalcin, Calcimar, Fortical) 200 IU/d in alternating nostrils or 100 IU/d sc   
  3. Estrogen-progestin therapy
    — Estrogen-progestin therapy is beneficial in postmenopausal women with primary hyperparathyroidism because of its ability to reduce bone resorption. In two trials, serum calcium concentrations decreased by 0.5 to 1.0 mg/dL (0.12 to 0.24 mmol/L) and bone density increased slightly. In a third, larger trial, 42 women with mild hyperparathyroidism were randomly assigned to treatment with placebo or conjugated estrogens (0.625 mg/day) plus medroxyprogesterone acetate (5 mg/day) for two years. The beneficial effect of hormone therapy on bone density persisted at year four, with between-group differences in hip, lumbar spine, and forearm bone density that ranged from 7 to 8.2 percent. However, there are significant risks associated with estrogen-progestin therapy, including increased risks of breast cancer, stroke, deep vein thrombosis, and coronary heart disease. Therefore, estrogen or estrogen-progestin therapy should not be a first-line therapy for women with primary hyperparathyroidism.    
  4. Raloxifene (Evista)  
    — Raloxifene, a selective estrogen receptor modulator is for the prevention and treatment of osteoporosis. In a study of 18 postmenopausal women with asymptomatic primary hyperparathyroidism, raloxifene (60 mg/day for eight weeks) reduced mean serum calcium concentration by 0.4 mg/dL at a single time point (8 weeks) . Further data are needed before recommending raloxifene
    forr this indication.  Side effects: Hot flashes, deep venous thrombosis.
  5. Calcimimetics
    (Sensipar) Cinacalcet: 30 mg/d to 50 mg bid
    — Calcimimetic agents activate the calcium-sensing receptor in the parathyroid gland, thereby inhibiting PTH secretion. In an initial dose-ranging study, 20 postmenopausal women with mild primary hyperparathyroidism were randomly assigned to a short-acting calcimimetic or placebo. Serum PTH concentrations were reduced by 51 percent after acute therapy with the highest dose of the calcimimetic and there was a slight fall in serum calcium concentrations. However, the effect was transient (lasting less than eight hours) and was associated with a two-fold increase in urinary calcium excretion.  
    A longer-acting calcimimetic drug, cinacalcet, is now approved by the United States Food and Drug Administration for the treatment of secondary hyperparathyroidism associated with renal failure and for hypercalcemia in parathyroid cancer. Although not yet approved for use in primary hyperparathyroidism, cinacalcet may normalize serum calcium in these  primary hyperparathyroidism patients. In a two-week placebo-controlled, dose-ranging (30 to 50 mg twice daily) trial of 22 patients, mean serum PTH and calcium fell to the normal range with no consistent increases in urinary calcium excretion, possibly due to a decreased filtered load of calcium.  In a one year trial of 78 patients with primary hyperparathyroidism randomly assigned to cinacalcet or placebo (12-wk dose-titration, 12-wk maintenance, and 28-wk follow-up phases), cinacalcet therapy normalized serum calcium in 73 percent of subjects compared to only 5 percent in the placebo group. Serum PTH concentrations decreased by 7.5 percent with cinacalcet, but increased in the placebo group. Bone mineral density was unchanged in both groups. Thus, cinacalcet may be a promising future medical therapy for primary hyperparathyroidism.
  6. Other therapies — Drugs on the horizon include calcitriol analogues that inhibit PTH secretion directly, but do not stimulate gastrointestinal calcium or phosphate absorption; and drugs that block the PTH receptor.

Drug Therapy for Secondary or Tertiary Hyperparathyroidism

  1. Phosphate binders :
    Calcium carbonate: 500-1000 mg tid with meals, Calcium acetate: 667 mg, 1-3 capsules tid with meals,
    Sevelamer: up to 5 g/d
    • Inhibit intestinal absorption of phosphate
    • Lowers serum phosphate level Hypercalcemia, constipation, other GI disturbance, soft tissue or vascular calcification with calcium salts; less hypercalcemia and decreased plasma bicarbonate with sevelamer
    • Most effective in combination with dietary phosphate restriction
  2. Vitamin D analogues  
    Calcitriol: 0.25-1.5 µg/d po, Paricalcitol: 5 µg/mL, 0.04 µg/kg·d iv, Doxercalciferol: 2.5 µg po twice weekly
    • Direct transcriptional suppression of PTH synthesis
    • Lowers serum PTH level Hypercalcemia with calcitriol and other analogues in higher doses
    • Use may be limited in presence of hypercalcemia, because these drugs may worsen it
  3. Calcimimetic agents  
    Cinacalcet: 30 mg/d to 50 mg bid
    • Stimulate calcium-sensing receptors on parathyroid cells, thereby inhibiting secretion of PTH
    • Lowers serum PTH level Use cautiously in patients with a history of a seizure disorder. 30% of patients can develop nausea and vomiting
    • Approved for use in patients with secondary hyperparathyroidism due to renal failure and parathyroid carcinoma only

   
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PREOPERATIVE LOCALIZATION OF THE HYPERPARATHYROIDISM TUMOR
  • 99m-technetium sestamibi scan, often in combination with a subtraction thyroid scan using 123-I-iodine or with sestamibi double phase studies has a predictive value that can range up to 90 to 100 percent for solitary adenomas. The results with a related radionuclide, technetium-99m tetrofosmin, are similar.  Sestamibi scanning may detect multiple involved glands or a mediastinal adenoma. However, scanning for hyperplastic glands or double adenomas is less accurate. In one prospective study of 387 patients the sensitivity for single adenomas was 90 percent, but 27 percent of double adenomas and 55 percent of hyperplastic glands were missed.  The specificity of sestamibi scanning can be enhanced with delayed (two-hour) imaging and three-dimensional imaging obtained by single photon emission computed tomography (SPECT). While sestamibi imaging is now the imaging procedure of choice, particularly for localization of parathyroid tumors in the mediastinum, it is more expensive and takes more time than ultrasonography.  However, some surgeons have not found sestamibi scanning to be very reliable.
  • The predictive value of ultrasonography, magnetic resonance imaging, or thallium-technetium dual isotope scintigraphy ranges from 40 to 80 percent.  
  • It is still unclear, furthermore, whether any imaging procedure should be performed before initial surgery.  Preoperative localization is of no value if bilateral neck exploration is to be performed; usually, parathyroidectomy is a short operation with low morbidity, and the cure rate is 93 to 98 percent.

For recurrent or persistent hyperparathyroidism — Five to 10 percent of patients undergoing surgery for hyperparathyroidism have persistent disease. The approach is different in patients with recurrent or persistent hyperparathyroidism because of the differences in etiologies and in surgical morbidity due to fibrosis as compared with unoperated patients. In several studies the abnormal parathyroid glands were found at the second operation in the following sites:

  • 30 to 54 percent were in the neck.
  • 16 to 34 percent were in the mediastinum.
  • 14 to 39 percent were retroesophageal.
  • 5 percent were in the aortic arch area.
  • 8 percent were in the upper cervical area.
  • A few were in the carotid sheath.

The success rate of reoperative surgery without preoperative localization is only 60 percent; this can be improved to 95 percent or more with localization. It should be noted that localization studies identifying a single adenoma do not exclude the existence of abnormal parathyroid glands in other locations; almost 30 percent of patients undergoing reoperation have multiple gland hyperplasia.

It is clear that localization studies are needed when reoperating for persistent disease, but which procedure or combination of procedures is best has not been determined.

   
 SX  |  DX | Screening  | Causes & Diff-Dx |  Surgical RX | Medical RX |  

       2006