Primary Hyperparathyroidism: Pathophysiology, Surgical Indications, and Preoperative Workup

Primary hyperparathyroidism (PHPT) is characterized classically by hypercalcemia and levels of parathyroid hormone (PTH) that are frankly elevated or inappropriate in the presence of hypercalcemia. Patients with the disease today in the United States bear little resemblance to those with the severe disorder of “stones, bones, and groans” described by Fuller Albright and others in the 1930s. Then, patients typically had skeletal manifestations described as osteitis fibrosa cystica, which were exemplified by brown tumors of the long bones; subperiosteal bone resorption; distal tapering of the clavicles and phalanges; and salt-and-pepper–appearing erosions of the skull on radiograph ( Figure 53.1 ). Nephrocalcinosis was also present in approximately 80% of patients. Neuromuscular dysfunction was characterized by proximal muscle weakness. The widespread use of automated biochemical screening in the United States, starting in the 1970s, and subsequently by other countries, signaled two important changes in the recognition of this disease. It became much more common with a 4- to 5-fold increase in incidence. The second noteworthy change was the recognition that a clear majority of patients discovered in this way did not manifest the classical features of the disease. They were said to be asymptomatic. Nephrolithiasis lingered as the most common overt clinical manifestation of the disease, but its incidence fell to 15% to 20%. Radiologic manifestations became a curiosity, and neuromuscular dysfunction essentially disappeared.

Little controversy exists concerning appropriate therapy for PHPT in its classic form. In the presence of symptoms, either of hypercalcemia or overt target involvement, surgery was and still is indicated. However, with clear-cut symptoms absent in most patients whose disease was discovered by biochemical screening tests, the need for parathyroidectomy in all patients was questioned. This dilemma led to four International Workshops on the Management of Asymptomatic Primary Hyperparathyroidism, the most recent of which occurred in 2013. Participants and attendees reviewed the features of the two presentations of the disease—symptomatic versus asymptomatic—with attention to technological advances that have provided over the past several decades greater insights into the extent to which asymptomatic disease could also be accompanied by subclinical manifestations of target organ involvement as well as by information about putative off-target actions of PTH in this disease. Moreover, long-term natural history studies of patients who did or did not undergo parathyroidectomy helped place revised guidelines into context. Approaches to medical management with pharmacologic approaches advanced. Finally, over the past 15 years, yet another phenotype of primary hyperparathyroidism emerged, namely in those who demonstrate elevated levels of PTH in the absence of hypercalcemia. This third phenotype, normocalcemic PHPT, presented yet another challenge to the management of this disease.

In this chapter, we review the chronology of advances in the various phenotypes of primary hyperparathyroidism while providing a newer perspective, namely that technology has helped reinterpret this disease. Worldwide, all three forms of PHPT coexist today with frequencies varying by countries and their different approaches to medical care as well as to individual epidemiologic features of the population.

Clinical Presentations of Primary Hyperparathyroidism

Symptomatic Primary Hyperparathyroidism

As noted earlier, this form of PHPT is historically the way this disease presented before the advent of multichannel screening technology. Symptoms were due to hypercalcemia, per se, often with levels of 13 to 16 mg/dL and with overt skeletal and/or renal manifestations. Over the years, it has become apparent that this form of PHPT can be exacerbated with regard to clinical symptomatology by vitamin D deficiency. The hypothesis of Stanbury in the early 1970s—namely that PHPT can worsen in the presence of vitamin D deficiency— has been documented clearly during the ensuing decades. The pathophysiology of this hypothesis relates to the normal physiologic relationship between vitamin D and PTH. With vitamin D deficiency, PTH levels will rise. This relationship is still evident in PHPT. One of the best examples of this relates to a comparison of two different cohorts of patients with PHPT from New York and China. The Chinese cohort was much more symptomatic; the group demonstrated average 25-hydroxyvitamin D levels of about 9 ng/mL, which was markedly low. On the other hand, the New York cohort, with much less symptomatology, had levels of 25-hydroxyvitamin D of 21 ng/mL. Giving credence to the concept that the asymptomatic variant of the disease surfaced with the use of biochemical screening, the New York cohort was identified in this way, but the Chinese cohort was identified only after patients manifested features of the disease.

Epidemiology of PHPT

PHPT mainly affects people in their middle years with a peak incidence between 50 and 60 years of age. However, the disease appears from infancy through all stages of life. Women are affected more frequently than men, approximately 3:1 to 4:1. Typically, when biochemical screening is part of a country’s healthcare system, patients are often discovered to have elevated serum calcium concentration during evaluations for an unrelated medical problem or simply though routine health screening. At the time of diagnosis, under these conditions, most patients with PHPT do not have classic symptoms or signs associated with disease. Kidney stones are uncommon, and clinical fracture events are rare. Diseases epidemiologically (although not etiologically) linked with PHPT, such as hypertension and peptic ulcer disease, are seen commonly but no more so than in unaffected individuals. Constitutional complaints, such as weakness, easy fatigability, depression, and intellectual weariness, also manifest themselves. Results of physical examination are generally unremarkable. Band keratopathy, a former hallmark of classic PHPT resulting from deposition of calcium-phosphate crystals in the cornea, is rarely seen today, even by slit-lamp examination. The neck shows no masses. The abnormal parathyroid cannot be felt. The neuromuscular system is normal on routine examination.

The differential diagnosis of PHPT includes the other major cause of hypercalcemia, malignancy, which is readily distinguished from PHPT. Patients with hypercalcemia of malignancy typically have symptoms with advanced disease that has already been diagnosed. An exception is multiple myeloma in which hypercalcemia can be the initial manifestation. Biochemically, PTH levels are suppressed in malignancy. Classic immunoassays for PTH, used widely now for more than 30 years, facilitate the distinction between primary hyperparathyroidism and hypercalcemia of malignancy. Very rarely, a patient with malignancy is shown to have elevated PTH levels resulting from the ectopic secretion of native PTH from the tumor itself. Much more commonly, the malignancy is associated with the secretion of PTH–related protein (PTHrP), a molecule that is not detected by immunoassays for PTH. It is more common for a malignancy to appear with coexisting PHPT than for hypercalcemia to be caused by ectopic PTH secretion from a malignancy.

Skeleton

Although osteitis fibrosa cystica, the classic radiologic depiction, is distinctly unusual in patients who have PHPT in the United States, this does not imply that the skeleton is unaffected in those with asymptomatic disease. There is now abundant evidence for skeletal involvement in the hyperparathyroid process. The availability of sensitive techniques to monitor the skeleton has given us an opportunity to address these issues in patients who have the asymptomatic variant of the disease.

Bone Densitometry

The advent of bone mineral densitometry as a major diagnostic tool for osteoporosis occurred when the clinical profile of PHPT was changing from a symptomatic disease to an asymptomatic one. Questions about skeletal involvement in PHPT could be addressed despite the absence of overt radiologic features of the disease. Dual energy x-ray absorptiometry (DXA) in PHPT has provided insight in this regard. Three-site densitometry (lumbar spine, hip, and distal 1/3 radius) has been particularly informative because of the proclivity of PTH to be catabolic at cortical sites (e.g., distal 1/3 radius) and anabolic at cancellous sites (e.g., lumbar spine). In PHPT, bone density at the distal third of the radius is diminished. Bone density at the lumbar spine is only minimally reduced, typically within 5% of age-matched mean values. The hip region, containing a relatively equal mixture of cortical and cancellous elements, shows a densitometric value that is intermediate between the cortical and cancellous sites ( Figure 53.2 ). These observations initially supported not only the notion that PTH is catabolic in cortical bone but also the view that PTH can have anabolic properties in cancellous bone under specific circumstances. In postmenopausal women with PHPT, the same pattern was observed. Thus postmenopausal women with PHPT show a reversal of the pattern typically associated with postmenopausal estrogen deficiency—namely preferential loss of cancellous bone. These observations suggested that PHPT may help protect postmenopausal women from cancellous bone loss due to estrogen deficiency.

The bone density profile in which skeletal mass is relatively preserved at the vertebrae and diminished at the more cortical distal radius does not always appear in PHPT. A small group of hyperparathyroid patients shows evidence of vertebral osteopenia at the time of presentation. In our natural history study, approximately 15% of patients had a lumbar spine Z score (number of standard deviations away from age and sex-matched mean) of less than 1.5 at the time of diagnosis. In addition, patients with PHPT can show uniform reductions in bone mineral density (BMD) at all sites, whereas others, although rare, have normal bone density at all sites.

New Insights Into the Skeleton Based Upon Imaging Technology

Although BMD is a gold standard for clinical assessment of the skeleton, it does not give direct insight into skeletal microstructure. The advent of high-resolution peripheral computed tomography (HRpQCT) permitted noninvasive assessment of skeletal microstructure in this disease. HRpQCT visualizes both the cortical and trabecular compartments of the skeleton and thus can ascertain the extent to which the trabecular skeleton can be involved in this disease. The impetus for this inquiry came from studies, noted later, that suggested from both epidemiologic and prospective data a global increase in fracture risk, not simply the nonvertebral skeleton as was suggested by DXA. By HRpQCT, we and others have shown that both the cortical and trabecular compartments of bone are adversely affected in PHPT. Stein et al. showed even further that by individual trabecular segmentation analysis, vertically oriented rods were predominant over horizontally disposed elements. This kind of topology results in reduced bone strength, as was shown by finite element analysis in this study.

HRpQCT provides great insight into skeletal microstructure in PHPT, but it is not and will never be clinically available on a routine basis. Potentially, a method to assess skeletal microstructure clinically would provide access to this kind of information to any clinician. The trabecular bone score (TBS) is a textural analysis of the lumbar spine image obtained by DXA. Based upon a software algorithm that can semiquantitatively determine the extent of homogeneity or heterogeneity of bone, it determines microstructural quality. As shown by Silva et al. and by Romagnoli et al., TBS scores are significantly lower in PHPT than lumbar spine bone mineral densitometry by DXA. Applied to PHPT, these new imaging technologies clearly demonstrate that both cortical and trabecular compartments of bone are affected.

Bone Histomorphometry

To a certain extent, analyses of percutaneous bone biopsies from patients with PHPT have confirmed the pervasive nature of skeletal involvement in PHPT. Cortical thinning and a very dynamic process associated with high turnover and accelerated bone remodeling are regularly observed. The inability to perceive trabecular involvement may speak to the possibility that the iliac crest, the site of the bone biopsy, as more direct measurements of the nonvertebral skeleton. It is of note that in HRpQCT studies, the radius and the tibia are measured.

Fractures

For many years, the question of fracture incidence in PHPT was an open one. Early studies by Dauphine et al. reported an increased prevalence of vertebral fractures in patients with mild PHPT, but other studies argued otherwise. Approximately 20 years ago, this question was addressed by a careful epidemiology survey of a well-defined cohort of PHPT patients. Kholsa et al. from Rochester, Minn., found increased incidence of vertebral, Colles’ rib, and pelvic (but not hip) fractures in patients with PHPT. The results of this study were initially interpreted as possibly due to selection bias, but they corresponded exactly with information from later studies in which the nonvertebral skeleton and, in particular, cortical and trabecular bone were clearly documented to be at risk in this disease, as noted earlier. Further support for the proposition that the trabecular skeleton is at risk for fracture in PHPT came from the work of Vignali et al. This group studied vertebral fractures in PHPT by x-ray and by vertebral fracture assessment. Vertebral fractures were seen much more frequently in patients with PHPT (24.6%) than in the control subjects (4.0%; p < 0.001).

Nephrolithiasis

Kidney stones remain the most common manifestation of the disease. The incidence has declined over the years, but again, application of imaging technology has given us new insight into prevalence of hypercalciuria, nephrolithiasis, and nephrocalcinosis in this disease.

Not surprisingly, more recent systematic evaluation of the kidneys among patients with PHPT, not known to have renal involvement, has revealed stones and/or nephrocalcinosis in 21% to 55% of patients.

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