Normocalcemic Hyperparathyroidism

Etiology

Normocalcemic primary hyperparathyroidism can be caused by a single adenoma, multiple adenomas, or multi-gland hyperplasia of the parathyroids, just as in the classical type of primary hyperparathyroidism (cPHPT). Several studies have shown an increased incidence of multi-gland adenomas in nPHPT.[3] Radiation to the neck increases the incidence of nPHPT.[4]

Normocalcemic secondary hyperparathyroidism can be caused by a vitamin D deficiency, renal failure, intestinal malabsorption syndromes, bariatric surgery, long-term reduced dietary calcium intake, renal calcium leak, and idiopathic hypercalciuria. The most common cause is end-stage renal disease which causes reduced vitamin D activation leading to lower intestinal calcium absorption resulting in hypocalcemia which induces severe secondary hyperparathyroidism. Serum phosphorus is also elevated. Treatment of hyperparathyroidism in end-stage renal disease usually includes vitamin D supplements (sufficient to maintain at least 20 ng/ml), phosphate binders, and calcimimetics to reduce the PTH levels. Parathyroid surgery is sometimes necessary for severe or refractory cases.

Other causes of secondary hyperparathyroidism include anticonvulsants, bisphosphonates, celiac disease, denosumab, diuretics (thiazides), and lithium. Drug-related secondary hyperparathyroidism can be verified by stopping the drug for several months and rechecking the PTH level. If the PTH was elevated due to a drug, it should normalize when the medication is withheld. If PTH remains elevated, then some other cause is responsible.

Rao et al. first proposed a biphasic progression of hyperparathyroidism in 1988. They suggested that parathyroid hormone levels are elevated during the initial phase, but serum calcium remains within normal parameters. This first phase is generally asymptomatic and was not identified as a precursor or early form of hyperparathyroidism until recently.[5] (The second phase would include hypercalcemia along with elevated parathyroid hormone levels and would be considered classic primary hyperparathyroidism.) Parathyroid hormone levels are not generally checked in patients with normal serum calcium titers. It is only recently that osteoporosis and metabolic bone disease centers have become proactive in evaluating potential bony defects in patients at risk of skeletal disease that these normocalcemic hyperparathyroidism conditions were detected.

Epidemiology

While the prevalence of PHPT is well known, the true prevalence of nPHPT is not, although it has been estimated to be from 5.5% to 17%.[1][2]

The reasons behind this are:

• Different studies have used different cutoffs for 25 hydroxyvitamin D{25(OH) vitamin D} levels and estimated glomerular filtration rate (eGFR) when interpreting PTH values.

• The varying accuracies of PTH assays and their interpretation in the context of the varying cutoffs mentioned above

• Measurement of total corrected calcium instead of ionized calcium

• There is an inherent difficulty in ordering a serum PTH in a normocalcemic individual who is asymptomatic and does not have end-organ damage

• The lack of a large population to study the natural history of nPHPT prospectively

• A clear referral bias in studies reported from tertiary centers

Further, it must be mentioned that the normal value range for PTH in a population is a Gaussian distribution curve. Therefore, it will be evident that around 2.5 percent of the population is expected to have PTH values just outside the upper range of normal yet not have the disease.

A patient whose baseline calcium is 8.9 mg/dl may, on developing PHPT, raise his calcium by 1 mg to 9.9 mg/dl and PTH to greater than 65 pg/ml. He would still technically be in the normal range for calcium and be passed off as nPHPT as he would appear to have isolated PTH elevation. So, individual normal values have to be considered. This fact is important but practically very difficult to implement.[6]

Some normocalcemic patients can become hypercalcemic during another measurement on a different day, which changes the classification and diagnosis.

Some studies have shown that when the total corrected calcium was normal, the ionized calcium could be elevated and insisted on its measurement to decide the final classification of hyperparathyroidism.[7]

Another study has shown that total serum calcium varies with albumin and other serum proteins, which further confuses the diagnosis.[8]

Even in patients with nPHPT, it is impossible to predict who will progress to classical PHPT and who will maintain their normocalcemic status and for how long; all possibilities have been observed. In addition, the longer the observation period, the greater the number of nPHPT patients who will become hypercalcemic, suggesting nPHPT may be a forme fruste or precursor of the classical variant. Older age and higher baseline serum and urinary calcium values more often progress to classical primary hyperparathyroidism.

In a recently published prospective study, nPHPT comprised 15.4 percent of all PHPT patients, with a higher female to male ratio.[7]

Parathyroid incidentalomas were found in some patients undergoing thyroid surgery. The patients with this finding were normocalcemic before surgery. When compared to those patients who were operated on for proven classical PHPT, the normocalcemic incidentaloma patients were younger and had parathyroid glands that weighed less. Biochemically and histologically, they were less hyperfunctioning and secreted less PTH. The sex distribution, cell type, and incidence of disease in multiple glands did not differ. These findings suggest that nPHPT is an earlier form or precursor of classic primary hyperparathyroidism.[9]

Pathophysiology

Normocalcemic hyperparathyroidism is defined as persistently elevated parathyroid hormone titers despite at least two separate, corrected serum calcium or ionized calcium levels over at least six months. This is needed to differentiate it from classic hyperparathyroidism. 

The suggested pathophysiology is an early form or precursor of classical hyperparathyroidism, relative hypercalcemia based on an individual patient's baseline, and response resistance in bone and kidney tissues to parathyroid hormone.[10]

Most patients are asymptomatic, but over a third will progress to symptomatic disease with either significant bone loss or nephrolithiasis.[10]

In nPHPT, the bone turnover markers and the net calcium release, as measured by urinary calcium/creatinine ratio, are lower than their hypercalcemic counterparts with similar PTH values. There is a decreased ability to suppress phosphate and promote calcium reabsorption in the renal tubules. Thus, for similar PTH concentrations, some patients became hypercalcemic while others did not, confirming tissue resistance to PTH in these patients.[11]

Studies from parathyroid glands of nPHPT patients show similarity to normal glands with no change in calcium-sensing receptors, chromogranin A, PTH, or mitotic index (Ki-67). However, decreased vitamin D receptor (VDR) expression and increased cyclin D1 observed in these patients are similar to diseased glands. Therefore, it has been postulated that the discordance between calcium-sensing receptors and either VDR or cyclin D1 or both could result in maintaining normocalcemia in nPHPT.[12]

In some studies, nPHPT patients have higher BMI than their hypercalcemic counterparts. The adequacy of estrogen, even in the postmenopausal period, helps resist the effects of PTH on target tissues in these patients and contributes to maintaining normocalcemia.[11]

Although PTH levels are lower than classical PHPT, the mild chronic elevation in nPHPT is probably sufficient to cause PTH-induced bone resorption.

Patients with nPHPT generally tend to have higher rates of cardiovascular complications, hyperaldosteronism, hypertension, and hyperglycemia due to insulin resistance, muscle tone, and overall quality of life.[13]

Renal calcifications are common in nPHPT. They tend to be associated with high serum PTH, increased 1,25(OH) vitamin D levels, and the degree of hypercalciuria.[14] Some patients with nPHPT present with nephrolithiasis, which may be silent and found only by imaging studies. Calcium oxalate stones are the most common, followed by calcium phosphate.[15] 

The increased rate of nephrolithiasis and bone loss is similar between normocalcemic and hypercalcemic hyperparathyroid patients.[10] The reasons for this are still unclear.[16]

The vast majority of hypercalciuric nephrolithiasis patients do not have normocalcemic hyperparathyroidism. Hypercalciuria is not consistently found in nPHPT, and all patients do not develop renal stones, so other factors must be involved:

Contributors to renal calculi other than hypercalciuria include:

• Aciduria

• High dietary salt 

• Hyperoxaluria  

• Hyperuricosuria

• Hypocitraturia 

• Hypovolemia, dehydration, and oliguria (low urinary volume)

History and Physical

Normocalcemic primary hyperparathyroidism 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 and 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.[17][18] 

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

Evaluation

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 ionized calcium (if available otherwise, total corrected calcium), P, PTH, eGFR, 25 OH vitamin D, 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. Some have proposed that an increased serum calcium/phosphate ratio might help identify independent parathyroid activity, but this has yet to be validated by prospective studies.[19] 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 of more use to exclude nPHPT than to diagnose it.[19][20]

Another potentially useful ratio is the PF index. It is designed to differentiate primary hyperparathyroidism from secondary hyperparathyroidism from vitamin D deficiency. The formula is serum calcium (mmol/L) x PTH (pg/mL)/phosphorus (mmol/L). The cutoff is 34. The PF index has a reported sensitivity of 96.9% and specificity of 97.6%, making it potentially very useful.[19]

In difficult cases, dynamic testing with a thiazide challenge test to exclude idiopathic hypercalciuria and even possibly a calcium loading test to clarify the diagnosis of nPHPT may be necessary. See the differential diagnosis section for details. 

In the rarer situation, where calcium and PTH are measured for other reasons, and normocalcemic hyperparathyroidism is suggested, then the other tests in the initial battery (DEXA scan, renal ultrasound, Sestamibi scan, 24-hour urine calcium, along with a review of medications) will rule out nSHPT and help diagnose nPHPT.

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

A yearly follow-up with DEXA, renal ultrasound, calcium, PTH, and urinary calcium excretion is recommended in patients who are managed medically. In selected patients, measurement of bone turnover markers (urine NTX, serum CTX, BSAP, osteocalcin) to follow patients on 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 their limitations.

• Serum total calcium: Correction for albumin required according to the formula: Corrected calcium = measured calcium + 0.8 (4.0-measured albumin). Note that serum calcium can be highly variable due primarily to dietary factors.

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

• 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, and PTH independence make this the ideal test for vitamin D status. PTH levels normally begin to rise when levels decrease below 30 ng/ml, so a higher 25 (OH) vitamin D level would be needed to diagnose nPHPT.[13][21]

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

• Serum albumin

• Serum BUN and creatinine (Cr), estimated glomerular filtration rate (eGFR), and PTH begin to rise when eGFR decreases below 60 ml/min/1.73 m2.[22] Therefore, for a diagnosis of nPHPT, the GFR should be >60 cc/min. 

• Urine calcium and creatinine: both spot and 24-hour samples

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

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

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

Biochemistry Summary

Normocalcemic primary hyperparathyroidism is defined as:

• At least two separate corrected or ionized calcium levels at least six months apart in the presence of persistently elevated PTH in the absence of any causes of secondary hyperparathyroidism.
• Ionized calcium is preferred.
• 25(OH) vitamin D should be 30 ng/ml or higher.
• GFR should be >60 ml/min.
• An increased serum calcium/phosphate ratio has been suggested as an additional criterion but has yet to be validated.

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, and 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 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 and is highly operator-dependent.

• Ultrasound alone is insufficient to aid 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.[23]

• Parathyroid incidentalomas are adenomas discovered during surgery or thyroid ultrasound examinations. They are generally smaller in size, weigh less, and produce less PTH than adenomas that produce hyperparathyroidism. Reports of FNA biopsy are rampant in the radiology literature, but the surgical guidelines on parathyroid surgery caution about several risks and sequelae and confine FNA exclusively for difficult and unusual cases.[24]

Renal ultrasound will document renal size, identify hydronephrosis and demonstrate nephrolithiasis of stones typically at least 4 mm in size. Precise identification of nephrocalcinosis and all renal calculi will require a non-contrast CT scan of the abdomen, which is considered the gold standard study.

Radionuclide Imaging[25]

• Tc 99m is a radiopharmaceutical 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 calcium channel blockers are more likely to have negative scan results.[26]

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

Tc99m Sestamibi scanning complements ultrasound, and the two together successfully localize many lesions than either alone, but even this combination sometimes has poor concordance in nPHPT.[27] While positive parathyroid scintigraphy rates are significantly less in normocalcemic than hypercalcemic hyperparathyroid patients (42% vs. 81%), it is still recommended as a valuable diagnostic tool even in nPHPT patients. (p<0.0001)[28] An MRI might be a consideration in such circumstances, but a 4D-CT scan would probably be preferred.[29][30]

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 two 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.[31][32] 

4D-CT scanning appears to be particularly useful in patients considering reoperation for persistent or recurrent disease. It has an initially reported sensitivity of 77%, but more recent studies put this higher (sensitivity 81.3%, specificity 95.5%, positive predictive value 87.1%).[31][33][34][35] It is particularly good at finding ectopic glands and has a reported 93.3% negative predictive value.[35] Compared to sestamibi scans, 4D-CT was found to have superior sensitivity for both single (92.5% vs. 72/1%) and multi-gland (58.2% vs. 30.8%) disease. A recent meta-analysis of 26 studies comparing 4D-CT and Sestamibi-SPECT/CT found 4D-CT to have higher sensitivity and specificity.[36] 4D-CT was particularly useful in parathyroid re-operations.[37] Problems with 4D-CT include limited availability, relatively high patient radiation exposure, and somewhat borderline specificity.[38]

Parathyroid Imaging: Which to Do First? Since the Sestamibi scan has the longest track record, high imaging sensitivity, and superior positive predictive value for parathyroid pathology, it is still probably the initial recommended scan for hyperparathyroidism. Ultrasound adds relatively little new information to a positive Sestamibi scan. If the Sestamibi scan is inconclusive, 4D-CT is now the recommended imaging modality.[30] 

A study utilized near-infrared light autofluorescence to locate the parathyroids with success in parathyroid surgery. More studies are needed to test the sensitivity, specificity, and predictive values of this localizing modality.[39]

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

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 indicate bone strength or quality. Fracture sites, arthritis, and degenerative bony 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, and ethnicity may influence the interpretation.

A trabecular bone score is the most cost-effective way of determining bone quality. It utilizes software along with data from the DEXA scan and bone mineral density (BMD) determinations and can independently predict fracture risk.

Other Imaging

MRI is not generally used for parathyroid imaging, but it has been reported to have a 79.9% sensitivity in detecting parathyroid adenomas. This increases to 91.5% when combined with ultrasound and Sestamibi scans.[29]

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 is not performed routinely. In nPHPT, HR-pQCT may be abnormal when the lumbar spine BMD is not reduced.[40]

Treatment / Management

Operative Management

Parathyroid surgery is the only definitive treatment for primary hyperparathyroidism, whether it is normocalcemic or hypercalcemic. There are no known medical treatments that can fully reproduce the benefits of a successful surgery. Among the recommendations and indications for parathyroid surgery by the expert panel on Asymptomatic Primary Hyperparathyroidism: (age less than 50 years, osteoporosis, creatinine clearance <60 ml/min, urinary 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.[41] Although the risk for recurrent renal calculi is not eliminated, it is decreased substantially, and renal function is preserved.[40] There is not enough evidence yet to attribute any benefit of parathyroid surgery in relieving neuropsychiatric or cardiovascular symptoms.(B2)

Parathyroid surgery performed by experienced parathyroid surgeons tend to have higher success rates, lower complications, and shorter hospital stays.[24] 

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.[3]

In rare cases, selective jugular venous sampling to localize the diseased glands may be considered.[42]

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.

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.[3] There is also a higher rate of reoperation in normocalcemic hyperparathyroid patients.[43](B2)

Long-term data on post-operative nPHPT patients is still lacking.[13]

Medical Management

Patients without an indication for surgery, who are unacceptable risks, or who refuse surgery can generally be managed by medications and serial observation.

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 calcium, P, and PTH levels were unchanged. Further studies are needed to recommend this therapy routinely, but it can be considered for those whose only complication of nPHPT is reduced bone mineral density.[44](A1)

The calcimimetic cinacalcet causes allosteric modification of the calcium-sensing receptors in the parathyroid and increases the set point for PTH secretion. In the calcium-sensing receptors of the renal tubules, it prevents calcium reabsorption. It is used in parathyroid carcinoma and SHPT in end-stage renal disease (ESRD) patients on dialysis. It 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 high risk for surgical procedures.

Cinacalcet results in a modest reduction in calcium, less so in PTH, and no significant changes in BMD or urinary calcium. 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.[15]

In summary, bisphosphonates can significantly increase bone mineral density but have relatively minimal effect on serum calcium levels. Calcimimetic agents can effectively lower serum calcium and especially PTH levels but have minimal effect on bone mineral density. Oral phosphate binders can be used selectively if necessary.

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

Etelcalcetide is FDA-approved in the US for secondary hyperparathyroidism in end-stage renal failure patients. There is no information on its use in primary hyperparathyroidism. Evocaclet is another calcimimetic agent but is only approved in Japan. 

Rank ligand inhibitors like denosumab have been used to treat hypercalcemia and are the most effective anti-resorptive agents, but there are no studies of their use in primary hyperparathyroidism.

Calcitonin may occasionally be used cautiously in cases of severe secondary hyperparathyroidism, as in some patients with end-stage renal failure. This is not the situation in normocalcemic hyperparathyroidism, so calcitonin generally has no place in treatment.

Those patients not requiring or not opting for surgery should be monitored with yearly serum calcium, P, intact PTH, eGFR, 24-hour urinary calcium excretion, and periodic renal imaging (for high-risk patients), with DEXA scans for BMD measurement at the lumbar spine, hips, and distal third of the radius every 1-2 years. If deterioration occurs (worsening bone density, nephrolithiasis, or fractures), 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.[45]

Differential Diagnosis

Normocalcemic secondary hyperparathyroidism also presents with a similar biochemical picture and must be ruled out before embracing 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, especially in the early stages. 

Normocalcemic secondary hyperparathyroidism 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 has been reported to help differentiate HPT from hypercalciuria. In the thiazide challenge test, 50 mg of hydrochlorothiazide is given orally every day for two weeks. Thiazides will decrease urinary calcium excretion, so a patient with nSHPT due to hypercalciuria will show a decrease in urinary calcium excretion and decreased or normalized PTH, while a patient with nPHPT is likely to become hypercalcemic with only minimal or no reduction in their PTH levels.[46]

Lithium deserves special mention. It can desensitize the calcium-sensing receptor to calcium and thereby shift the setpoint to the right, release PTH and cause nSHPT. It can unmask and also cause classical PHPT. Single PTH producing parathyroid adenomas, 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 calcium 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 calcium and vitamin D should be ensured in these patients, especially when malabsorption issues are present, to prevent SHPT.[47]

Patients with cPHPT 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 present with bone pains, myalgia, and proximal muscle weakness. After the correction of their vitamin D deficiency, hypercalcemia is unmasked. They should be handled as other cPHPT patients; calcium supplements should not be withheld because PTH elevation occurs reflexively. Maintenance doses of vitamin D should be continued and are considered safe.[48][49][50]

Familial hypocalciuric hypercalcemia is an inherited disorder that causes abnormally high calcium levels in the blood (hypercalcemia) but with low to moderate levels of calcium in the urine (hypocalciuria). It is always important to rule out benign familial hypocalciuric hypercalcemia before making a final diagnosis of hyperparathyroidism. Familial hypocalciuric hypercalcemia is associated with mild hyperparathyroidism. It is caused by a mutation in the calcium-sensing receptor gene of the parathyroid gland and renal tubule. Chemically, patients will have mild hyperparathyroidism, hypercalcemia, hypocalciuria, hypomagnesemia, and hypophosphatemia. It is also characterized by a low calcium/creatinine clearance ratio. This can be calculated by the following: urine calcium x serum creatinine) divided by (serum calcium x urine creatinine).[51] Patients with familial hypocalciuric hypercalcemia rarely have symptoms, and their hyperparathyroidism does not require surgery or any other treatment. When parathyroid surgery is inadvertently performed on these individuals, the result is usually permanent hypoparathyroidism but with persistent hypocalciuria, which demonstrates that the persistently low urinary calcium levels are not parathyroid hormone-dependent. 

An oral calcium loading test may help clarify the diagnosis of nPHPT in difficult cases:

One gram of oral calcium is given, and serum calcium 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. Calcium 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 calcium after loading) and the baseline PTH is termed PTH inhibition rate (PTH-IR). The change in calcium levels from baseline to peak concentration after loading is termed delta calcium. 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.[52][53]

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 before the test can be formally recommended.[54]

Prognosis

Surgically managed nPHPT patients generally do well. The newer minimally invasive procedures are less intrusive with shorter operating times and fewer complications. Intraoperative monitoring of serum PTH levels has yielded better outcomes. However, even with experienced surgeons, operative failure or early recurrence does occur, given the difficulty in localizing the smaller adenomas and the higher involvement of multiple parathyroids. Follow-up with serial PTH levels is mandatory as per the guidelines of the American Association of Endocrine Surgeons (AAES). A PTH drop of more than 50% from baseline is usually a reliable indicator of surgical success.[55]

Patients with nPHPT undergoing parathyroid surgery tended to have an increased rate of reoperation that was more than double the rate of hypercalcemia hyperparathyroid patients. They also were much more likely to develop permanent hypocalcemia postoperatively (11.4% vs. 1.4%).[56] 

For nPHPT patients managed medically, serial monitoring with yearly calcium, PO4, PTH, eGFR, and DEXA scans every 1-2 years 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 serum calcium, high urinary calcium, and advanced age have been shown to favor progression to hypercalcemic primary hyperparathyroidism.

Complications

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

MIS has several benefits for patients, such as less dissection, minimal blood loss, less hematoma formation, more use of local anesthesia and regional sedation, reduced operating time, and shorter hospital stays, with 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 a 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 an elevated PTH up to 6 months after surgery. When PTH levels return to normal initially but increase after six months, it is termed a recurrence. If a reoperation is considered, extensive patient counseling with a multi-disciplinary team should be involved; proper communication among the team members is crucial.[24]