Continuing Education Activity

Normocalcemic hyperparathyroidism presents a unique diagnostic challenge due to its normal serum calcium levels despite elevated parathyroid hormone levels. Normocalcemic hyperparathyroidism can overlap with primary or secondary hyperparathyroidism, necessitating thorough evaluation to differentiate between these conditions. The diagnosis of normocalcemic hyperparathyroidism requires excluding secondary causes of elevated parathyroid hormone through a comprehensive clinical history, physical examination, and targeted laboratory investigations. Treatment strategies for normocalcemic hyperparathyroidism focus on addressing the underlying parathyroid gland abnormalities, surgical parathyroidectomy in select patients, and long-term monitoring to assess treatment efficacy and prevent the recurrence of hyperparathyroidism-related complications.

This activity for healthcare professionals aims to enhance learners' understanding of the diagnostic criteria for normocalcemic hyperparathyroidism, competence in implementing appropriate therapeutic strategies, and utilization of an interprofessional approach to improve outcomes.

Objectives:

• Assess clinical indicators and laboratory findings suggestive of normocalcemic hyperparathyroidism in patients.

• Differentiate between normocalcemic hyperparathyroidism and secondary hyperparathyroidism.

• Apply appropriate treatment modalities for normocalcemic hyperparathyroidism.

• Apply interprofessional team strategies to improve care coordination and patient outcomes when managing normocalcemic hyperparathyroidism.

Introduction

Normocalcemic primary hyperparathyroidism (NHPT) is a relatively new classification of primary hyperparathyroidism (PHPT). The definition of NHPT is a disorder in which elevated parathyroid hormone (PTH) levels are the result of autonomous hypersecretion from 1 or more parathyroid glands, and the albumin-adjusted and ionized serum calcium levels are consistently within the normal range when measured at least twice over 6 months.[1][2][3][4] Before establishing a diagnosis of NHPT, all causes of secondary hyperparathyroidism (SHPT) must be excluded.[5][6][7][8][9]

In SHPT, the PTH elevation and parathyroid gland hyperplasia develop in response to a low serum calcium stimulus from diverse causes such as low vitamin D or chronic renal failure.[10] The PTH remains elevated as long as the low calcium stimulus persists and returns to normal as soon as it is corrected. Patients with chronic SHPT typically develop hyperplasia of all 4 parathyroid glands, which can lead to tertiary hyperparathyroidism.[10] Excluding SHPT by a thorough history, physical examination, and directed laboratory investigations is essential before diagnosing NHPT. In those with SHPT, medical treatment is directed at correcting the causes of the reduced serum calcium, which increases PTH. In contrast, the treatment of NHPT is focused on the abnormal parathyroid gland(s), which may include surgical parathyroidectomy.[7][8]

In addition to differentiating NHPT from SHPT, there is a significant overlap between NHPT and PHPT, with the latter characterized by elevated serum calcium. Many patients with NHPT go on to develop PHPT, suggesting that NHPT may be an early presentation of PHPT in some cases. Predicting which patients will develop the hypercalcemia associated with PHPT is impossible. Therefore, clinicians must continue to monitor serum calcium levels. Diagnosis and treatment of NHPT and PHPT are very similar. See StatPearls' companion reference, "Primary Hyperparathyroidism," for more information.

Etiology

NHPT can be caused by a single adenoma, multiple adenomas, or multigland hyperplasia of the parathyroid glands, just as in the classical type of hypercalcemic PHPT. Several studies have shown an increased incidence of multigland adenomas in NHPT.[11] Radiation to the neck increases the incidence of NHPT.[12]

SHPT can be caused by vitamin D deficiency, chronic kidney disease (CKD), intestinal malabsorption syndromes, bariatric surgery, long-term reduced dietary calcium intake, and hypercalciuria.[10] In CKD, reduced vitamin D activation leads to decreased intestinal absorption of calcium. Lower levels of serum calcium then induce a secondary increase in the secretion of parathyroid hormone.[10][13] Treatment of hyperparathyroidism in CKD can include vitamin D supplements, sufficient to maintain a 25-hydroxyvitamin D level of at least 30 ng/mL, calcitriol (ie, activated vitamin D), phosphate binders, and calcimimetics to reduce PTH secretion.[10] Parathyroid surgery is sometimes necessary in patients with severe or refractory disease.[14][15] Other causes of SHPT include older anticonvulsants (eg, phenytoin and phenobarbital), celiac disease, and medications including bisphosphonates, denosumab, diuretics, and lithium. Drug-related SHPT can be verified by stopping the drug for several months and rechecking the PTH level.[10] If a drug elevated the PTH level, then levels should normalize when the medication is withheld. If PTH remains elevated, then another cause is responsible.[9][10]

In 1988, Rao et al first proposed a biphasic progression of hyperparathyroidism.[16] They suggested that PTH levels are elevated during the initial phase, but serum calcium remains within the reference range. This first phase is generally asymptomatic and was not identified as a precursor or early form of hyperparathyroidism until recently. The second phase would include hypercalcemia along with elevated PTH levels and would be considered classic PHPT.[9][16]

Other potential causes of NHPT include partial resistance to parathyroid hormone, decreased production of 1,25-dihydroxyvitamin D in older individuals, and reduced calcium-sensing receptor activation on parathyroid cells by calcium.[9] PTH levels are not generally checked in patients with normal serum calcium levels. Recently, osteoporosis and metabolic bone disease centers have become proactive in evaluating potential risk factors of skeletal disease, leading to identifying patients with NHPT.[9]

A patient with developing PHPT whose baseline calcium is initially 8.9 mg/dL may have an increase of 1 mg/dL in their calcium level to 9.9 mg/dL and PTH to a value that exceeds the upper limit of the reference range. This patient would still have a calcium level within the expected reference range for the general population but would be diagnosed with NHPT due to the PTH elevation. So, clinicians should consider individual baseline values. This fact is essential but very difficult to implement in clinical practice.[17] Another consideration is that the normal value range for PTH in a population is a Gaussian distribution curve. Therefore, approximately 2.5% of the population is expected to have PTH values just outside the upper range of normal yet not have any disease.

Epidemiology

In a recently published prospective study, NHPT comprised 15.4% of all patients with PHPT, with a higher female-to-male ratio.[18] The overall prevalence of NHPT is thought to be between 0.4% and 0.6%.[13] The incidence of asymptomatic hyperparathyroidism may be challenging to assess for the following reasons:

• Because PTH levels are not generally checked in patients with normal serum calcium levels but are more likely to be measured in those with nephrolithiasis and during the evaluation of patients with osteoporosis, a selection bias may be present.
• Different studies have used different cutoffs for 25-hydroxyvitamin D levels and estimated glomerular filtration rate (eGFR) when interpreting PTH values, and the assays have differing accuracy rates.
• Some studies have only measured the total corrected calcium without determining whether the ionized calcium is elevated.
• The lack of a large population prevents prospectively studying the natural history of NHPT.
• Some normocalcemic patients can become hypercalcemic when the calcium is measured on a different day, which changes the classification and diagnosis.[6][7][8][9][19]

Even in patients with NHPT, identifying the patients who will progress to classical PHPT and those who will maintain their normocalcemic status, and for how long, is impossible as all these scenarios have been observed. In addition, the longer the observation period, the greater the number of NHPT patients who will become hypercalcemic, suggesting NHPT may be a precursor of the classical variant. Older age and higher baseline serum and urinary calcium values are more likely to progress to classical PHPT.

Parathyroid incidentalomas were reported in some normocalcemic patients undergoing thyroid surgery.[20] Compared to patients who underwent surgical therapy for proven classical PHPT, the normocalcemic incidentaloma patients were younger and had parathyroid glands that weighed less. Biochemically and histologically, these patients secreted less PTH. The sex distribution, cell type, and disease incidence in multiple glands did not differ, which suggests that NHPT is an earlier form or precursor of classic PHPT.[20]

Pathophysiology

To differentiate it from hypercalcemic PHPT, NHPT is defined as persistently elevated parathyroid hormone levels despite normal corrected serum and ionized calcium measured at least twice over a period that spans 6 months.[4][10] Some suggested pathophysiologic mechanisms include an early form or precursor of classical PHPT, relative hypercalcemia based on an individual patient's baseline, calcium dietary deficiency, and resistance of bone and kidneys to the effects of PTH.[21]

In NHPT, the bone turnover markers and the net calcium release, measured by the urinary calcium/creatinine ratio, are lower than their hypercalcemic counterparts with similar PTH values. The renal tubules are less able to suppress phosphate and promote calcium reabsorption. Thus, for similar PTH concentrations, some patients became hypercalcemic while others did not, confirming tissue resistance to PTH in these patients.[22] A large study comparing patients with NHPT and PHPT found significantly higher levels of 25-hydroxy vitamin D and serum phosphorus in patients with NHPT than in PHPT.

Studies from parathyroid glands of NHPT patients showed similar expression of the calcium-sensing receptor (CaSR), chromogranin A, PTH, and mitotic index (Ki-67) compared to normal parathyroid glands.[23] Glands from those with hypercalcemic hyperparathyroidism had reduced expression of the CaSR. However, decreased vitamin D receptor (VDR) expression and increased cyclin D1 were observed in the glands of both normocalcemic and hypercalcemic patients.[23] Therefore, experts postulated that discordance between CaSR and either VDR or cyclin D1 could result in maintaining normocalcemia in NHPT.[23]

Furthermore, the adequacy of estrogen, even in the postmenopausal period, could reduce the effects of PTH on target tissues and contribute to maintaining normocalcemia.[22] Although PTH levels are lower than classical PHPT, the mild chronic elevation in NHPT is probably sufficient to cause PTH-induced bone resorption. Moreover, while there are conflicting data, some patients with NHPT have been reported to have higher rates of cardiovascular complications, hyperaldosteronism, hypertension, and hyperglycemia due to insulin resistance, muscle tone, and overall quality of life.[1][9]

Additionally, renal calcifications are common in NHPT. They tend to be associated with high serum PTH, increased 1,25-dihydroxy vitamin D levels, and a degree of hypercalciuria.[24] Many patients with NHPT present with nephrolithiasis, which may be silent and found only by imaging studies. Calcium oxalate stones are the most common stone type in the general population, but calcium phosphate is more likely in patients with hyperparathyroidism. The increased nephrolithiasis and bone loss rate is similar between normocalcemic and hypercalcemic patients with hyperparathyroidism.[21] The reasons for this are still unclear.[25] The vast majority of patients with hypercalciuric nephrolithiasis do not have normocalcemic hyperparathyroidism. Hypercalciuria is not consistently found in NHPT, and all patients do not develop renal stones, so other factors must be involved. Contributors to renal calculi other than hypercalciuria include the following:

• Aciduria
• High dietary salt intake
• Hyperoxaluria
• Hyperuricosuria
• Hypocitraturia 
• Hypovolemia, dehydration, or oliguria (ie, low urinary volume) [26][27][28][29][30]

History and Physical

NHPT is largely asymptomatic, but some have fractures or renal stones. Even asymptomatic patients may have abnormalities in dual-energy x-ray absorptiometry scans (DEXA) or renal ultrasounds. Elevated blood pressure and neuropsychiatric symptoms may accompany NHPT, but whether a direct relationship exists is unclear.

The clinical history should focus on possible causes of SHPT. Clinicians should inquire if any symptoms of celiac disease, gastric surgery, and other malabsorptive disorders are present. Clinicians should obtain an estimated oral calcium intake, an assessment of the risk for vitamin D deficiency, and a thorough medication history checking for any drugs that can cause SHPT. A family history of renal stones or osteoporosis in younger relatives should prompt a search for familial causes of PHPT. Rare case reports of NHPT presenting as acute parathyroid infarction or parathyroid carcinoma have been published.[31][32] 

Evaluation

Laboratory Studies

In most cases, a diagnosis of NHPT is made when patients presenting with osteoporosis or renal stones are investigated proactively. In such presentations, initial investigations should include serum calcium and albumin to calculate the corrected calcium phosphorus, eGFR, 25-hydroxyvitamin D level, and urinary calcium excretion. If the corrected calcium is normal, ionized calcium must be measured before establishing a presumptive diagnosis of NHPT. The diagnosis is confirmed if laboratory studies repeated in 6 months have similar findings.[1] These results and a thorough review of the patient's medications exclude SHPT and diagnose NHPT.

The clinical picture dictates the need for other investigations, including liver function tests and serum magnesium. Some have proposed that an increased serum calcium/phosphate ratio might help identify independent parathyroid activity, but prospective studies have not validated this.[33] Two studies looking at this found very high negative predictive values for the albumin-adjusted calcium/phosphorus ratio of 88% and 95%, suggesting that this calculation may be more useful to exclude than diagnose NHPT.[33][34]

A short-term oral calcium challenge has been suggested for patients with presumed NHPT before considering surgery or other therapy. In a recent study, 55% of patients initially diagnosed with NHPT were found to normalize their PTH levels after a clinical trial of oral calcium supplementation, indicating they suffered from SHPT due to relative calcium deficiency. The same study found that 20% of study patients developed hypercalcemia with supplementation, signifying classical PHPT.[35] In complex cases, dynamic testing with a thiazide challenge test to exclude idiopathic hypercalciuria and possibly a calcium loading test to clarify the diagnosis of NHPT may be necessary.[9] When the initial tests are consistent with NHPT, the calcium and PTH must be repeated in 3 to 6 months before a diagnosis of NHPT can be confirmed.

A potentially helpful ratio in the diagnosis of NHPT is the parathyroid function index, a formula specifically designed to differentiate PHPT from SHPT due to vitamin D deficiency. The formula is serum calcium (mmol/L) x PTH (pg/mL)/phosphorus (mmol/L). The cutoff is 34, meaning a higher reading indicates PHPT, while lower results suggest SHPT from low vitamin D levels.[36] The parathyroid function index has a reported sensitivity of 96.9% and specificity of 97.6%, making it potentially very useful.[36] Additional testing in larger populations is required before the parathyroid function index can be formally recommended. Once diagnosed with NHPT, patients must be evaluated using the guidelines established for those with hypercalcemic PHPT, including 3-site DEXA and renal imaging looking for occult calcifications.[37] The following biochemical laboratory studies can be used to establish an NHPT diagnosis:

• Total serum calcium, ionized calcium, and albumin

• Corrected calcium: calculated by measured calcium + 0.8 (4.0-measured albumin)

• Serum intact PTH: second and third-generation assays may be used; third-generation may be more accurate in patients with renal failure

• Serum 25-hydroxyvitamin D: >30 ng/mL excludes vitamin deficiency as a cause of SHPT [1][38]

• Serum blood urea nitrogen (BUN) and creatinine, estimated glomerular filtration rate (eGFR): PTH rises when eGFR decreases below 60 ml/min/1.73 m² [39]

• A 24-hour urine calcium and creatinine

• Repeated serum calcium and intact PTH: performed after a course of supplemental dietary calcium to identify patients with hyperparathyroidism secondary to calcium deficiency [35]

• Celiac disease screening: in selected patients

• Other serum tests: eg, phosphorus, alkaline phosphatase, and magnesium

• Serum 1,25-dihydroxy vitamin D: not routinely measured as levels are normal or even raised in vitamin D deficiency and PHPT

• Selective jugular venous sampling: to localize the diseased glands in rare cases [40]

Imaging Studies

The diagnosis of NHPT is made by biochemical laboratory testing, so imaging should not be used to establish the diagnosis. However, imaging modalities are useful for preoperative localization, especially if minimally invasive surgery is planned, multigland disease is suspected, or reoperation is required. Neck ultrasonography and parathyroid nuclear medicine (Tc-sestamibi) scans are standard imaging tests for the localization of hyperfunctioning parathyroid glands. However, these tests are not considered definitive because there can be false-negative results, and they are generally less helpful in multigland parathyroid disease and NHPT. They should not be ordered unless there are plans for surgery. Imaging is most useful for the surgeon as a "roadmap" in localizing enlarged, hyperfunctioning parathyroid glands.[41]

Cervical ultrasonography

Normal parathyroid glands are rarely visible in ultrasound scans; however, enlarged glands are seen as oval hypoechoic masses with a peripheral vascular ring. The parathyroid glands are seen in inferior or posterior locations to the thyroid gland and are sometimes confused with peripherally situated thyroid nodules. Ultrasound is less efficient in detecting smaller lesions, multi-gland disease, and ectopic adenomas in retro-esophageal, retro-tracheal, and mediastinal locations. Neck ultrasonography is highly operator-dependent but can be very accurate in centers with experience and expertise.

The thyroid gland should also be imaged simultaneously so that any identified abnormalities may be treated in the same surgical setting.[42] Parathyroid incidentalomas are adenomas discovered during surgery or thyroid ultrasound examinations. They are generally smaller, weigh less, and produce less PTH than adenom, causing hyperparathyroidism. Reports of ultrasound-guided fine needle biopsy are reported in the radiology literature, but the surgical guidelines on parathyroid surgery caution about several risks and sequelae. Fine needle biopsy is used almost exclusively for complex and unusual cases.[43]

Radionuclide imaging with Tc 99m sestamibi [44]

Tc 99m is a radiopharmaceutical coupled to 6, sesta meaning 6, units of methoxyisobutylisonitrile (MIBI) ligands that transport it to target organs. Tc 99m is a lipophilic cation that, when injected intravenously, distributes proportionally to blood flow. Cell composition determines the amount of absorption and is directly proportional to its mitochondrial content. Oxyphil cells are rich in mitochondria. Tc 99m is taken up by abnormal parathyroid tissue and retained. The principle behind this modality is that the Tc 99m sestamibi elutes earlier from the thyroid gland than parathyroid adenomas. A delayed scan after 1 to 4 hours will show the adenomatous parathyroid tissue with increased Tc 99m sestamibi uptake and help in its localization. The gamma rays emitted during radionuclide imaging as the isotope decays are imaged with a gamma camera.

Sestamibi scintigraphy with SPECT (single-photon emission computed tomography) adds a 3-dimensional component to the gamma camera images, improving the sensitivity of detecting enlarged parathyroid glands. An earlier washout of the nuclear material from the smaller adenomas or hyperplastic parathyroids can lead to a negative scan, as found in NHPT. In multiple adenomas, a preferential uptake and retention by 1 adenoma over the others may be a reason for not detecting other enlarged glands. Additionally, the presence of p-glycoprotein in the parathyroid cells and calcium channel blocker use are more likely to produce negative scan results.[45] Other confounders are coexisting thyroid lesions that display delayed washout and can result in a false positive scan.

Tc 99m sestamibi scanning complements ultrasound, and together, they successfully localize more lesions than either alone, but even this combination sometimes has poor concordance in NHPT.[46] While positive parathyroid scintigraphy rates are significantly less in normocalcemic than in patients with PHPT (42% vs. 81%), Tc 99m sestamibi scanning is still recommended as a valuable preoperative diagnostic tool even in NHPT.[47] When the parathyroid scan and ultrasound are negative or provide discordant results, a magnetic resonance imaging (MRI) might be considered. However, a four-dimensional computed tomography (4D-CT) scan would probably be preferred.[48][49]

Four-dimensional computed tomography

A 4D-CT scan was initially reported to have a sensitivity of 77%, but more recent studies put this higher (sensitivity 81.3%, specificity 95.5%, positive predictive value 87.1%).[2][41][50][51][52] This modality is particularly good at finding ectopic glands and has a reported 93.3% negative predictive value.[52] Compared to sestamibi scans, 4D-CT was found to have superior sensitivity for both single (92.5% versus 72/1%) and multigland (58.2% versus 30.8%) diseases. A recent meta-analysis of 26 studies comparing 4D-CT and sestamibi-SPECT/CT found 4D-CT to have higher sensitivity and specificity.[53] In the case of parathyroid reoperations, 4D-CT is particularly useful.[54] 

Some studies report greater success in NHPT with 4D-CT and novel PET tracers like 11C-methionine, F18-choline, and F18-FDG, but these have to be tested in larger patient populations to be routinely recommended.[41][50][55] Problems with 4D-CT include limited availability, relatively high patient radiation exposure, and somewhat borderline specificity.[56] MRI is not generally used for parathyroid imaging, but it has been reported to have a 79.9% sensitivity in detecting parathyroid adenomas. The sensitivity increases to 91.5% when combined with ultrasound and sestamibi scans.[48] In general, ultrasound and sestamibi scans are the initial imaging procedures. Other imaging modalities should be considered if the results are negative or discordant. During surgery, near-infrared light autofluorescence to locate the parathyroids has been used with some success. More studies are needed to test this localizing modality's sensitivity, specificity, and predictive values.[57] Finally, patients with negative or equivocal scans but a biochemically confirmed diagnosis of NHPT who have indications for surgery will still need surgery by someone highly skilled in performing parathyroidectomies.

Additional imaging studies

DEXA (dual-energy x-ray absorptiometry) scans of the lumbar spine, the hip, and the distal third of the radius determine the T score based on the standard deviation compared to a young healthy adult's bone density.[58] T scores are always negative, reflecting some loss of bone mineral density over time compared to the theoretical optimal level.[58] Although a good measure of bone density, the T score does not indicate bone strength or quality. Fracture sites, arthritis, and degenerative bony changes all influence values and must be considered when interpreting the DEXA data.[58] A T score of -2.5 or lower is generally considered diagnostic of osteoporosis.[58] A trabecular bone score is the most cost-effective way of determining bone quality and is an indirect analysis of trabecular microstructure extracted from data obtained from the DEXA.[59][60] The trabecular bone score demonstrates decreased connectivity of the trabecular spinal microstructure in patients with PHPT, although this may appear normal on the DEXA scan.[60][61]

High-resolution peripheral quantitative computed tomography (HR-pQCT) has been used to study defects in bone microarchitecture even when bone density is not grossly abnormal.[62] This test is still in research settings and is not performed routinely. In NHPT, HR-pQCT may be abnormal when the lumbar spine bone mineral density is not reduced.[62]

Patients with NHPT need renal imaging with ultrasound, plain x-rays, or CT scans to screen for calcifications. Renal ultrasound will document renal size, identify hydronephrosis, and demonstrate nephrolithiasis of stones typically at least 4 mm in size. While renal ultrasound is not ideal for identifying smaller stones, the test is inexpensive, easy to perform, and readily available. The most accurate imaging for detecting renal calculi, calcifications, and nephrocalcinosis is the noncontrast renal CT scan.[29]

Treatment / Management

Medical Management

Patients without an indication for surgery can generally be followed with nonoperative surveillance. Medical therapy is appropriate for those with surgical indications but who have a high operative risk or refuse surgery. Bisphosphonates and calcimimetic medications are typically utilized in these instances. Estrogens increase bone mass density in patients with PHPT. Decisions on whether to prescribe estrogens in postmenopausal female patients must be based on the expected benefit balanced against the potential risks. The only bisphosphonate that has been tried in a study of NHPT with osteoporosis is alendronate.[63] In a study of 15 patients with osteoporosis given alendronate plus vitamin D, 15 matched controls were given vitamin D alone. After treatment, the alendronate group showed a more significant improvement in bone mass density. Serum calcium, phosphorus, and PTH levels were unchanged.[64] Further studies are needed to recommend this therapy routinely, but it can be considered for those whose only complication of NHPT is reduced bone mineral density.[64] In 2 larger, 10-year, randomized, double-blinded multinational studies involving 994 osteoporotic women, alendronate treatment significantly increased bone mineral density, which did not last when the medication was discontinued.[65]

Cinacalcet, a calcimimetic drug, causes allosteric modification of the calcium-sensing receptors in the parathyroid gland and decreases parathyroid hormone secretion. In the renal tubules, cinacalcet reduces calcium reabsorption and is used in parathyroid carcinoma and SHPT due to CKD. Cinacalcet can also be used in those with intractable hypercalcemia in classical PHPT, hypercalcemic patients after failed parathyroid surgery, and those who refuse surgery or are at too high a risk for surgical intervention.[66] Cinacalcet reduces serum calcium, less so in parathyroid hormone levels, but no significant changes in bone mineral density or urinary calcium.[66] A small prospective randomized pilot study involving 10 patients treated for 10 months, which included NHPT patients, showed safety and benefit with cinacalcet in reducing the number and size of renal calculi; however, the study included relatively few patients and was unblinded.[67] More studies with larger numbers in a blinded fashion with a crossover should help address these unanswered questions.

In summary, bisphosphonates can significantly increase bone mineral density but have a relatively minimal effect on serum calcium levels. Calcimimetic agents can effectively lower serum calcium and parathyroid hormone levels but have minimal effect on bone mineral density. If patients need interventions to reduce the serum calcium and treat osteoporosis, they can be treated with cinacalcet and alendronate.

Medical management monitoring

For patients where observation is the selected course of action, periodic monitoring is required. If the hypercalcemia rises, complications develop, or PTH-related symptoms continue, then surgery is recommended.[5] Current guidelines for monitoring patients who do not meet the criteria for surgery include:

• DEXA scan of 3 sites every 1 to 2 years

• A 24-hour urine calcium excretion, if clinically indicated

• Abdominal imaging for calcifications, if clinically indicated.

• Annual serum calcium, 25-OH vitamin D, and measurement of creatinine clearance or eGFR [68]

• Vertebral x-ray as indicated

Limiting dietary calcium intake can increase parathyroid hormone levels, while supplemental calcium can reduce these.[5][69] The consensus opinion among experts is that dietary calcium intake should follow normal nutritional guidelines. Vitamin D should be supplemented if the 25-hydroxyvitamin D is <30 ng/mL based on studies showing that vitamin D can lower blood parathyroid hormone and improve bone mineral density without significantly increasing serum or urinary calcium levels.[5][70]

Operative Management

Parathyroid surgery is the only definitive treatment for normocalcemic or hypercalcemic PHPT.[15][71][72] Minimally invasive surgical techniques have been developed for this procedure.[73] No known medical treatments can fully reproduce the benefits of a successful parathyroid surgery.[72] Some studies have shown bone mineral density (BMD) improvement after parathyroidectomy.

The recommendations and indications for parathyroid surgery by the expert panel on Asymptomatic Primary Hyperparathyroidism, including patients aged younger than 50 years, osteoporosis, creatinine clearance <60 ml/min, urinary calcium >300 mg/24 hours in men and >250 mg/24 hours in women, and nephrolithiasis, can be equally applied to NHPT.[5][72][74] Parathyroid surgery performed by experienced parathyroid surgeons tends to have higher success rates, lower complications, and shorter hospital stays.[43] 

Although the risk for recurrent renal calculi is not eliminated, the risk is substantially decreased, and renal function is preserved.[62] The recurrence rate of nephrolithiasis and nephrocalcinosis can be further reduced by performing a 24-hour urine test for kidney stone prevention and optimizing any remaining risk factors.[30] There is not enough evidence yet to attribute any benefit of parathyroid surgery in improving neuropsychiatric symptoms or cardiovascular problems.[5]

Intraoperative PTH monitoring with a rapid assay using the Miami criterion of a 50% drop from baseline to check for completeness of removal of abnormal parathyroid tissue has been tested in NHPT patients and found to be equally predictive as in PHPT.[11] The intraoperative gamma probe relies on tracer retention of >20% in diseased glands and can be used for monitoring. However, this probe is inferior to intraoperative PTH and needs specialized equipment and personnel that are not always available at all centers. The most common surgical finding is a single adenoma, but encountering multiple parathyroid adenomas is more common in normocalcemic (12%) than in hypercalcemic (4%) hyperparathyroidism.[11] There is also a higher rate of reoperation in NHPT.[75]

Differential Diagnosis

SHPT presents with a similar biochemical picture and must be carefully excluded before establishing a diagnosis of NHPT.[10] Causes of SHPT include:

• Calcium deficiency
• Chronic kidney disease
• Hypercalciuria
• Increased fibroblast growth factor-23 with hypophosphatemia
• Malabsorptive disorders
• Bariatric surgery
• Celiac disease
• Inflammatory bowel disease
• Medications
  •  Anticonvulsants (phenytoin, phenobarbital)
  •  Bisphosphonates
  •  Denosumab
  •  Diuretics
  •  Lithium
• Obesity
• Paget disease of bone
• Vitamin D deficiency

SHPT caused by hypocalcemia due to hypercalciuria can result from high sodium intake, excess tea or coffee consumption, and loop diuretics like furosemide.[10] A thorough history will exclude these causes. Genetic defects causing hypercalciuria are rare and can be detected by genetic testing.[76] 

A thiazide challenge test has been reported to help differentiate PHPT from hypercalciuria. In the thiazide challenge test, 50 mg of hydrochlorothiazide is given orally every day for 2 weeks. Thiazides will decrease urinary calcium excretion, so a patient with SHPT due to hypercalciuria will have a reduction of urinary calcium excretion and decreased or normalized PTH, while a patient with NHPT is likely to become hypercalcemic with only minimal or no reduction in their PTH levels.[77] An oral calcium loading test may help clarify the diagnosis of NHPT in difficult cases. A single 1 g dose of oral calcium is given, and serum calcium and PTH values are measured at regular intervals from 0 to 120 minutes. In patients with NHPT, there is only minimum suppression of PTH from baseline, whereas, in normal individuals and SHPT, there is a marked decrease.[78] Calcium loading can also be done intravenously, and the measurements made.[79] The ratio of the decrease in PTH (which usually happens in 80 to 120 minutes and parallels the increase in calcium after loading) and the baseline PTH is termed the PTH inhibition rate (PTH-IR). The change in calcium levels from baseline to peak concentration after loading is termed the delta calcium. The ratio of these 2 calculated values was used in a study to differentiate the various types of hyperparathyroidism and was also recommended as a test to decide when PTH secretion becomes autonomous in SHPT due to CKD.[10][79] These results are preliminary and need to be confirmed in large-scale studies.[79]

Causes of vitamin D deficiency include inadequate sunlight exposure, diets poor in vitamin D, lack of fortified foods, conditions producing malabsorption including bariatric surgical procedures, various medications that accelerate vitamin D metabolis. High-risk populations include older adults, malnourished children, pregnant and lactating women, and patients with chronic kidney disease, especially in the early stages.[80] Importantly, patients with PHPT may have a coexisting vitamin D deficiency, which masks their hypercalcemia. They would then present with normocalcemic hyperparathyroidism. Depending on the degree of vitamin D deficiency, they may be asymptomatic or present with bone pain, myalgia, and proximal muscle weakness. After the correction of their vitamin D deficiency, hypercalcemia is unmasked. They should then be managed as PHPT patients. They should maintain a normal calcium intake and take vitamin D supplements to achieve and maintain 25-hydroxyvitamin D levels greater than 30 ng/mL.[80][81][82][83]

Lithium can desensitize the parathyroid calcium-sensing receptor to serum calcium, shifting the setpoint to the right, increasing the release of PTH.[84][85] Lithium can unmask and also cause classical PHPT.[86] Single PTH-producing parathyroid adenomas, as well as multigland disease, have been reported with long-term lithium use.[86] Cinacalcet has been shown to be effective in managing lithium-associated hyperparathyroidism.[86][87]

Normocalcemic Primary Hyperparathyroidism and Secondary Hyperparathyroidism in Chronic Renal Disease Differentiation

NHPT can closely mimic SHPT in patients with chronic renal disease. Additionally, PHPT can certainly occur in patients with renal failure and reduced GFR (<60 mL/min), further complicating their differentiation. NHPT requires the elimination of all other causes of hyperparathyroidism, making it difficult or even impossible to differentiate between these 2 diagnoses in CKD when the GFR is less than 60 mL/min. NHPT and SHPT from chronic renal failure may actually be describing the same pathological entity. Notable differences include:

• Patients with PHPT are more likely to have overt hypercalcemia than those with SHPT.

• Vitamin D levels are typically normal or elevated in NHPT but reduced in SHPT from chronic renal disease.

• Serum phosphate is typically low in NHPT but elevated in SHPT from chronic renal disease.

• The parathyroid function index serum calcium (mmol/L) x PTH (pg/mL)/phosphorus (mmol/L) is more than 34 in NHPT and less than 34 in SHPT from chronic renal disease.

• The serum calcium/phosphate ratio tends to be elevated in NHPT but reduced in SHPT from chronic renal disease.

• Serum phosphate levels are likely reduced in NHPT but elevated in SHPT from renal failure.

• A sestamibi scan is more likely to show a hypersecreting parathyroid adenoma in NHPT while tending to show parathyroid hyperplasia in SHPT from chronic renal disease.[9][36][88][89][90][91] 

Prognosis

Surgically managed patients with NHPT generally do well; they avoid complications and increase bone mineral density.[92] The newer minimally invasive surgical parathyroid procedures are less intrusive, with shorter operating times and fewer complications.[71][73] Intraoperative monitoring of serum PTH levels has yielded better outcomes.[71][93] However, even with experienced surgeons, operative failure or early recurrence does occur, given the difficulty in localizing smaller adenomas and a greater incidence of multiple parathyroid adenomas in NHPT. A decrease of PTH of more than 50% from baseline is usually a reliable indicator of surgical success during surgery.[94]

High normal serum calcium, high urinary calcium, and advanced age have been shown to favor progression to classic hypercalcemic PHPT.[6] Current guidelines for monitoring patients with hyperparathyroidism include annual measurement of serum calcium, 25-hydroxyvitamin D, and creatinine clearance with DXA scans repeated every 1 to 2 years.[5] Abdominal imaging and 24-hour urine for calcium should be ordered if clinically indicated.[5]

Complications

Patients with NHPT are more likely to have multigland disease than those with classic hypercalcemic hyperparathyroidism; therefore, they are more likely to require bilateral neck exploration. While uncommon when performed by experienced parathyroid surgeons, complications of parathyroidectomy include injury to the recurrent laryngeal nerve, wound hematoma, and postoperative hypocalcemia.[15] Patients with NHPT undergoing parathyroid surgery tended to have an increased rate of reoperation that is more than double the rate of hypercalcemic patients with PHPT and are more likely to develop permanent hypocalcemia postoperatively (11.4% versus 1.4%).[95] About 25% of patients with NHPT may have nephrolithiasis or nephrocalcinosis.[24][96][97] Those individuals who are not surgical candidates need to be monitored for the development of hypercalcemia and are at risk of developing renal calcifications as well as losing bone mineral density.[9]

Consultations

Specialties that may need to be involved in caring for patients with NHPT include:

• Endocrinology
• Endocrine surgery (otolaryngologists or endocrine surgeons) 
• Gastroenterology
• Nuclear medicine
• Radiology
• Urology

Deterrence and Patient Education

Patients with NHPT should be taught in simple language the autonomous nature of the parathyroids in NHPT and the implications of a raised PTH. When surgical treatment is suggested, clinicians should discuss all options with patients with explanations using anatomic models, video lessons of the actual surgery, possible postoperative complications, recovery periods, and a simplified but comprehensive explanation of the technology used.

Patients with NHPT selected for surveillance must receive education on the importance of periodic monitoring, the risks of developing hypercalcemia, the potential complications of parathyroid hormone excess, and the methods to ensure adequate calcium and vitamin D intake. Those requiring treatment with antiresorptive medications need careful instruction on dosage, administration, side effects, therapy duration, follow-up frequency, and required surveillance tests. The health literacy of the individuals involved should be considered in formulating a patient education plan.

Pearls and Other Issues

Key factors to bear in mind when managing NHPT include:

• NHPT is a recognized phenotype and a possible early precursor of PHPT.

• The diagnosis requires both normal ionized and corrected calcium levels measured at least twice over 6 months.

• The diagnosis of NHPT demands the meticulous exclusion of all other possible causes of SHPT.

• The most common causes of SHPT are renal insufficiency with an eGFR <60 ml/min and vitamin D deficiency.

• NHPT and SHPT, when related to chronic renal failure, may be the same disorder.

• A clinical trial of oral calcium supplementation has been suggested for all patients diagnosed with NHPT before starting therapy or considering surgery. This will normalize PTH levels in patients with calcium deficiencies, resulting in SHPT.

• Although asymptomatic for the most part, NHPT is not always an indolent condition.

• Several studies have shown that NHPT can cause end-organ damage even when maintaining normocalcemia.

• Frequent presentations include osteoporosis, osteopenia, nephrolithiasis, and, in some instances, fractures.

• In NHPT, the parathyroid glands are generally smaller, are more likely to involve multiple glands and secrete less PTH than hypercalcemic patients with PHPT.

• A lower secretion of PTH and resistance to its action in the bone and kidneys may explain the maintenance of normocalcemia.

• A trial of oral calcium supplementation should be undertaken before initiating any long-term therapy or surgery for NHPT to evaluate for relative hypocalcemia.

• Some NHPT patients progress to develop overt hypercalcemia, but predicting which ones will progress or when is impossible, so regular follow-up is mandatory.

• Ultrasound and nuclear scans are localizing procedures if surgery is planned but do not have any role in diagnosing NHPT.

• A 4D-CT scan has greater sensitivity in identifying abnormal glands than ultrasound or nuclear scans.

• Indications for surgery are similar to classical PHPT and equally successful in improving bone mineral density and reducing renal problems.

• Serial observation is the rule for patients not willing to undergo or requiring immediate parathyroid surgery or with an unacceptably high surgical risk, with appropriate action taken as needed.

Enhancing Healthcare Team Outcomes

The primary care clinicians should utilize the appropriate laboratory tests to diagnose and differentiate SHPT from NHPT, refer difficult or doubtful cases to the endocrinologist, and coordinate with other specialists as indicated. The radiologist, nuclear medicine physician, and surgeons will need a thorough history, especially what medications the patient takes, any previous surgical procedures, allergies, and the reason for the tests. Each of them will be able to counsel patients appropriately for necessary testing, suggest possible or better alternatives, provide the correct interpretation, and communicate this to the treating physician. Gastroenterologists and bariatric surgeons should be knowledgeable about SHPT and ensure collaboration with endocrinologists in preventing and treating the condition. Endocrine and high-volume parathyroid surgeons (eg, otolaryngologists and endocrine surgeons) tend to have better outcomes.

Parathyroid surgeons should communicate the indications for parathyroidectomy, discuss the pros and cons of various procedures, anticipate complications, and coordinate pre and postoperative medical management with endocrinologists. A close working relationship with the laboratory personnel is paramount when performing intraoperative PTH monitoring. Pharmacists identify correct dosage, drug interactions, contraindications, and signs of toxicity and communicate effectively with endocrinologists and other clinicians. Nurses are skilled in the early identification of complications. They also play an essential part in patient education and instruction. They help prepare patients for various investigations while counseling and allaying concerns, fears, and anxieties. Nurses also provide critical pre and postoperative care and promptly communicate patient condition changes with physicians.