PHPT occurs predominately in women (3:1 versus male) age >50 years and the disease severity shows geographic variability. For example: In the United States (US) the incidence is relatively stable to slightly declining, depending on the database used, although in some racial groups there has been increasing prevalence (ranges: all women 34–268 per 100,000 patient years and all men 13–85 per 100,000 patient years) [2, 3]. In contrast, other geographic centers still report a significant frequency of more severe, classical disease. In Asia, the evolving access to medical care reveals a shift towards the newer “classic” asymptomatic presentation; likely representing increased access to testing. The prevalence of asymptomatic PHPT rose from 5 to 59 % in Hong Kong between 1973 and 2002 [4] in contrast to a mainland Chinese cohort examined between 1958 and 1993 where 97 % of patients had target organ effects including nephrolithiasis , osteoporosis , pathologic fractures, and severe skeletal changes such as osteitis fibrosa cystic [5, 6]. A separate Chinese cohort had an increased incidence of the asymptomatic presentation from 20 to 60 % between 2000 and 2010 whereas previously about 60 % of patients had the classical form. Additionally, recent cohort data from Brazil and Argentina also showed more classical, symptomatic disease (53 % of all PHPT diagnoses; 25 % nephrolithiasis , 25 % osteitis) with very low bone mineral density and single-gland presentation in 87 % of PHPT patients [7–9]. In a cross-sectional study comparing data from Italy and the US, Italian men and to a lesser degree women, had greater serum calcium levels and lower bone density despite having similar PTH levels with a matched US cohort [10]. These geographic studies highlight PHPT progression, suggesting that time of disease activity, access to medical evaluation, and possibly other regional variables including genetic and dietary differences will influence the degree of pathology. Whether there should be adjustment to the treatment guidelines to reflect regional differences is not yet clear. Further monitoring is needed to determine if there will be a continued shift away from the classical phenotype towards the asymptomatic phenotype in these geographic centers as there has been in North America and in parts of Europe.

The asymptomatic PHPT common to North America and Europe is characterized by nonspecific symptoms familiar to any primary care patient population. The list of mild symptoms potentially attributable to hypercalcemia from PHPT may include fatigue, neuromuscular complaints, polydipsia, and polyuria. More significant neuromuscular symptoms can be seen with severe hypercalcemia, although the severity of the hypercalcemia may not correlate directly with disease severity. Some surveys note a constellation of neuropsychiatric and constitutional complaints, but these are not often reversed following surgery [11, 12], suggesting that these common symptoms should not be over-stated as the result of PHPT. The primary target organ effects are in the kidney as nephrolithiasis or nephrocalcinosis, and the skeleton as preferential cortical bone loss at the distal 1/3 radius. Severe skeletal changes are infrequent in Europe and North America (<5 %) where nephrolithiasis has also declined in all PHPT patients from 30 % (before 1970) to 10–20 %. Conversely, it is estimated that 3 % of all kidney stone patients have PHPT [12, 13]. More frequent lab testing likely has decreased the length of time to diagnosis and subsequently the incidence of severe skeletal sequelae and nephrolithiasis . In contrast, it is still common to see minimal hypercalcemia not evaluated in patients until years after the initial abnormality was first found. Time of disease presence is likely one variable in disease progression at the target organs and potentially for symptoms. Very mild hypercalcemia may escape notice longer and therefore not trigger an evaluation when compared with more severe hypercalcemia. In the classical presentation and possibly in mild PHPT present for years, there may be more significant neuromuscular symptoms including progressive fatigue, weakness, or even myopathy [14]. There also may be an increased frequency of neuropsychiatric and gastrointestinal symptoms, specifically, common gastritis or gastroesophageal reflux complaints, depression, anxiety, and mild cognitive changes [15]. Peptic ulcer disease is not significantly increased and pancreatitis is seen only rarely with severe hypercalcemia. These observations suggest that all patients with PHPT require a complete evaluation for target organ involvement. The prevalence of the classical presentation in other geographic centers or in patients having PHPT for many years highlights that PHPT has the potential to cause severe clinical harm when left undiagnosed, requiring prompt evaluation of any hypercalcemia. Whether there are specific risk factors predisposing patients to increased disease severity or more rapid progression is unknown.

Some studies have suggested an increased risk of mortality and morbidity in severe classical PHPT [16, 17]. Cardiovascular changes may occur, including arterial and valvular calcifications with increases in all cause cardiovascular mortality. These long-term risks are likely significant enough to warrant consideration in at-risk populations where PHPT has been present for many years although the definition of that threshold is not clear; however, the risks in asymptomatic PHPT are also not at all clear and lack prospective trials. Most outcomes studies failed to show direct benefit to surgery versus observation in cardiac functional or structural indices [18, 19], despite data suggesting that PTH elevations and/or hypercalcemia may be associated with worsening of Left Ventricular hypertrophy, aortic valve calcification, and carotid intimal medial thickness [20, 21]. Variability in these observational studies and the lack of controlled prospective trials suggest that progression of cardiac disease in asymptomatic PHPT should not prompt either additional evaluation of these risks nor their inclusion in surgical criteria. Current clinical guidelines do not recommend cardiovascular risk factor measurements as part of the diagnostic evaluation or surgical intervention solely for reduction in cardiovascular sequelae [12, 22].

If an increase in all cause mortality exists in classical disease, is there also a risk in patients with long-present, untreated asymptomatic disease and are there criteria for including these factors in the clinical decision-making algorithm? This premise is critical to our understanding of the differences between these two patient populations and by extrapolation, the outcomes in surgically and nonsurgically treated patients. Variability in data collection, the at-risk study populations, definitions of diagnosis, and variable mortality of up to 30 % in some cohorts have confounded interpretation, but analyses suggest there is a significant mortality risk in some patients [17, 23]. A recent study of an Australian cohort showed a significant decreased 10-year survival of all PHPT patients compared with the control population (versus no PHPT; relative survival rate 87 %), while there was no statistical difference in survival between the surgical and nonsurgical PHPT groups [24]. Further comparison of the PHPT groups (surgically and nonsurgically treated, compared to controls) revealed a slow decline in relative nonsurgical patient survival through 12 years from diagnosis, followed by a more rapid decline in years 12–20 (63 %, 20-year relative survival) that was independent of calcium and PTH levels. This is similar to some studies where there was no mortality difference with short-term follow-up in the treated versus untreated PHPT groups, or others where nonsurgically treated PHPT patients had increased all-cause mortality with variable conclusions on whether a positive correlation of PTH and calcium was present [17, 23, 25, 26]. Other study populations have suggested that serum PTH levels independent of serum 25-hydroxy Vitamin D3 (25(OH)D3) and calcium levels may contribute to increased mortality, although the mechanism for this association is not clear [27, 28]. These variable mortality data require further investigation to answer three important questions:

Until these issues are resolved in randomized, well-matched populations with controls, the question of direct impact of PHPT on mortality remains open.

Consideration for surgical management in at-risk populations with single-gland disease who do not yet meet surgical criteria is a reasonable question, especially since well-defined skeletal and renal sequelae can be improved. Long-term studies and prospective age-matched cohorts are needed to replicate the Australian cohort [24], since these and other longitudinal data [29] suggest that observation past a threshold of years results in a transition of mortality and morbidity to levels associated with classical disease and with significant worsening of all cause mortality. Further analysis of at-risk matched populations of surgically treated and medically observed patients are required to determine if there is a temporal or clinical marker threshold independent of current surgical criteria where surgery may be offered to all appropriate patients.

The typical PHPT patient has mild hypercalcemia, usually less than 1 standard deviation (approximately ≤1.0 mg/dL; 0.25 mmol/L) above the upper normal range limit of serum calcium. Hypercalcemia is usually found on incidental lab screening since these asymptomatic patients rarely have specific physical complaints that would suggest a calcium abnormality. The evaluation focuses first on biochemical confirmation of the diagnosis, then target organ involvement and finally the need for either medical or surgical intervention or both, with diagnostic imaging only becoming necessary if surgical correction is pursued.

The biochemical definition of PHPT includes: hypercalcemia, hypophosphatemia, a low to low normal 25(OH)D3 level, a normal to increased 1,25-dihydoxy Vitamin D3 [1,25(OH)₂D3] level, elevated PTH, and variable 24-h urine calcium levels that are frequently high normal to overt hypercalciuria in ~30 % of patients. Patients with severe hypercalciuria (>400 mg/24 h) may benefit from kidney stone risk analysis using metabolic urine profiles [30, 32]. Renal function is usually normal, but a reduction in overall Glomerular Filtration Rate (GFR) and a rise in serum creatinine can occur in those patients with baseline renal dysfunction or when using GFR altering medications such as diuretics. The thiazide diuretics may exacerbate hypercalcemia in older patients or in those using calcium supplements. Thiazides can also unmask very mild PHPT in the setting of Vitamin D3 deficiency when hypercalcemia is not evident prior to thiazide initiation.

Plasma calcium levels are usually tightly bracketed within a sub-fraction of the usual laboratory range; therefore, all elevated plasma calcium levels should be viewed as abnormal and investigated. Even high normal calcium levels might be considered suspicious in some patients as concomitant Vitamin D3 and/or dietary calcium deficiency or significant hypercalciuria may blunt the hypercalcemic effect of PHPT resulting in calcium levels just below the abnormal range (e.g., 9.9–10.3 mg/dL, when the lower abnormal limit is 10.4 mg/dL). These levels may be appropriate for a small fraction of the population with normal renal function, but careful examination of other deficiencies often increases the suspicion for mild PHPT. Upwards of 90 % of all confirmed outpatient hypercalcemia is due to PHPT or Humoral Hypercalcemia of Malignancy. If the hypercalcemia is determined to be PTH-dependent then the majority of these patients will have PHPT from a single-gland adenoma, with a small subset (~10 %) having multiple gland hyperplasia, Familial HPT, Syndromic PHPT (Multiple Endocrine Neoplasia (MEN) 1 or 2) or FHH.

Most outpatient hypercalcemia is likely due to PHPT; however, one must consider FHH and the issue of normocalcemic hyperparathyroidism in PHPT differential diagnosis and prior to determining who is an appropriate surgical candidate.

The true incidence of FHH is not well understood. Differentiation of PHTP from FHH is critical since some case series estimate between 10 and 24 % of all failed parathyroidectomies may be due to misdiagnosis in a patient with FHH, suggesting the overall incidence of FHH may approach 1 in 10³–10⁵ [33, 34]. The most recent (2014) PHPT diagnosis guidelines have reinstituted the recommendation for measuring 24-h urine calcium and calculating a calcium/creatinine ratio (Ca/Cr) in all suspected PHPT patients. In those who do not meet the classic definition of biochemical hyperparathyroidism, further workup including repeating the Ca/Cr, correcting calcium or Vitamin D3 deficiencies, adjusting renal acting medications and genetic testing (CaSR; Calcium Sensing Receptor) in appropriate patients is necessary to find FHH patients who might otherwise have an unneeded surgery [30, 35]. Interestingly, there is small subset of FHH patients that have demonstrable adenomas. Whether these patients are at greater risk for bone density loss or nephrolithiasis is not clear. In both these FHH patients and those with primary hypercalciuria, there are likely physiologic influences via the CaSR that may induce parathyroid hyperplasia, so adenoma development and even multigland involvement in these patients further confounds the diagnostic overlap with PHPT. Additional case series and extended follow-up are required to examine any mutation-/genotype-specific risk in these and all FHH patients. There are no current prospective matched cohort studies or guidelines addressing these overlap patients, so careful and coordinated individual assessment is warranted to determine the appropriate risks and benefits for either medical or surgical intervention. Surgical therapy is not required in a patient with biochemically and/or genetically proven classic FHH.

Another recent confounder to PHPT differential diagnosis is a patient with an upper normal serum calcium level and elevated PTH that has been termed “normocalcemic hyperparathyroidism .” The PTH elevation in a number of these patients is appropriate and may be related to secondary causes such as Vitamin D3 deficiency, medications (e.g., lithium), primary hypercalciuria, or renal failure and therefore does not require an evaluation for PHPT or surgical intervention. As previously suggested (above), some of these patients will have very mild PHPT and are Vitamin D3 and/or calcium deficient and will manifest hypercalcemia if adequate stores are replenished and the patient follows a normal calcium diet. Once these confounders are ruled out there may still be a very small subset of all patients with PTH elevations and an inappropriate PTH response to calcium (prevalence estimated as 0.4–3.1 %; [36]). Some of these patients will proceed toward overt hypercalcemia within 3 years [37] and therefore have PHPT. Proper interpretation of laboratory data is necessary to correctly rule in or out the appropriate diagnosis so only PHPT patients that will benefit from surgical intervention are offered a surgical approach.

Bone loss in PHPT is most prevalent at cortical bone of the distal 1/3 radius, whereas trabecular bone at the hip and spine is more preserved. Bone turnover accelerates in PHPT and bone biopsies show a reduction in micro-architectural stability [38, 39], which can increase overall fracture risk. Occasionally accelerated bone loss similar to that of post-menopausal osteoporosis is seen; therefore, a complete bone loss risk evaluation should be completed on each PHPT patient. Measurement of cortical bone density by DXA (Dual energy X-ray Absorptiometry) is a critical component for quantitation of target organ risk from PHPT. Despite recommendations in 2009 for 3-site Bone Mineral Density (BMD) measurements in all PHPT patients [31], these are not routinely performed in preoperative assessments [40]. Disparate 3-site BMD with preferential low bone mass or osteoporosis at the distal 1/3 radius compared to the hip and spine can be a clue in the patient with minimal or intermittent hypercalcemia that PHPT has been present longer than suspected and also serves as a marker for clinical intervention if there is significant bone loss or osteoporosis . Other studies using newer bone density or bone quality measurements demonstrate that trabecular bone (hip, spine) is likely affected even in mild disease, suggesting a more global skeletal affect and increased risk of bone loss and fracture at all sites.

Increased rates of bone loss and osteoporosis are associated with an increased rate of fracture; however, in PHPT a direct association with increased fracture rates is not clear. Most cohort studies contain mixed populations of asymptomatic and more severe, classical disease where fracture risk is increased [41, 42]. There are differences in some studies for vertebral and nonvertebral fracture risk with some reporting no risk and some an increased risk for both vertebral and nonvertebral sites, especially the distal 1/3 radius [43, 44]. Metabolic factors including low Vitamin D3 levels may independently contribute to fracture risk in these cohorts, irrespective of PTH levels [45]. Despite the limited data and mixed populations of those PHPT patients with asymptomatic versus classical disease, there appears to be an overall increased risk of fracture in PHPT. Other factors leading to bone loss in men or pre-menopausal women, active post-menopausal bone loss, or significantly low bone mass (t-score <−2.0) at more than one site especially in younger patients (age <50 years old) are important additive risks for bone loss and fracture when present with PHPT. More advanced spine or hip bone mineral density loss found in a newly diagnosed PHPT patient may confer an increased fracture risk. If future data in nonsurgical PHPT patients further characterizes an increased hip or lumbar spine fracture risk and/or an increase in overall mortality and morbidity, this would suggest a reexamination of the bone density and bone loss criteria used for recommending surgery. How the time of disease, metabolic factors, and other risk factors for bone loss affect the overall fracture incidence and risk of future fracture in nonsurgically treated patients are important questions to be answered in well-matched prospective trials.

The effects of PHPT on the kidney are both metabolic and pathologic. Nephrolithiasis and nephrocalcinosis are still relatively common even in asymptomatic PHPT. Clinically silent stones in PHPT patients are estimated at 7–15 % when screening abdominal ultrasound or spiral CT is performed [46] and at 55 % in mixed symptomatic/asymptomatic populations [47]. PHPT increases the filtered load of calcium and eventually can lead to absorptive hypercalciuria, one risk factor for stone development. Additionally, the elevated PTH increases renal production of 1,25(OH)₂D3 by conversion from 25(OH)D3 through direct activation of 1-alpha hydroxylase, increasing calcium absorption from the intestine. Chronic hypercalciuria may lead to reduction in GFR and acceleration of age related renal decline or failure. Other metabolic and genetic risk factors in stone development suggest that for most patients with nephrolithiasis , hypercalciuria is not the sole risk factor. A more comprehensive stone risk analysis is now recommended with overt hypercalciuria (>400 mg/24 h) or in those PHPT patients with documented nephrolithiasis /nephrocalcinosis [30]. These 24-h urine panels assess a variety of risk factors (e.g., oxalate) that increase the risk of stones in the setting of hypercalciuria and aid in prescribing appropriate therapeutic interventions including increased hydration, low oxalate diets or decreasing urine acidity with potassium citrate.

Patients with asymptomatic hypercalcemia presumed to have single-gland PHPT should have a complete clinical workup to establish the biochemical diagnosis and assess their risks for complications. Once the diagnosis of a PTH-dependent hypercalcemia is made, differentiating single-gland PHPT from multigland or syndromic PHPT requires a thorough assessment of presentation, family history, and appropriate imaging studies. Careful evaluation of patients in whom minimal calcium elevation and/or low to low normal urinary calcium levels are found is required to resolve overlap with FHH, avoiding mis-diagnosis and unnecessary surgery.

A workup for hypercalcemia in the asymptomatic patient includes: