Primary Hyperparathyroidism: Still Evolving? (1997)

OVER THE PAST TWO DECADES, the presentation of primary hyperparathyroidism in affected patients has changed to that of a largely asymptomatic disease as multichannel screening tests have predominated in the medical marketplace. Concurrently, our understanding of the demographics, the molecular and cellular physiology, and natural history of the disease has increased substantially. With this enhanced appreciation of the disorder, guidelines for management of the disease have become firmly entrenched. In the accompanying Clinical Review, Drs. Silverberg and Bilezikian detail the explosive information that has charted the course of the disorder in recent years and the resultant care guidelines. These observations clearly delineate current, exciting information about the disease and the various arguments supporting accepted therapeutic strategies. In addition, the review details the potential that the now well established presentation of the disease is about to change once again. In essence, Drs. Silverberg and Bilezikian raise several innovative notions about the cause(s) of the apparent evolution and offer a caveat for those of us in the medical profession who care for the affected population. The authors have alerted us to be aware! Our first step of course is to read the review and develop our own opinions. Enjoy the opportunity! Marc Drezner, M.D. Editor-in-Chief Mild hypercalcemia is the hallmark of primary hyperparathyroidism as it is seen in the United States today. Unlike the disease described by Albright in the 1930s and 1940s,(1, 2) specific manifestations of primary hyperparathyroidism are uncommon. Nephrolithiasis, still the most common complication, is now found in fewer than 20% of patients. Osteitis fibrosa cystica, with its attendant radiographic features of osteopenia, subperiosteal bone resorption, brown tumors, bone cysts, and “salt and pepper” skull, is rare. The neuromuscular syndrome of primary hyperparathyroidism is virtually never seen anymore. Rather, the vast majority (approximately 80%) of patients with primary hyperparathyroidism in this country have no signs or symptoms referable to their disease at the time of diagnosis. With the advent of a sophisticated and specific set of technologies, however, it has become feasible, over the past 15 years, to evaluate the typical patient with asymptomatic primary hyperparathyroidism in ways that have helped to establish prudent guidelines for surgical or medical management. This report reviews our current understanding of this disorder and our approach to it. We also consider the possibility that the clinical profile of primary hyperparathyroidism may be about to change once again. Primary hyperparathyroidism may occur at any age, but the middle years, 40–65, predominate. The incidence is approximately 1 per 1000.(3) Primary hyperparathyroidism affects women more than men by almost 3:1. Women within the first decade after menopause appear most likely to develop primary hyperparathyroidism. In 80–85% of adults who undergo parathyroid surgery, a single adenoma is found. In approximately 15–20% of patients, all four glands are involved in a hyperplastic process. A remaining few cases of primary hyperparathyroidism are due to multiple adenomas, and in fewer than 0.5% of hyperparathyroid subjects, parathyroid carcinoma is found. The molecular and cellular pathophysiology of primary hyperparathyroidism has been the subject of much investigation over the past decade.(4) In the aggregate, the data suggest that most adenomas are monoclonal expansions of a single abnormal parathyroid cell.(5, 6) Such an observation implies an underlying molecular abnormality of that cell, giving it and its progeny a growth “advantage” over the normal cells of the gland. Despite the plausability of this reasoning, no single molecular abnormality has been identified to account for all adenomas. Indeed, in most cases of parathyroid adenoma, no specific mutation can be identified. Nevertheless, genetic abnormalities have been described in primary hyperparathyroidism. The cyclin D1/PRAD 1 proto-oncogene has received the most attention. In a small number of cases, a chromosomal rearrangement involving this cell cycle regulatory gene places it in proximity to the 5′ regulatory region of the parathyroid hormone gene.(6-8) Such proximity provides a facile explanation for abnormal growth of that cell. A second molecular mechanism is inactivation of tumor suppressor genes. In support of this mechanism, loss of heterozygosity on chromosome 11q13, chromosome 1p, and other loci has been found in some parathyroid adenomas.(9, 10) Tumor suppressor genes have been implicated most often in the multiple endocrine neoplasia syndromes in which primary hyperparathyroidism is common, in an increasing number of sporadic parathyroid adenomas, and in parathyroid carcinoma. A third putative molecular mechanism involves the calcium-sensing receptor gene. While mutations in this gene are clearly involved in familial hypocalciuric hypercalcemia, in neonatal severe primary hyperparathyroidism,(11, 12) in Jansen's metaphyseal chondrodysplasia,(13) and in some cases of sporadic hypoparathyroidism,(14, 15) it has been exceedingly difficult to implicate such mutations in primary hyperparathyroidism.(16, 17) Except for the genetic syndromes of multiple endocrine neoplasia, multiple glandular parathyroid pathology is believed to be polyclonal in origin. Occasionally even here, however, monoclonality has been demonstrated both by X chromosome inactivation analysis and by allelic loss of chromosome 11 markers.(18-20) The majority of patients with primary hyperparathyroidism are diagnosed when hypercalcemia is incidentally discovered on the multichannel screening test. Specific symptoms referable to hypercalcemia are typically not present. A history of previous neck irradiation, or endocrinopathy in the patient or a family member, or of other disorders epidemiologically associated with primary hyperparathyroidism (e.g., hypertension, peptic ulcer disease) may be obtained. Although patients sometimes complain of weakness, they are not weak clinically and do not have overt neuromuscular disease.(21) Other nonspecific features such as easy fatigability, intellectual weariness, or even depression may be reported. It has not been possible to quantify such symptomatology nor is it certain that there is an etiological relationship between primary hyperparathyroidism and these constitutional features.(22) They are usually, therefore, not factored into the assessment of symptomatology. Physical examination is generally unremarkable. The diagnostic hallmarks of primary hyperparathyroidism are hypercalcemia and elevated levels of parathyroid hormone. Improved assays for intact parathyroid hormone, including the immunoradiometric (IRMA) and immunochemiluminescent (ICMA) assays, show elevations in about 90% of patients.(23) When the parathyroid hormone concentration is not frankly elevated but in the upper range of normal, the diagnosis of primary hyperparathyroidism can still be made with confidence because it is inappropriately “increased” in the face of hypercalcemia. Virtually all other causes of hypercalcemia, with the exception of those associated with lithium and thiazide use, are associated with suppressed levels of parathyroid hormone. Further laboratory evaluation shows the serum phosphorus concentration to be in the low normal range and serum 1,25-dihydroxyvitamin D (1,25(OH)2D) and urinary calcium excretion to be in the high normal range. The latter essentially rules out the remote possibility of familial hypocalciuric hypercalcemia. A clearly low serum phosphorus concentration is seen in fewer than 25% of patients, elevated 1,25(OH)2D in approximately 30%, and high urinary calcium excretion in approximately 40% of patients. While osteitis fibrosa cystica has become a rarity in countries where the multichannel screening test is routinely used, it has become clear over the past decade that the skeleton remains very much a target of the hyperparathyroid process. Parathyroid hormone is well known to augment both bone resorption and bone formation.(24) The availability of sensitive biochemical indicators of both processes highlights the increase in bone turnover seen even in a typical patient with mild disease.(25) Indices of bone formation including total and bone-specific alkaline phosphatase (ALP) activity and osteocalcin are in the upper range of normal or modestly elevated.(26, 27) Similarly, sensitive indices of bone resorption such as urinary hydroxypyridinium cross-links of collagen are in the upper range of normal or modestly elevated in primary hyperparathyroidism.(25, 28-30) Bone densitometry has revolutionized our ability to assess the skeleton in patients with asymptomatic primary hyperparathyroidism. It has become a critically important and widely accepted aspect of the routine evaluation of the patient.(31) Information from noninvasive bone mass measurement by this means is now established as an important guideline for management. When bone mass is reduced in primary hyperparathyroidism, cortical bone—best measured at the proximal third of the distal radius—is affected first.(32) Relative preservation of bone mass is seen at sites more enriched in cancellous bone such as the femoral neck and the lumbar spine. This contrasts with the picture in nonhyperparathyroid, postmenopausal women, in whom bone loss due to estrogen deficiency involves cancellous sites first. Thus, despite the disposition of the postmenopausal skeleton to lose cancellous bone, the hyperparathyroid postmenopausal skeleton appears to maintain it. This observation illustrates the powerful anabolic effect of parathyroid hormone at cancellous skeletal sites. Histomorphometric studies of bone biopsy specimens have confirmed both the high turnover state and cortical bone loss in primary hyperparathyroidism.(33, 34) Cancellous bone volume, however, is maintained.(35-37) Furthermore, trabecular structure is preserved in primary hyperparathyroidism, with increased trabecular number, connectivity, and width of trabecular packets relative to age- and sex-matched control subjects.(38) These findings again are of special interest with regard to postmenopausal women, who make up the majority of patients with primary hyperparathyroidism. In general, these women do not appear to demonstrate superimposed effects of menopause upon the skeleton at the time the diagnosis of primary hyperparathyroidism is made. Instead, they are relatively protected from the deleterious effects of estrogen deficiency on cancellous bone. Recently, efforts to elucidate the pathogenesis of skeletal changes in primary hyperparathyroidism have focused attention upon cytokines, some of which have been identified as putative mediators of the skeletal effects of parathyroid hormone. Early investigations in this area suggest that insulin-like growth factor (IGF-1) and its binding proteins may be involved in the anabolic actions of parathyroid hormone.(39) In contrast, the bone-resorbing cytokines, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), have been shown to be increased in primary hyperparathyroidism.(40) IL-6 and TNF-α both correlate with parathyroid hormone and with bone resorption markers in primary hyperparathyroidism. Further studies are needed to clarify the significance of these observations and to document whether these cytokines are directly associated with the skeletal manifestations of the disease. Besides the serum calcium concentration and parathyroid hormone level, routine diagnostic studies in primary hyperparathyroidism include the serum phosphorus, ALP (or other marker of bone formation), 25-(OH)D, 1,25(OH)2D, BUN, and creatinine concentrations. A 24-h urine collection is obtained for calcium and creatinine. It is often helpful to measure a urinary marker of bone resorption, such as deoxypyridinoline or N-telopeptide of collagen. Bone densitometry by dual-energy X-ray absorptiometry is obtained but routine skeletal radiographs are not. The aforementioned tests allow the clinician to determine whether the patient with primary hyperparathyroidism is a candidate for surgery. Guidelines for surgery are still based upon the National Institutes of Health Consensus Development Conference on the Management of Asymptomatic Primary Hyperparathyroidism.(41) Surgery is advised in patients who meet any of the following criteria: (1) serum calcium >12 mg/dl; (2) marked hypercalciuria (>400 mg/day); (3) any overt manifestation of primary hyperparathyroidism (nephrolithiasis, osteitis fibrosa cystica); (4) markedly reduced cortical bone density (radius Z score <2.0); (5) reduced creatinine clearance in the absence of another cause; or (6) age <50 years. Using these guidelines, the categorization of patients into surgical or nonsurgical groups is different from the breakdown of asymptomatic versus symptomatic patients. Now, approximately 50% of patients will meet one or more of these criteria. Of this number, the majority (60%) will be asymptomatic but will have become surgical candidates by virtue of age, hypercalciuria, or low bone mass. In practice, not everyone meeting these criteria undergoes surgery, nor is parathyroidectomy limited to those who do. Personal and physician input remain very important, as are intercurrent medical conditions that can influence the choice. Once a decision for surgery is made, referral to an expert parathyroid surgeon is mandatory. Surgeons who are not intimately familiar with the nuances of parathyroid surgery are not going to do as well as the experienced parathyroid surgeon whose success rate is a remarkable 95%.(42) Some have argued for performing preoperative localization tests on all patients prior to surgery in order to assist even the expert surgeon. But the available techniques are still imperfect, including99mTechnetium sestamibi imaging.(43, 44) In the aggregate, they are expensive, they are less accurate than the expert parathyroid surgeon, they do not improve upon the expert surgeon's success rate, and sometimes they can be misleading. Preoperative localization tests are usually reserved for patients who have had previous neck surgery. In these patients, the operation is much more difficult and any clues can be helpful to the surgeon. After curative surgery, recovery is rapid.(45) Serum calcium returns to normal within hours to a few days thereafter. There is a 90% reduction in recurrent renal stones among those with nephrolithiasis.(46-48) Bone mass also improves after surgery, with a 12% increase in the lumbar spine and femoral neck over the ensuing 4 years.(45) Cortical bone of the distal radius also improves. The increase in bone mass is most dramatic in the subset of patients (15% of our cohort with primary hyperparathyroidism) who present with the atypical picture of reduced vertebral bone density.(49) In these patients, a marked 20% improvement in lumbar spine bone density has led us to propose that vertebral osteopenia be added to the list of guidelines for surgery in this disease. Approximately 50% of patients do not meet any surgical criteria. They are generally followed without operative intervention. Several groups have confirmed that both biochemical and densitometric indices are stable in these patients with follow-up periods of up to a decade.(50-52) Most patients who do not undergo parathyroidectomy are not given medications. Oral phosphate has some utility in controlling hypercalcemia, but it can be associated with further increases in parathyroid hormone and theoretically can lead, over the long term, to metastatic calcifications.(53) Estrogen therapy may be useful in postmenopausal women, leading to a modest reduction in the serum calcium level (about 0.5 mg/dl), but no change in the serum phosphorus or in the parathyroid hormone concentration.(54-56) The antiresorptive bisphosphonates have been investigated in primary hyperparathyroidism. Neither etidronate nor clodronate has been shown to be effective.(57) The newer, more potent bisphosphonates, alendronate and risedronate, might be expected to have greater potential, but experience with them has been limited,(58, 59) and no conclusions can yet be drawn. Development of calcimimetic drugs, which serve as calcium receptor agonists and dampen the responsiveness of the parathyroid cell, holds significant promise. These agents lower the serum calcium concentration by reducing the secretion of parathyroid hormone.(60, 61) Patients with primary hyperparathyroidism who do not undergo surgery are followed with serum calcium determinations every 6 months and urinary calcium and bone mineral densitometry annually. If a stable course can be documented over a substantial period of time (4 years), monitoring can become less frequent. Patients are always instructed to maintain good hydration, to avoid thiazide diuretics, and to be modest in their dietary calcium intake. Diets high in calcium, especially those in whom the 1,25(OH)2D is elevated, can lead to hyperabsorption of calcium and worsening hypercalcemia.(62) Diets low in calcium can conceivably lead to further stimulation of parathyroid hormone. The recommendations for calcium intake follow those of the Consensus Development Conference on Optimal Calcium Intake.(63) Prior to the 1970s, primary hyperparathyroidism diagnosed in the of a for the of associated with the such as symptomatic hypercalcemia, or The incidence of the disorder primary hyperparathyroidism an endocrine any asymptomatic patients with primary hyperparathyroidism not discovered because the diagnostic the serum calcium not routinely The and clinical of primary hyperparathyroidism a dramatic change in the with the availability of the serum calcium concentration due to the In this primary hyperparathyroidism as a very common not with and as it in but as an asymptomatic After the of patients with primary hyperparathyroidism by multichannel it that the incidence of the disease its and a be This state be lower than the in incidence that within the first few years of the the Instead, at in the incidence of primary hyperparathyroidism has been despite the availability of the Thus, than a state been over the past the incidence of primary hyperparathyroidism may be These observations are and be confirmed by studies in other in the United one for this that the aforementioned is not of the of primary hyperparathyroidism, it be that are about to experience a in the incidence of this common in care that for biochemical determinations be and If these become will not order a serum If do not routinely order a serum calcium, primary hyperparathyroidism will no be diagnosed by Rather, the physician will order the serum calcium when or there are features in the history and examination that to that test. In other the decision to order the serum calcium to the that the If this is to be one might that primary hyperparathyroidism is about to from our clinical that the incidence of the disease will no its and that will a disease whose time has and as it this is the that the calcium is critically important for all that are much more of hypercalcemia as an abnormality that can that the serum calcium be known in the of diagnosis and of other and that for the of a serum calcium can be If this it any in the with which a serum calcium is and incidence will not change substantially. Furthermore, it is possible that primary hyperparathyroidism an disorder, for it once again as a symptomatic disease. In those of the where are not routinely primary hyperparathyroidism remains a symptomatic disease. The experience in of and illustrates this This analysis us with at one have not seen more symptomatic disease over the past a of asymptomatic there are patients who still present with primary hyperparathyroidism. it be that our has been that have the disease in everyone it to that But that is not one some of those patients who are to develop to after of the that such patients are all upon they develop from countries in which the is not available might the to this Several the have documented that symptomatic hyperparathyroidism typically in patients who have severe D It as it believed years that the of D deficiency and primary hyperparathyroidism patients to develop the skeletal manifestations of primary therefore, may not have seen more symptomatic disease over the past is because D has been the than the exception in the United here, however, are about to a Our is to much less than because of about and In addition, the of that the for the of to D in the a for the as the of other such as the and make of D more In addition, are few and between (e.g., is the D deficiency become more in the United primary hyperparathyroidism may once again become a more symptomatic disease. We are still with a number of our is about primary hyperparathyroidism. for which more information is needed include of potential of such as the and certain of patients who may be at such as patients have not been long without to assess the course of skeletal Similarly, patients have not been long after curative surgery to to the increase in bone mass We greater understanding of the underlying and cellular for the effects of parathyroid hormone on cancellous and cortical bone in the preoperative state and the anabolic effect following parathyroid surgery. the disorder monitoring because it may well be again our This in by National Institutes of Health and