Presentation, Evaluation, and Management of Primary Hyperparathyroidism
Author: Cynthia G. Kreger, MD, Associate Professor of Internal Medicine, The Ohio State University Health Sciences Center, Columbus, OH.
Peer Reviewer: D. Sudhaker Rao, MBBS, FACP, Division Head, Bone & Mineral Division; Director, Bone & Mineral Research Laboratory, Henry Ford Health System, Detroit, MI, and Clinical Assistant Professor of Medicine, University of Michigan, Ann Arbor, MI.
Introduction
Hypercalcemia is a fairly common laboratory finding and may result from any one of several causes. (See Table 1.)1,2 In more than 90% of the cases, however, it is due to either primary hyperparathyroidism (PHPT) or malignancy.1,2 In outpatient settings, the etiology of hypercalcemia is most often PHPT.3 It is for this reason that the primary care physician should be thoroughly familiar with the current presentation, evaluation, and management of this common condition.
The clinical picture of primary hyperparathyroidism has changed dramatically over the last 60 years. Historically, this diagnosis was made during the search for an underlying cause of non-traumatic bone fractures, recurrent nephrolithiasis, or symptomatic hypercalcemia. Definitive surgical cure with parathyroidectomy was the recommended treatment. In the last several decades, it has become apparent that not only are there many more individuals in the population with mild PHPT, but that the clinical picture and natural history of this condition have changed.2,4-8 As a result, many clinicians have questioned the need for surgical intervention as the recommended treatment for all patients.5,6,8 A thorough understanding of the emerging picture of this condition, natural history, and complications is needed to determine who may be safely considered for judicious medical monitoring and who should be referred for surgical intervention.
Definition, Epidemiology, and Pathology
Definition. The hallmark of PHPT is hypercalcemia in conjunction with excessive or inappropriately elevated levels of parathyroid hormone. In this condition, there is an intrinsic abnormality in the parathyroid gland. In contrast, secondary hyperparathyroidism is a response to an extrinsic demand for increased levels of parathyroid hormone, found in conjunction with low or normal levels of serum calcium.
Incidence and Prevalence. Once characterized by "bones, stones, and groans" and found as an endocrine rarity, PHPT is now one of the most commonly diagnosed endocrine disorders.6 This may be primarily attributed to the introduction of automated biochemical testing in the 1960s and 1970s, which provided clinicians with routine serum calcium levels on patients for whom an indication for ordering the test was lacking, thus incidentally identifying cases of hypercalcemia.4,6,8 As a result, the incidence (the number of new cases diagnosed over a specified period of time) of this condition in the United States rose four-fold and is now estimated at approximately 100,000 new cases/year.4,8-10 The prevalence (the proportion of the population affected with the disorder at a given time) is 1-5 cases per 1000 adults.4,8,9 Although PHPT may occur at any age, it is most commonly found in the fifth and sixth decade of life, with a preponderance in postmenopausal women, regardless of race.9,10
Etiology and Pathology. Current research suggests that the etiology of PHPT is monoclonal expansion of a single abnormal cell in a majority of cases.2,10 Prior neck irradiation may be a risk factor (reported in 15-25% of patients),8,9 although the significance of this association is unclear. In 80-85% of the cases, PHPT is caused by a solitary parathyroid adenoma.2,4,10 Less commonly, there is hyperplasia of all four glands (15-20%), multiple adenomas (2-4%), or parathyroid carcinoma (0.5-1%).2,4,10
Clinical Presentation and Varieties of PHPT
Asymptomatic PHPT. Table 2 outlines the most common clinical presentations of PHPT. The vast majority of patients, greater than 80% in the United States, do not have symptoms traditionally associated with hypercalcemia or parathyroid hormone excess; nor do they have the complications historically found with PHPT.2,4,8,10 Symptomatic hyperparathyroidism is the exception rather than the rule. The lack of traditional signs and symptoms is generally attributed to the mild degree of hypercalcemia, the relative stability of the calcium level, and to the slow rate of rise of the calcium.8 Most commonly, the clinician finds an incidentally elevated calcium level on a routine battery of tests, in an otherwise asymptomatic individual, and subsequently makes the diagnosis of PHPT.
It should be noted that the term "asymptomatic" in this context excludes neurobehavioral symptoms. Careful history taking, however, commonly reveals several nonspecific symptoms as outlined in Table 3.7,8 The prevalence of these symptoms has been noted to be greater in patients with PHPT compared to other outpatients, although this is not a consistent finding.7,8 These rather vague symptoms are not clearly due to the disorder as they do not correlate with the serum calcium nor PTH level, and they do not necessarily resolve with parathyroidectomy.6,7 There are, however, many anecdotal reports of patients feeling "much improved" after parathyroidectomy,11 but consistent, quantitative data in this area are lacking. In sum, no clear conclusions can be drawn regarding a relationship between these constitutional symptoms and PHPT; thus, these are disregarded when evaluating a patient for symptoms of hyperparathyroidism.
Table 1. Causes of Hypercalcemia
· Primary hyperparathyroidism
· Malignancy
· Non-parathyroid endocrine disorders
· Granulomatous disorders
· Medications
· Familial hypocalciuria hypercalcemia
· Immobilization
· Parenteral nutrition
· Aluminum excess
· Renal diseases
Adapted from Reference 1
History and Physical Examination. Despite the above, the patient should be diligently questioned about a prior history of fractures or stone disease, as well as classic symptoms of hypercalcemia or overt neuromuscular disease. In addition, a history of concurrent endocrinopathies in the patient or other family members should be sought. Prior history of head and neck irradiation should be ascertained. Use of thiazide diuretics or lithium should be ruled out. Although the association of thiazide and thiazide-like diuretics with PHPT is controversial,7 lithium has clearly been associated with a clinical profile very similar to PHPT after extended use of the drug.2,7
The physical exam of these patients is generally unremarkable. Although hypertension may be found, this has not been definitively related to hyperparathyroidism.4,7 Palpable enlargement of the parathyroid glands is rare and usually only found when parathyroid cancer is present.4,12 Objective signs of the neuromuscular syndrome of PHPT (muscle atrophy, overt weakness, gait disturbance, hyperreflexia, or tongue fasiculations) are generally not found.4,13 Testing for muscle weakness should be routinely performed, however, particularly evaluating for subtle proximal muscle weakness by asking the patient to rise from a sitting position unassisted with both arms folded across the chest.
Symptomatic Renal Disease. The incidence of stone disease in patients with hyperparathyroidism has decreased significantly, from more than 50% several decades ago to most likely less than 10% in more recent series.2,4,6,14 The pathogenesis of stone formation in PHPT remains unclear, although the associated finding of hypercalciuria in 35-40% of these patients may play a role.4,14
Table 2. Clinical Presentation of Patients with PHPT
· Asymptomatic mild hypercalcemia
· Mild hypercalcemia with nephrolithiasis
· Mild hypercalcemia with osteopenia
· Moderate hypercalcemia with osteitis fibrosa cystica
· Acute life-threatening hypercalcemia
· Multiple endocrine neoplasia syndromes
· Parathyroid carcinoma
Adapted from Reference 4
In addition to nephrolithiasis, nephrocalcinosis (calcium-phosphate crystals deposited throughout the renal parenchyma), although quite rare, may also be seen.4 Chronic hypercalcemia itself can cause tubulointerstitial damage and renal insufficiency, even without overt evidence of stone disease, nephrocalcinosis, or hypercalciuria.
Skeletal Disease. Clinically, the classic picture of osteitis fibrosa cystica, characterized by bone pain, pathologic fractures, and specific radiographic manifestations, is now rarely seen. The skeleton is, however, a primary target for excessive PTH, with subtle changes in bone density and architecture found even in mild hyperparathyroidism.2,6,15 The availability of bone densitometers has paved the way for detecting these subtle manifestations of parathyroid dependent bone disease and now play an important role in the evaluation and management of the patient with PHPT.15
The effect of excess parathyroid hormone secretion on bone metabolism is complex, exerting both an anabolic and catabolic effects, and the effects are different at different skeletal sites. In PHPT, increased bone resorption and, thus, decreased bone density is commonly found in cortical bone of the appendicular skeleton.10,13,15 This is best evaluated by measuring bone density at the proximal third of the distal radius.10,13,15 A majority of patients with mild, asymptomatic PHPT will have cortical osteopenia greater than expected for age, race, and gender at the time of diagnosis.7,10,13,15,18
Concern has been raised about the deleterious nature of PTH excess over time in promoting osteopenia and thus raising the risk of fracture. Although there are conflicting results,16,17 most studies have not demonstrated progressive cortical bone loss over time,4,6,7,18 and, thus far, studies have not consistently revealed an increased risk of fracture of long bones or of the proximal femur.7,19,20
In contrast to cortical bone, there appears to be relative preservation of cancellous bone of the vertebral spine in a majority of patients with hyperparathyroidism.4,21,22 This preferential preservation of cancellous bone is most strikingly appreciated in postmenopausal women who are at risk for early, accelerated vertebral bone loss due to estrogen deficiency.10,23,24 This has been an important finding, as it has dispelled the concern that postmenopausal women (the largest proportion of patients with PHPT) who are at risk for vertebral osteoporosis are at even greater risk if they have concomitant PHPT and should thus undergo parathyroidectomy.10,23,24 There appears to be, however, a subgroup of postmenopausal women who do not manifest this relative preservation of cancellous bone but instead are found to have vertebral bone loss in the face of PHPT and thus should be managed differently.17,25
The hip is a near even mixture of cortical and cancellous bone; thus, in PHPT, it may show accelerated bone loss as compared to the vertebral spine.15 In evaluating dual photon absorptiometry reports, this disproportionate bone loss may be a clue to search for underlying hyperparathyroidism. The biochemical reasons for the differential effect of PTH on various bone sites is not yet fully understood.
Table 3. Nonspecific Symptoms in Patients with PHPT
· Anxiety
· Depression
· Memory difficulty
· Concentration difficulty
· Inner tension
· Reduced sleep
· Indecision
· Aggressiveness
· Easy fatigability
· Sadness
Adapted from References 7 and 11
Acute Symptomatic PHPT. There is a small minority of patients with hyperparathyroidism (0.7-3%) who present with acute life-threatening symptoms.26 The calcium and parathyroid hormone levels in these patients are remarkably high. The calcium may be in the 15.0-26.0 mg/dL range, while the PTH level may be up to 20 times normal.26 Most patients presenting with acute PHPT have evidence of skeletal and renal involvement.26 Intercurrent illness, bed rest, and/or volume depletion may be contributors to this more acute, symptomatic presentation of PHPT and may cause an otherwise asymptomatic patient to become symptomatic. The treatment of these patients is acute medical management of the life-threatening hypercalcemia followed by definitive surgical cure.
Parathyroid Cancer. Parathyroid cancer is a rare cancer with low malignant potential, demonstrating an indolent nature, with primarily local recurrence and late metastasis.12 There is no evidence for malignant transformation of hyperplastic or adenomatous parathyroid tissue.12 The clinical profile of the patient with parathyroid cancer differs from the patient with benign PHPT as outlined in Table 4.12 The challenge to the clinician is to consider this possibility when evaluating patients with PHPT.
Table 4. Characteristics of Parathyroid Carcinoma as Contrasted to Mild, Benign PHPT
· Female to Male ratio 1:1
· Serum Ca level much higher
· Invariably symptomatic with traditional signs and symptoms of hypercalcemia
· PTH level much higher
· Higher level of alkaline phosphatase
· Frequent evidence of renal and skeletal involvement
· May have palpable neck mass
· May have paralysis of recurrent laryngeal nerve
Adapted from Reference 12
MEN Syndromes. Multiple endocrine neoplasia (MEN) type I is characterized by benign tumors of the parathyroid, pancreatic islet, and anterior pituitary cells. Most commonly, these patients present with PHPT, and, in a majority of cases (50%), have evidence of nephrolithiasis and, less commonly (10%), clinically apparent bone disease.14 There is not the female predominence in the MEN I syndrome seen in sporadic PHPT, and patients most commonly present at an earlier age.14 In contrast, MEN IIa is characterized by medullary carcinoma of the thyroid gland, pheochromocytoma, and parathyroid hyperplasia. The parathyroid disease in these patients, however, is most commonly entirely asymptomatic.14
Other Associated Disorders/Conditions. Although the skeleton and kidneys are the organs traditionally linked to parathyroid disease, the effect on other end organs has been questioned. The role of PHPT and cardiovascular disease is controversial. In some series, hypertension was more prevalent in patients with PHPT compared to controls and, in some cases, reversed after parathyroidectomy.2,6 There are reports of associated left ventricular hypertrophy, calcific myocardial deposits, calcific valvular disease,29,30 and an increased risk of death with PHPT.6,9 In one recent series of patients, parathyroidectomy was associated with reversal of left ventricular hypertrophy in a subset of patients.30 Thus far, the strongest association of cardiac disease with PHPT appears to be in older patients with higher calcium levels and more severe, classic, parathyroid disease.29 More data are needed to clearly define the association of PHPT with heart disease and how this applies to the majority of patients with mild, seemingly asymptomatic, PHPT.
Table 5. Disorders Loosely Associated with PHPT
· Gout
· Pancreatitis
· Pseudogout
· Hypertension
· Peptic ulcer disease
· Nonparathyroid cancers
Several other disorders have been loosely associated with PHPT. (See Table 5.)7 The data, however, are equivocal. Peptic ulcer disease and pancreatitis do not appear to be found with greater frequency in patients with mild PHPT compared to controls.7 There are some reports of an increased frequency of nonparathyroid cancers in patients with PHPT.6,7 Although this appears somewhat coincidental, more data are needed to be certain that a higher likelihood of cancer in patients with PHPT does not exist.
Table 6. Biochemical Manifestations of PHPT
· Elevated serum calcium concentration (most commonly less than 1 mg/dL above normal)
· Elevated parathyroid hormone level (usually less than 2 ´ upper limits of normal)
· Mildly low serum phosphorus level (less than 2.5 mg/dL-25% of the time)
· Modestly elevated alkaline phosphatase level
· Low or normal 25-hydroxyvitamin D
· Mildly elevated 1-25 dihydroxyvitamin D (frankly elevated 25-35% of the time)
· High normal 24 hour urine calcium excretion (> 250 mg in women, > 300 mg in men - 35-40%)
Adapted from Reference 4
Diagnosis and Biochemical Evaluation
The characteristic biochemical manifestations of PHPT are summarized in Table 6. The hallmark is persistent hypercalcemia, although occasional fluctuations into the normal range can be noted. The hypercalcemia is usually mild, in the range of 1 mg/dL above normal.4,5 Measurement of total serum calcium is the least expensive, most available, and most reliable measurement if evaluated in light of the serum albumin concentration.5,8 If hypoalbuminemia is suspected, then an ionized calcium level should be obtained. To confirm the diagnosis of hypercalcemia, it is important to eliminate, if possible, any drugs the patient may be taking that can increase the serum calcium concentration (see Table 7) and consider obtaining the sample in the fasting state.
Concomitant measurement of intact parathyroid hormone is needed to secure the diagnosis. In 90% of cases, the PTH level will be frankly elevated, although generally less than two times the upper limits of normal.4,10 In the other 10% of cases, the PTH concentration may be in the upper range of normal but inappropriately "increased" in the face of hypercalcemia and thus consistent with PHPT.4,10 In contrast, in all other nonparathyroid causes of hypercalcemia the PTH concentration will be undetectable or very low. Ectopic secretion of PTH is so rare that the clinician only needs to consider this when the patient has a known malignancy or has already undergone unsuccessful neck exploration for hyperparathyroidism.5
Table 6 also outlines other biochemical changes seen in PHPT that are consistent with, although not diagnostic of, the disorder.4,10,13 Markers of bone turnover, such as the total alkaline phosphatase level, and the bone specific isoenzyme, tend to be high normal or mildly elevated when adjusted for age. The serum phosphorus level is generally low to low normal. 25-hydroxyvitamin D is in the lower normal range. In addition, 1,25-dihydroxyvitamin D is high normal or frankly elevated, and 24-hour urinary calcium excretion is in the high normal to excessive range. A majority of patients with mild, asymptomatic, PHPT will have a similar biochemical profile.4,10,13
Table 7. Medication That Can Cause Hypercalcemia
· Thiazide Diuretics*
· Lithium
· Vitamin A Toxicity
· Vitamin D Toxicity
· Mik-alkali syndrome
· Estrogens/Antiestrogens
* although many question this relationship
Adapted from Reference 1
Table 8. Indications for Surgery in Otherwise Asymptomatic Patients with PHPT
· Markedly elevated serum calcium level (e.g., 1-1.6 mg/dL above accepted normal range).
· Previous episode of life threatening hypercalcemia.
· Decreased creatinine clearance (e.g., CrCl decreased to 30% of age-matched normal values).
· Presence of kidney stones.
· Markedly increased 24-hour urine calcium excretion (e.g., greater than 400 mg/24).
· Substantially decreased bone mass (e.g., bone mass more than 2 SDs less than those of age-matched controls).
· Patients for whom medical follow-up is not desirable nor suitable. (e.g., patients who request surgery, patients who are unlikely to return for consistent follow-up, patients with coexisting illnesses that complicate management, or patients less than 50 years old).
Adapted from Reference 5
Other studies that should be obtained include a serum creatinine level and 24-hour urine creatinine clearance to evaluate for renal insufficiency.4,8,10,13 Dual energy x-ray bone densitometry, including evaluation of the forearm (which best reflects cortical bone), should be obtained to assess the effect of PTH-dependent changes in bone density.4,8,10,13 Routine radiographs of the skeleton and routine abdominal films looking for renal stones are not necessary.4,8,10,13 Bone biopsy is generally used only for research purposes. What role echocardiography or cardiac magnetic resonance imaging should play in the evaluation of the patient with PHPT remains unclear.
Management of the Patient with PHPT
Historically, untreated PHPT was associated with severely progressive metabolic bone disease, recurrent nephrolithiasis, or otherwise symptomatic hypercalcemia. Thus, treatment was definitive surgical cure with parathyroidectomy. Currently, the majority of data favors a stable clinical and biochemical course for mild, asymptomatic PHPT diagnosed fortuitously.18,24,26 The calcium and PTH levels tend to remain fairly constant.18,24,26 Osteopenia at cortical sites tends to be non-progressive,18,24,26 and an increased risk for osteoporotic fractures has not been demonstrated.18,24,26 There is no current evidence to suggest that patients with mild PHPT will suffer progressive renal impairment.18,26 Acute, hypercalcemic crises are uncommon.27 As a result, an NIH conference was convened in 1990 to develop guidelines for the diagnosis and management of asymptomatic primary hyperparathyroidism, including the proper role of surgical intervention.5
Table 9. Suggested Surveillance and Recommendations for Asymptomatic Patients with PHPT Not Undergoing Surgery
MONITOR SEMIANNUALLY
Blood pressure
Serum calcium determination
Serum creatinine
Creatinine clearance
24-hour urine calcium concentration
Development of symptoms traditionally associated with PHPT
MONITOR ANNUALLY
Bone densitometry with DEXA (repeated after 1-2 years)
ADDITIONAL RECOMMENDATIONS
Avoid dehydration and immobilization
Consume a diet adequate in calcium
Avoid or use cautiously thiazide diuretics
Adapted from Reference 5
Parathyroidectomy. Patients manifesting symptomatic PHPT with either significant bone, renal, gastrointestinal, or neuromuscular symptoms should be evaluated for surgical management by an experienced parathyroid surgeon.5 The referral to a surgeon with expertise in this area is supported by the high cure rate (95%) as compared to that with surgeons of lesser experience.5,10,13 Preoperative localization of the abnormal parathyroid tissue is not supported by the current data.5,10,13 Localization techniques are expensive, imperfect, and add little to the accuracy for surgical cure in the hands of an expert surgeon.5,10,13 After successful parathyroidectomy, the biochemical abnormalities normalize. In addition, bone density generally improves at all sites, although less vigorously at cortical sites.23,31
Asymptomatic patients who have any one of the criteria listed in Table 8 should also be considered for surgery.5,13 Age less than 50 has been suggested as a criterion for consideration for surgical intervention because of the limited knowledge regarding the long-term consequences of untreated PHPT and the length of time close medical follow-up would be needed. These guidelines are an attempt to identify patients who may be at risk for end organ complications of PHPT or symptomatic hypercalcemia, if not provided definitive therapy with parathyroidectomy. Currently, there are no data supporting the predictive value of these criteria. Others have suggested that patients with very low vertebral bone mass found in conjunction with PHPT be offered parathyroidectomy. Although an uncommon finding, such patients have demonstrated marked improvement in bone mass after surgical treatment regardless of the cause for the vertebral bone loss.13,25
These are only guidelines, and individual physician discretion, the patient's comorbid illnesses, patient preference regarding surgery, and access to an experienced surgeon are all additional factors influencing the management decision. Any patient who meets criteria for surgery and declines recommended surgery should be followed closely for progressive complications of hypercalcemia.
Medical Monitoring. Asymptomatic patients who have only mildly elevated serum calcium concentrations, no previous episodes of life-threatening hypercalcemia, normal renal function, and normal or only mildly diminished bone mass, may be considered for close medical monitoring.5 The goal of monitoring in a patient not undergoing surgical cure is to detect a rise in calcium level, renal impairment, presence of kidney stones, or significant change in bone density. Table 9 outlines the guidelines for judicious medial monitoring.5 Once stability is determined over a three-year period, the interval for monitoring can be extended. It should be noted that the burden as well as expense of medical follow-up, vs. surgical treatment, has not been studied.
Patients being followed medically should be instructed to avoid dehydration or immobilization, both of which may worsen hypercalcemia.32,33 Despite the hypercalcemia, a diet adequate in calcium (approximately 1000 mg/d) should be recommended except in patients with a history of nephrolithiasis.34 A diet deficient in calcium may theoretically increase the stimulus to PTH secretion.32,33 Although there are few formal studies evaluating the safety of thiazide diuretics in patients with PHPT, most recommend cautious use if at all.5,32,33
Despite the debate over the last 30 years about how to manage patients with asymptomatic PHPT, these guidelines are clearly in evolution. If, indeed, clinically significant consequences for silent PHT mediated bone loss become apparent, or an increase in cardiovascular morbidity and mortality is found among patients with very mild PHPT, then a call for surgical treatment of all patients may again be appropriate.
Pharmacologic Therapy. There is presently no specific medical treatment for hyperparathyroidism. Drug intervention is currently aimed at decreasing parathyroid hormone action on target tissues such as bone. Although oral phosphate therapy has been associated with a decrease in serum calcium in some patients, it is not currently recommended due to concern regarding potential metastatic calcification as well as uncertainty about the long-term effect on renal function and bone metabolism.32,33 Oral estrogen in postmenopausal women has been shown to decrease serum calcium, decrease urinary calcium excretion, improve calcium balance, and decrease the reabsorption rate at bone.23,33,35,36 Thus, oral estrogen (transdermal estrogen has not been studied in this population) may be a useful treatment in postmenopausal women with PHPT unless otherwise contraindicated. The older biphosphonates (etidronate and clodronate) have not been shown to be effective in treatment of PHPT.32,33 The role of the newer biphosphonates (alendronate and risendronate) in patients with PHPT has yet to be fully studied.32,33,37
A new class of drug, calcimimetic molecules, which mimic the effect of calcium on calcium receptors with resultant decreases in PHT and calcium levels and increased calcium excretion, is being studied.38,39 Although the long-term safety and efficacy have yet to be established, promise exists for such medical treatments in the future.
Conclusion. What was once a rare endocrine disorder is now a very common one, with a different clinical presentation than that described by Albright in the 1930s. It is not entirely clear why this is the case. Much is yet to be understood regarding the relationship of primary hyperparathyroidism to neurobehavioral symptoms, risk of bone fracture, and cardiovascular disease. The clinician, however, can feel fairly confident that if, indeed, the patient has no symptoms traditionally associated with hyperparathyroidism, has only mild hypercalcemia, normal and stable renal function for age, and stable or normal bone mass, then a watchful approach is a safe management strategy. It remains to be seen if the apparent prevalence of this disorder in the population will undergo yet another change as clinicians find themselves no longer obtaining "routine" chemistries, including calcium levels, in this age of managed care. In addition, it remains to be seen what effect, if any, vitamin D deficiency in our current diet40 will have on the presentation of this common endocrine disorder.
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