nPHPT is largely asymptomatic, but a few have fractures or renal stones. Even those without symptoms may have abnormalities in DEXA (dual-energy X-ray absorptiometry) or renal ultrasound scans. Elevated blood pressure, neuropsychiatric symptoms may accompany nPHPT, but it is unclear if there is a direct relationship.

Rare case reports of nPHPT presenting as acute parathyroid infarction or parathyroid carcinoma have appeared.[10][11] 

A family history of renal stones or osteoporosis in younger relatives should prompt a search for familial PHPT.

Biochemistry

A diagnosis of nPHPT in most cases is made when patients presenting with osteoporosis or renal stones are investigated proactively. In such presentations, reasonable initial investigations would include serum iCa (if available otherwise total corrected Ca), P, PTH, eGFR, 25 OHD, and urinary calcium excretion. The results from these and a thorough review of the patient's medications would suffice to exclude nSHPT and diagnose nPHPT. The clinical situation dictates other investigations like liver function tests and serum Mg. In difficult cases, dynamic testing with a thiazide challenge test (TCT) to exclude idiopathic hypercalciuria, and Ca loading test to clarify the diagnosis of nPHPT may be necessary. See the differential diagnosis section for details. 

In the rarer situation, where Ca and PTH are measured for other reasons, and nHPT is suggestive, then the other tests in the initial battery, DEXA scan, renal ultrasound, along with a review of medications will rule out nSHPT and help diagnose nPHPT.

In both instances, the Ca and PTH must be repeated on different occasions, and the diagnosis of nPHPT confirmed. The results of these tests can also guide the clinician in selecting patients for PTX following the expert panel recommendations. 

In patients who are managed medically, a yearly follow up with DEXA, renal ultrasound, Ca, PTH, and urinary Ca excretion is recommended. In selected patients, measurement of bone turnover markers (urine NTX, serum CTX, BSAP, osteocalcin) to follow patients on treatment with antiresorptive therapy for osteoporosis in medically managed nPHPT may be utilized. Changes in these parameters are observed earlier than in bone densitometry.

The biochemical tests used are listed below with notes on the rationale for choosing them and limitations.

• Serum total calcium: Correction for albumin required according to the formula: Corrected Ca = measured Ca + 0.8 (4.0-measured albumin) 

•   Serum ionized calcium: Influenced by pH: acidosis increases and alkalosis decreases results

•   Serum phosphorus (P)

•   Serum alkaline phosphatase (BSAP): In selected patients, measurement of bone-specific alkaline phosphatase, a marker of bone formation, may be helpful.

•   Serum 25(OH) vitamin D: Large stores, a long half-life, PTH independence makes this the ideal test for vitamin D status. PTH begins to rise when levels decrease below 30 ng/ml.[12]

•   Serum intact PTH: Both second and third-generation assays may be used, but in renal failure, the latter has an edge.

•   Serum albumin

•   Serum BUN and creatinine (Cr), estimated glomerular filtration rate (eGFR), PTH begins to rise when eGFR decreases below 60 ml/min/1.73 m2.[13]

•   Urine Ca and Cr: both spot and 24-hour samples

•   Liver function tests: to rule out liver diseases causing sPHPT

•   Serum magnesium (Mg): hypomagnesemia may underestimate PTH elevation as it decreases the secretion and action of PTH

•   Serum 1,25 (OH)2D: not routinely measured as levels are normal or even raised in both vitamin D deficiency and primary hyperparathyroidism

Imaging studies

The diagnosis of nPHPT is biochemical. Imaging modalities are useful for preoperative localization, especially if minimally invasive surgery (MIS) is planned, multi-gland disease is suspected, or reoperation is required. They have no role in diagnosis per se. A reasonable initial test is a cervical ultrasound followed by a Tc99m nuclear scan to localize the abnormal parathyroids before surgery. The typical findings in ultrasound, Tc99m scans, other tests, and their limitations are listed below. As far as the newer testing modalities reviewed below are concerned, there is not enough evidence to recommend them routinely. Success rates with these tests vary and are guided by institutional practices, individual acquaintance, and availability of experts, and the practitioner should consult the multi-disciplinary team before embarking on these expensive investigations.

Cervical ultrasonography

• Normal parathyroid glands are rarely visible in ultrasound scans.

• Enlarged glands are seen as oval hypoechoic masses with a peripheral vascular ring.

• The parathyroids have polar arteries, whereas lymph nodes have hilar ones.

• They are seen in inferior or posterior locations to the thyroid gland and 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 and are highly operator dependent.

• Ultrasound alone is insufficient as an aid to preoperative localization before minimally invasive surgery.

• The thyroid gland is also scanned at the same time as abnormalities found may be treated in the same surgical setting.[14]

• Parathyroid incidentalomas (PTI) are adenomas discovered during surgery or nowadays during thyroid ultrasound examinations. They are smaller in size, weigh less, and produce less PTH. Reports of FNA biopsy are rampant in the radiology literature, but the surgical guidelines on parathyroid surgery caution of several risks and sequelae and confine FNA exclusively for difficult and unusual cases.[15]

Renal ultrasound will document renal size, nephrocalcinosis, nephrolithiasis, and hydronephrosis.

Radionuclide imaging[16]

• Tc 99m is a radiopharmaceutical that is coupled to six (sesta means six) units of methoxyisobutylisonitrile (MIBI) ligands that transport it to target organs.

• It is a lipophilic cation that, when injected intravenously, distributes proportionally to blood flow.

• It is taken up by abnormal parathyroids and retained. The principle behind this modality is that the Tc99m sestamibi elutes earlier from the thyroid gland than parathyroid adenomas.

• A delayed scan after 2 to 4 hours will show the adenomatous parathyroid with increased uptake of the Tc99m sestamibi and help in its localization.

• The gamma rays emitted as the isotope decays are measured with a gamma counter on the surface.

• The cell composition will determine the amount of absorption and is directly proportional to its mitochondrial content. Oxyphil cells are rich in mitochondria and show well in oxyphil tumors.

• Sestamibi scintigraphy with SPECT (single-photon emission computed tomography) adds a three-dimensional component to the gamma camera images, which increases accuracy.

• Tc99m sestamibi SPECT/CT adds a second imaging modality CT (computed tomography) using x-rays in the same sitting as the nuclear scan. This method combines images from two different scans together to obtain greater detail, yet the above combination detects multi-gland disease poorly.

• An earlier washout of the nuclear material from the smaller adenomas or hyperplastic parathyroids can lead to a negative scan, as found in nPHPT.

• In multiple adenomas, a preferential uptake and retention by one adenoma over the others is the reason for not detecting the other glands.

• The presence of p-glycoprotein in the parathyroid cells and patients on Ca channel blockers are more likely to have negative scan results.[17]

• Other confounders are coexisting thyroid lesions that display delayed washout.

In many cases, Tc99m sestamibi complements ultrasound, and the two together successfully localize many lesions than either alone, but even this combination has poor concordance in nPHPT.[18]

99mTc-sestamibi/123I subtraction protocol involves two radioisotopes used simultaneously rather than sequentially, and there are reports of localizing multi-gland disease better than the above methods. In this technique, since iodine is involved, patients on thyroxine replacement should stop treatment for 2 weeks before the test.

Some studies report greater success in nPHPT with 4D CT and novel PET tracers like 11C-methionine and 18F-FDG, but these have to be tested in larger patient populations to be routinely recommended.[19][20]

A study utilized near-infrared light autofluorescence to locate the parathyroids with success in PTX. More studies are needed to test the sensitivity, specificity, and predictive values of this localizing modality.[21]

Finally, patients with negative or equivocal scans but a biochemically confirmed nPHPT who have indications for surgery will still need a referral to an endocrine surgeon.

DEXA (dual-energy x-ray absorptiometry) scans of the lumbar spine, the hip, and the distal third of the radius determine the T score, which is the standard deviation (SD) compared to a young healthy adult's bone density. Although a good measure of bone density, it does not tell us the bone strength or quality. Fracture sites, arthritis, degenerative changes all influence values and have to be taken into account before decisions are made based on DEXA. Moreover, changes in bone density can only be appreciated at yearly intervals. Ethnicity may influence interpretation. Trabecular bone score (TBS) is the most cost-effective way of determining bone quality. It utilizes software along with data from BMD and can independently predict fracture risk.

Other imaging:

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. This test is still in research settings and not routinely done. In nPHPT, HR-pQCT may be abnormal when the lumbar spine BMD is not reduced.[22]

To operate or not to operate, that is the question.

PTX is the only definitive treatment for PHPT, whether it is nPHPT or classical PHPT. There are no known medical treatments that can fully reproduce the benefits of a successful surgery. Among the recommendations for PTX by the expert panel on Asymptomatic Primary Hyperparathyroidism, age less than 50 years, osteoporosis, creatinine clearance < 60 ml/min, urine calcium > 400 mg/24 hours, and nephrolithiasis can be equally applied to nPHPT and studies have shown improvement in bone mineral density (BMD) after parathyroidectomy (PTX).[23] Although the risk for recurrent renal calculi is not eliminated, it is decreased substantially, and renal function is preserved.[22] There is not enough evidence yet to attribute any benefit of PTX in relieving neuropsychiatric or cardiovascular symptoms.

PTX performed by endocrine surgeons (ES) tend to have higher success rates, lower complications, and shorter hospital stay.[15] 

Intraoperative PTH (ioPTH) monitoring with a rapid assay using the Miami criterion of a fifty percent drop from baseline to check for completeness of removal of abnormal parathyroid tissue has been tested in nPHPT patients and found to be equally predictive as in cPHPT.[1]

In rare cases, selective jugular venous sampling to localize the diseased glands may be considered.[24]

The intraoperative gamma probe relies on tracer retention of more than 20 percent in diseased glands has also been utilized, but it is inferior to ioPTH and needs specialized equipment and personnel not always available at all centers.

Medical Management

Patients without indications for surgery or who refuse surgery can be managed by serial observation and medications.

The only bisphosphonate that has been tried in a study in nPHPT with osteoporosis is alendronate. In this study, 15 patients with osteoporosis were given alendronate plus vitamin D, and 15 matched controls were given vitamin D alone. After treatment, the alendronate group showed greater improvement in BMD. Serum Ca, P, and PTH levels were unchanged. Further studies are needed to recommend this therapy routinely but can be considered in those whose only complication of nPHPT is reduced bone mineral density.[25]

The calcimimetic cinacalcet causes allosteric modification of the calcium-sensing receptors (CaSR) in the parathyroid and increases the set point for PTH secretion. In the CaSR of the renal tubules, it prevents Ca reabsorption. It is used in parathyroid carcinoma, SHPT in end-stage renal disease (ESRD) patients on dialysis. It can also be used in those with intractable hypercalcemia in classical PHPT, patients who are hypercalcemic after failed PTX, those who refuse surgery or are at high risk for a surgical procedure. Cinacalcet results in a modest reduction in Ca, less so in PTH, and no change in BMD or urinary Ca. A small prospective randomized pilot study involving ten patients treated for ten months, which included nPHPT patients, showed safety and benefit with cinacalcet in reducing the number and size of calculi. This study had very few numbers and was unblinded. More studies with larger numbers in a blinded fashion with a crossover should help address these unanswered questions. There are gastrointestinal side-effects, and the drug is expensive.[9]

Other drugs used in PHPT are estrogen, which increases BMD while maintaining serum Ca and PTH and mildly decreasing urinary Ca (uCa) and raloxifene, which in the short-term reduces serum Ca but does not affect uCa or PTH. BMD data are not available for the latter. Studies in nPHPT are warranted.

Those patients not requiring or not opting for surgery should be monitored with a yearly serum Ca, P, intact PTH, eGFR, urinary Ca excretion, and periodic renal imaging (for high-risk patients) and DEXA scans for BMD measurement at the lumbar spine, hips, and distal third of the radius. If deterioration occurs, then surgery is recommended. For those patients who cannot be relied upon to follow up, surgery may be offered in the beginning in hypercalcemic PHPT, but there is no consensus for those with nPHPT.[26]

nSHPT also presents with a similar biochemical picture and must be ruled out before embarking on a diagnosis of nPHPT. Causes of nSHPT include vitamin D deficiency (VDD) from inadequate sunlight exposure, diets poor in vitamin D (VD), eating unfortified foods, conditions producing malabsorption including bariatric surgical procedures, various medications that accelerate vitamin D metabolism, high-risk populations like older adults, malnourished children, pregnant and lactating women, HIV infection and its treatment, hypercalciuria, and chronic kidney disease in the early stages. 

nSHPT caused by hypercalciuria can result from excess sodium intake, excess tea, and coffee consumption, loop diuretics like furosemide, and a thorough history will exclude these causes. Genetic defects causing hypercalciuria are rare and detected by genetic testing.

A thiazide challenge test (TCT) has been reported to help differentiate HPT from hypercalciuria. In the TCT, 50 mg of hydrochlorothiazide is given orally daily for two weeks. A patient with nSHPT due to hypercalciuria will show a decrease in urinary Ca excretion and decreased or normalized PTH while a patient with nPHPT is likely to become hypercalcemic with only minimal reduction in the PTH levels.[27]

Lithium deserves special mention. It can desensitize the Ca sensing receptor to Ca and thereby shift the setpoint to the right, release PTH and cause nSHPT. It can unmask and also cause classical PHPT. A single adenoma, as well as multi-gland disease, have been reported with long-term lithium use.

Bisphosphonates and denosumab have been reported to cause hypocalcemic SHPT as well as nSHPT during treatment for osteoporosis. A case of insufficient Ca but adequate vitamin D intake with nSHPT is reported in a patient on a drug holiday from alendronate. It is important to consider these drugs when SHPT/PHPT are being entertained as diagnoses. Adequate Ca and vitamin D should be ensured in these patients, especially when malabsorption issues are present to prevent SHPT.[28]

Patients with cPHPT may have coexisting vitamin D deficiency which masks the hypercalcemia. They present with normocalcemic hyperparathyroidism. Depending on the degree of deficiency of vitamin D, they may present with bone pains, myalgia, and proximal muscle weakness. After the correction of vitamin D deficiency, hypercalcemia is unmasked. They should be handled as other cPHPT patients; calcium supplements should not be withheld because PTH elevation occurs reflexly. Maintenance doses of vitamin D should be continued and are safe.[29][30][31]

Calcium loading test may help clarify the diagnosis of nPHPT in difficult cases:

One gram oral calcium is given, and serum Ca and PTH values are measured at regular intervals from 0 to 120 minutes. In patients with nPHPT, there is only minimum suppression of PTH from baseline, whereas, in normal individuals, and nSHPT, there is a marked decrease. Ca loading can also be done intravenously and the measurements made.

The ratio of the decrease in PTH (which usually happens in 80 to 120 minutes and parallels the increase in Ca after loading) and the baseline PTH is termed PTH inhibition rate (PTH-IR). The change in Ca levels from baseline to peak concentration after loading is termed delta Ca. The ratio of these two calculated values was used in one study to differentiate the various types of hyperparathyroidism. It was also recommended as a test to decide when PTH secretion becomes autonomous in SHPT due to CKD. These results are preliminary and need to be confirmed in large scale studies.[32][33]

Recently a parathyroid function index (PFI) has been described to differentiate cPHPT, nPHPT, nSHPT, and normal individuals. The product of serum total corrected calcium times PTH divided by the serum P (all in SI units) gives the PFI. A value of 34 is recommended as the cut-off to distinguish PHPT from nSHPT and normals. More testing in larger populations is required to recommend this test.[34]

• Bisphosphonates
• Hypercalciuria
• Lithium
• Normocalcemic secondary hyperparathyroidism
• Vitamin D deficiency

Surgically managed nPHPT patients generally do well. The newer procedures are less invasive with shorter operation times and fewer complications. Intraoperative monitoring of serum PTH has yielded better outcomes. Even with experienced surgeons, operation failure or recurrence do occur given the difficulty in localizing the smaller adenomas and higher involvement of multiple parathyroids. Follow up with serial PTH is mandatory as per the guidelines of the AAES (American Association of Endocrine Surgeons).

For medically managed nPHPT patients, serial monitoring with Ca, PO4, PTH, eGFR, and DEXA scans yearly is recommended. It is virtually impossible at the present level of understanding to confidently and correctly predict which patient with nPHPT will progress to develop hypercalcemia and hence the need for regular monitoring. High normal Ca, high urinary Ca, and advanced age have shown to favor progression to hypercalcemic PHPT.

Patients with nPHPT who are surgical candidates are often treated with newer minimally invasive techniques(MIS) techniques with fewer complications.

MIS has several benefits to patients, such as less dissection, minimal blood loss, less hematoma formation, more use of local anesthesia and regional sedation, shorter operation time and hospital stay and fewer nerve injuries, and resultant voice problems. Localization procedures preoperatively, if successful, will lead to greater success in MIS. When diseased glands are not identified by MIS, it may be necessary to convert to bilateral neck exploration. This is true when glands are small and in multi-gland disease, a situation not uncommonly seen in nPHPT.

Operative failure in nPHPT is defined as the persistence of elevated PTH up to 6 months after surgery. When PTH returns to normal initially but increases after six months, it is termed recurrence. If reoperation is considered, extensive patient counseling and a multi-disciplinary team should be involved, and proper communication within the team members is crucial. Care should be taken that there are no discordant views expressed to patients or their caregivers.[15]

• Endocrinology

• Endocrine surgery

• Laboratory medicine 

• Nuclear medicine

• Radiology

• Bariatric surgery

• Gastroenterology

• Pharmacy

• Nursing

Patients with nPHPT should be taught in simple language the autonomous nature of the parathyroids in nPHPT and the implications of a raised PTH. When surgical treatment is suggested, all options should be discussed with explanations on anatomy using models, video lessons of the actual surgery, possible postoperative complications, recovery periods, do's and don'ts, and a simplified explanation of the technology used.

Patients with nPHPT choosing medical management should receive education on the medications used, dosage, administration instructions, warning symptoms of reactions or side-effects, duration of therapy, frequency of follow-up, and tests required. The health literacy of the patients should be taken into account in formulating patient education in all instances.

• nPHPT is now a recognized phenotype of PHPT.

• It may be an earlier form of classical PHPT.

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

• Several studies have shown that nPHPT can cause end-organ damage even when normocalcemia is maintained.

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

• The diagnosis of nPHPT demands meticulous exclusion of possible causes of nSHPT.

• iCa values are preferred over total Ca corrected to albumin.

• A second or third generation PTH assay should be used, and iCa and PTH repeated to establish nPHPT.

• Many earlier studies have used liberal cut-offs for eGFR, and 25 OHD levels and findings should be interpreted with caution.

• In nPHPT, the parathyroids are smaller, involve multiple glands, secrete less PTH, and produce lower levels of bone markers. 

• A lesser secretion of PTH and resistance to its action in the bone and kidney may explain the maintenance of normocalcemia

• Some nPHPT patients progress to develop hypercalcemia, but it is impossible to predict which one will progress and when so regular follow-up is mandatory.

• The diagnosis of nPHPT is biochemical and is established by consistently normal iCa with elevated PTH.

• Ultrasound and nuclear scans are localizing procedures if surgery is planned but do not have any role in the diagnosis of nPHPT.

• Ultrasound is less predictive and discordant with Tc99m sestamibi nuclear scans in many cases of nPHPT.

• Newer localization procedures are being increasingly used and helpful.

• Indications for surgery are similar to classical PHPT and successful in improving BMD and reducing renal problems.

• MIS, along with ioPTH monitoring, has revolutionized PTX with minimal complications when performed by competent endocrine surgeons. 

• For others, not willing or needing PTX serial observation is the rule and action taken as needed.

• Alendronate has been tried in nPHPT in a small trial and found to help improve BMD.

• More long-term prospective multi-center trials in populations from the community should be undertaken to study the natural history of nPHPT systematically. This will provide opportunities to establish revised normal ranges for PTH in a vitamin D replete population and answer some of the burning questions of this newer phenotype of PHPT.

The primary care provider should utilize the appropriate tests to diagnose and differentiate nSHPT from nPHPT, refer difficult or doubtful cases to the endocrinologist, and coordinate with other providers.

The radiologist, nuclear medicine physician, and laboratory technologist will need a good history, especially what medications the patient is taking, any previous procedures, allergies, and reason for the tests. Each of them will be able to counsel patients correctly for the tests, suggest better alternatives, provide the correct interpretation, and communicate this to the treating physician.

Gastroenterologists and bariatric surgeons should be knowledgeable about nSHPT and ensure collaboration with endocrinologists in preventing and treating the condition.

Endocrine surgeons or high volume general surgeons have better outcomes.[15] [Level 2]

Endocrine surgeons should communicate indications for parathyroidectomy, discuss the pros and cons of various procedures, anticipate complications, and coordinate pre and postoperative medical management with endocrinologists. When intraoperative PTH monitoring is done, a close working relationship with the laboratory personnel is paramount.

Pharmacists identify correct dosage, drug interactions, contraindications, and signs of toxicity and communicate effectively with endocrinologists and other providers.

Nurses are skilled in early identification of complications. They will also play a part in patient education, preparing them for investigations and counseling and allaying fears, and provide pre and postoperative care and communicate changes in the patient's condition promptly with physicians.