Diagnosis Of Normocalcemic Primary Hyperparathyroidism Research Articles

The Eucalcemic Patient With Elevated Parathyroid Hormone Levels.

Primary hyperparathyroidism (PHPT) is classically characterized by hypercalcemia with elevated or inappropriately normal parathyroid hormone (PTH) levels. Elevated PTH levels in the presence of normal calcium levels are not infrequently found during the evaluation of metabolic bone disorders or kidney stone disease. This can be caused by secondary hyperparathyroidism (SHPT) or normocalcemic primary hyperparathyroidism (NPHPT). NPHPT is due to autonomous parathyroid function whereas SHPT is caused by a physiologic stimulation to PTH secretion. Many medical conditions and medications can contribute to SHPT, and differentiation between SHPT and NPHPT may be difficult. Cases are presented to illustrate examples. In this paper, we review the distinction between SHPT and NPHPT as well as end organ effects of NPHPT and outcomes of surgery in NPHPT. We suggest that the diagnosis of NPHPT be made only after careful exclusion of causes of SHPT and consideration of medications that can increase PTH secretion. Further, we advise a conservative approach to surgery in NPHPT.

The effects of season (spring versus autumn) on diagnosis ofnormocalcemic primary hyperparathyroidism.

BackgroundRaised parathormone (PTH) and normal calcium concentrations can be observed both in normocalcemic primary hyperparathyroidism (nPHPT) and in secondary hyperparathyroidism, e.g. due to vitamin D deficiency. We assessed the impact of season on the validity of diagnosis of nPHPT in terms of screening investigations to be performed in the primary care settings.Material and methodsOn two occasions (March/April & September/October) we measured vitamin D (25OHD), PTH and total calcium in 125 healthy subjects, age range 6-50, not taking any vitamin D supplements.ResultsIn autumn there was an increase in 25OHD concentrations (from 18.1 ± 7.37ng/ml to 24.58 ± 7.72ng/ml, p<0.0001), a decline in PTH from 44.40 ± 17.76pg/ml to 36.63 ± 14.84pg/ml, p<0.001), without change in calcium levels. Only 45 subjects (36%) were vitamin D sufficient (25OHD>20/ml) in spring versus 83 (66.4%) in autumn, p<0.001. Elevated PTH concentrations were noted in 10 subjects in spring (8%) and in six subjects (4.8%) (p<0.05) in autumn. In spring, however, eight out of ten of these subjects (80%) had 25OHD<20 ng/ml, versus one in six (16.7%) in autumn (p<0.01). Normalization of PTH was observed in seven out ten subjects (70%), and all of them had 25-OHD<20 ng/ml in spring.ConclusionsIn spring elevated PTH concentrations in the setting of normocalcemia are more likely to be caused by 25OHD deficiency rather by nPHPT. In contrast, in autumn, increased PTH concentrations are more likely to reflect nPHPT. We postulate that screening for nPHPT should be done in 25OHD replete subjects, i.e. in autumn rather than in spring.

Occult Renal Calcifications in Patients with Normocalcemic Primary Hyperparathyroidism and Their Association with the Parathyroid Hormone-Vitamin D Axis.

Normocalcemic primary hyperparathyroidism (NPHPT) is characterized by elevated serum levels of parathyroid hormone (PTH) with persistently normal serum calcium concentrations after excluding secondary causes of hyperparathyroidism. Urolithiasis and/or nephrocalcinosis may occur in hypercalcemic PHPT, but little is known about these complications in NPHPT. Objectives. To identify occult urolithiasis and nephrocalcinosis in asymptomatic patients with NPHPT and evaluate biochemical markers as risk predictors for the development of renal calcification (RC). Methods. Cross-sectional analysis of 34 patients with no history of urolithiasis and/or nephrocalcinosis. The diagnosis of NPHPT was as follows: elevated serum PTH (reference range: 15–65 pg/mL), normal albumin-corrected serum calcium, normal urinary calcium excretion, serum 25(OH)D >30 ng/mL, eGFR (CKD-EPI) > 60 mL/min/1.73 m2, without intestinal disease, and not on medications such as thiazide diuretics, lithium, bisphosphonates, or denosumab. Patients were categorized according to the presence or absence of RC identified by renal imaging. Their clinical and biochemical characteristics were then compared. Results. The patients had a mean age of 67.97 ± 10.45 years, predominantly postmenopausal women (88.2%); serum PTH, 119.67 ± 64.44 pg/mL; 25(OH)D, 39.00 ± 8.88 ng/dL; 1.25(OH))2D, 74.53 ± 26.37 pg/mL; corrected serum calcium, 9.34 ± 0.62 mg/dL; and 24-hour urinary calcium, 134.87 ± 79.68 mg/day. RC was identified in 26.5% of the patients. There was no difference in anthropometric and clinical parameters, renal function, 25(OH)D, and urinary pH in patients with or without RC. Patients with RC had higher PTH values (176.22 vs. 99.32 pg/mL, P = 0.001), 1.25(OH) 2D (96.83 vs. 62.36 pg/mL, P = 0.005), and 24-hour urinary calcium (181.9 vs. 117.94 mg/day, P = 0.037). Conclusion. Occult renal calcifications are common in NPHPT and are associated with increased serum PTH, 1.25(OH))2D, and 24 h urinary calcium.

Bone and primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is a disease caused by excessive and inappropriate secretion of parathyroid hormone resulting in hypercalcemia. It is usually diagnosed incidentally in case of hypercalcemia, osteoporosis or, more rarely, renal involvement such as lithiasis. The clinical presentation reflects hypercalcemia and involves several organs, mainly the cardiovascular system, bone, and kidneys. However, most patients with PHPT are asymptomatic. The diagnosis is biological, obvious when serum calcium and parathyroid hormone levels are high, but difficult when one of these two values is normal. The diagnosis of normocalcemic PHPT is possible only after ruling out all causes of secondary hyperparathyroidism. Parathyroid imaging does not contribute to the positive diagnosis but guides surgery and rules out an associated thyroid abnormality. Parathyroid surgery is the gold standard treatment. Parathyroid surgery is indicated in the presence or risk of complications, and it is the only treatment that prevents fractures. Pharmaceutical treatments have only limited effects on complications and are limited to cases where surgery is contraindicated. After parathyroid surgery, the use of bisphosphonates must be avoided as they seem to interfere with the parathyroidectomy's fracture-preventing effects. In the absence of surgical indication, medical monitoring of patients includes assessment of laboratory values, bone density, and renal function.

Appropriate Cutoff for 25OHD Levels in the Diagnosis of Normocalcemic Primary Hyperparathyroidism (NPHPT): A Systematic Review

Introduction: The Fourth International Workshop in 2014 delineated guidelines for the diagnosis of NPHPT which include ruling out secondary causes of hyperparathyroidism, and recommended cutoffs for 25 vitamin D (25OHD) to be ≥20ng/mL. Keeping in mind that the exact levels to optimize 25OHD in hyperparathyroid states are unknown, we aim to review possible variation in the prevalence of NPHPT if 25OHD cutoffs were to be raised to rule out vitamin D deficiency with more specificity. Methods: A PubMed search was conducted with key words “normocalcemic primary hyperparathyroidism” to review studies about NPHPT and 25OHD status. 533 articles were found, and 127 articles were identified by title/abstract screening with year of publication between 2014 to 2020. Ten studies were identified for the systematic review based on full text review for relevance. Results: Studies have been conducted in various countries across all continents to characterize NPHPT further. 5/10 studies used 25OHD cutoff of ≥20ng/mL and 4 studies had a cutoff of ≥30ng/mL and 1 study looked into the difference in prevalence with both cutoffs. All 3 studies from Italy used the higher cutoff. Rosario et al from Brazil reported a decrease in prevalence of NPHPT from 6.8% (25OHD≥20ng/mL) to 0.74% by supplementing those subjects to 25OHD ≥30ng/mL without any increase in serum calcium or parathyroid hormone (PTH) levels.1 Wang et al found that when total 25OHD levels were kept between 30–40 ng/mL, free 25OHD levels were actually lower compared to normal subjects.2 Conclusion: The levels of 25OHD that would define deficiency in NPHPT remain undetermined and both >20 ng/mL and >30ng/mL have been studied as cutoffs. It is well known that vitamin D insufficiency (25D 20-30ng/mL) drives up PTH and supplementation to 30-40ng/mL is required to reduce such effects. Wang et al suggest that free 25OHD levels correlate better with PTH as compared to total 25OHD and maybe a more reliable marker of 25OHD status. We suggest that a diagnostic criterion of ≥30ng/mL would be more appropriate in ruling out 25OHD deficiency in this special population. The role of free 25OHD levels in PHPT needs further evaluation.

Celiac disease as differential diagnosis of normocalcemic hyperparathyroidism

ABSTRACT There is no recommendation to investigate celiac disease (CD) in patients with elevated parathyroid hormone (PTH) and normal blood calcium if they are asymptomatic, especially if they do not have hypovitaminosis D. CD was diagnosed in a 30-year-old asymptomatic man without vitamin D deficiency, who had total calcium 9.2 mg/dl, 25-hydroxyvitamin D 36 ng/dl, PTH 112 pg/ml, total IgA 42 mg/dl, anti-tissue transglutaminase (tTG) IgA 22 U/ml. Duodenal biopsy by endoscopy confirmed CD. The patient started a gluten-free diet that was maintained. After six months, the patient had total calcium 9.5 mg/dl, 25-hydroxyvitamin D 42 ng/dl, and PTH 48 pg/ml. In most patients with elevated PTH and normal blood calcium, clinical history, assessment of renal function, vitamin D and phosphorus measurement, and calciuria define the cause of secondary hyperparathyroidism. However, in the few cases in which this initial investigation is negative, even asymptomatic individuals should be tested for CD antibodies before the diagnosis of normocalcemic primary hyperparathyroidism is made.

How to manage an isolated elevated PTH?

The aim of this article is to discuss the diagnostic approach of an increased serum PTH concentration in a normocalcemic, normophosphatemic patient. Detection of this biological presentation is frequent in routine practice all the more that PTH reference values established in vitamin D replete subjects with a normal renal function are used by the clinical laboratories. The first step in this diagnostic approach will be to rule out a cause of secondary hyperparathyroidism (SHPT). Among these, the most frequent are vitamin D deficiency, very low calcium intake, impaired renal function, malabsorptions, drugs interfering with calcium/bone metabolism, such as lithium salts and antiresorptive osteoporosis therapies, hypercalciuria due to a renal calcium leak. If no cause of SHPT are evidenced, the diagnosis of normocalcemic primary hyperparathyroidism (PHPT) should be considered. A calcium load test is a very useful tool for this diagnosis if it shows that serum PTH is not sufficiently decreased when calcemia rises frankly above the upper normal limit. In a normocalcemic patient with hypercalciuria and a high serum PTH concentration, a thiazide challenge test may help to differentiate SHPT due to a renal calcium leak from normocalcemic PHPT. Beyond the discussion of this diagnostic flowchart, we also discuss some points about the merits and the difficulties of measuring and interpreting ionized calcemia and 24-h calciuria.

Is Normocalcemic Primary Hyperparathyroidism Harmful or Harmless?

Primary hyperparathyroidism (PHPT) is reported to be associated with an increased frequency of hypertension, however, information in this regard is sparse in relation to normocalcemic primary hyperparathyroidism (NPHPT). The aim of this study was to determine the association between NPHPT and blood pressure. We retrospectively enrolled 940 patients who visited the Fujian Provincial Hospital between September 2010 and December 2013 with a measured serum parathyroid hormone (PTH) and calcium level. Among them, 11 patients were diagnosed with NPHPT, while 296 cases with normal PTH and albumin-adjusted serum calcium. Systolic blood pressure (SBP), diastolic blood pressure (DBP), intact serum PTH, and serum calcium were recorded. There were no significant differences between subjects identified with NPHPT and those with normal PTH in terms of age, sex, body mass index, serum calcium, 25-Hydroxyvitamin D, serum creatinine, fasting plasma glucose, triglycerides, total cholesterol, high density lipoprotein, and low density lipoprotein. The subjects with a diagnosis of NPHPT had higher levels of SBP (141.9 ± 20.2 vs 131.2 ± 16.5, P = .041) and DBP (85.2 ± 12.4 vs 76.8 ± 10.3, P = .026) than the subjects in the cohort with normal PTH. After adjustment for all potential confounders, risks (odds ratios and 95% confidence interval) of SBP and DBP in NPHPT patients were 1.035 (1.000, 1.071) and 1.063 (1.004, 1.125), respectively (P < .05). The NPHPT had higher risk of high blood pressure than subjects with normal PTH. It is worth considering the necessity of more aggressive therapeutic intervention aimed to normalize PTH even if patients with NPHPT continue to be normocalcemic.

Surgically Proven Normocalcemic Primary Hyperparathyroidism: Speculation of the Possible Role of Estrogen in the Etiology of this Disease in Premenopausal Women

We herein report a rare case of surgically proven normocalcemic primary hyperparathyroidism (NCHPT). A premenopausal 51-year-old woman was referred to our clinic because parathyroid adenoma was detected on neck ultrasonography (US). The patient's serum calcium concentration was 9.3 mg/dL and the intact parathyroid hormone (PTH) level was 128.8 pg/mL. The findings of almost all other examinations were also compatible with a diagnosis of NCHPT. Then, parathyroidectomy was performed. The serum calcium and PTH concentrations reduced significantly but remained within the normal ranges. A histological examination demonstrated parathyroid adenoma. A review of this case and the associated literature suggests that estrogen plays a significant role in the etiology of NCHPT in premenopausal women.

Calculating an individual maxPTH to aid diagnosis of normocalemic primary hyperparathyroidism

We aimed to validate a nomogram for diagnosing primary hyperparathyroidism (PHP), particularly when normocalcemic PHP and vitamin D (VitD25) deficiency coexist. The nomogram calculates maximal upper limit of normal PTH unique for each person by maxPTH = 120 - [6*calcium] - [½*VitD25] + [¼*age]. PHP is suspected when serum PTH exceeds maxPTH. Normocalcemic PHP (NCPHP) was defined as always normal serum calcium (8.5-10.5 mg/dL) with PTH >60 pg/mL preoperatively and VitD25 deficiency as <31 ng/mL. A total of 477 patients had operatively and histologically proven PHP. Overall and including those with classical presentation (high serum levels of calcium and PTH), the nomogram predicted PHP in 97% patients. A total of 66 had NCPHP: 47 with low VitD25 levels (20 ± 0.4 ng/mL) made initial PHP diagnosis challenging; 19 had normal VitD25 status. Although the level of serum calcium concentrations were equivalent in these 2 groups (10.1 ± 0.4 mg/dL), PTH was greater in patients with concurrent VitD25 deficiency (129 vs 97 pg/mL, P = .04). However, when used to calculate maxPTH, the nomogram predicted PHP correctly in all 66 NCPHP patients (100%). The maxPTH nomogram functions as expected to classify patients with PHP and may aid in the diagnosis of NCPHP regardless of vitamin D status and repletion, reassuring primary providers and surgeons alike to embark on appropriate and timely PHP management.

Hyperparathyroïdie primitive

Primary hyperparathyroidism (PHPT) is due to an inappropriately increased secretion of parathyroid hormone (PTH) by an autonomous parathyroid gland inducing hypercalcemia. It is most often diagnosed after a fortuitous diagnosis of hypercalcemia, or when searching for secondary causes of osteoporosis or renal lithiasis. Clinical presentation depends on patient age, on the degree of hypercalcemia, and/or on the clinical complications concerning mostly bone, kidney, and the cardiovascular system. Most PHPT patients are asymptomatic. The diagnosis of PHPT relies on the biological presentation. The diagnosis is easy when serum calcium and PTH levels are both increased above normal, but may be more difficult when one of these two parameters is normal. In case of normal calcemia, the diagnosis of normocalcemic PHPT is possible but only after exclusion of all the potential causes of secondary hyperparathyroidism. Parathyroid imaging has no diagnosis value for PHPT but may localize the diseased gland(s) and thus help during surgery, and may detect an associated throid disorder. The treatment of choice is parathyroid surgery (parathyroidectomy) but its indication is based on existing complications, or risk of complications. In PHPT patients with no clear indication for parathyroid surgery, checking biological parameters (serum calcium, PTH and creatinine) and bone mineral density regularly is mandatory.

Osteoporosis, PTH elevada y calcio iónico inadecuadamente “normal”

La medición de las hormonas calciotrópicas y el calcio sérico de forma rutinaria en pacientes evaluados por osteoporosis lleva a la identificación de sujetos normocalcémicos con niveles elevados de hormona paratiroidea. Se describe el caso de una mujer de 53 años con osteoporosis, en la cual se encuentra un nivel sérico elevado de hormona paratiroidea con niveles inadecuadamente “normales” de calcio iónico. En la resonancia magnética nuclear del cuello aparece una tumoración quística compatible con adenoma paratiroideo. Se realizó una cervicotomía debido a la disminución severa de la masa ósea y el hallazgo en la RMN. La descripción anatomopatológica del tejido resecado confirma el diagnóstico de hiperparatiroidismo primario normocalcémico. Se revisa la posible etiología y discutimos la presentación de esta forma inusual de hiperparatiroidismo primario como una causa no sospechada de osteoporosis. The measurements of calciotropic hormones and serum calcium routinely in evaluation of patients for osteoporosis, carries to identify normocalcemic subjets with elevated parathyroid hormone. We describe a case of a 53 year-old woman with osteoporosis who has high level of parathyroid hormone with inapropiately normal levels of ionized calcium. In the nuclear magnetic resonance of the neck appears a cystic tumor compatible with parathyroid adenoma. Cervicotomy was done due to the severe bone mass decrease and the discovery in the MRI. Pathological description of chirurgic piece confirms the diagnosis of normocalcemic primary hyperparathyroidism. We revise the possible ethiology and discuss this unusual way of presentation of primary hyperparathyroidism

Characterization of normocalcemic primary hyperparathyroidism

The introduction of multichannel serum biochemistry testing in the early 1970s uncovered a large number of patients with primary hyperparathyroidism who were asymptomatic, turning an extremely rare and severe disease into a fairly common and benign condition (1). The diagnosis of primary hyperparathyroidism—whether symptomatic or not—still requires hypercalcemia along with an elevated intact parathyroid hormone (PTH) level (2). Recently, endocrinologists have become aware of patients with normocalcemic primary hyperparathyroidism. This entity has not been characterized systematically, and it is not yet clear whether this is a “forme fruste” of the disease or a harbinger of the hypercalcemic type (3). The purpose of the present study was to define the characteristics of patients with this diagnosis in one endocrine outpatient clinic during the last 5 years. METHODS We reviewed medical records of patients with a diagnosis of primary hyperparathyroidism (International Classification of Diseases, Ninth Revision, code 252.0) seen in the endocrine clinic at Tel Aviv Sourasky Medical Center between January 1998 and October 2003. (Institutional review board approval was not required for this study.) The diagnosis of normocalcemic primary hyperparathyroidism was confirmed if a patient had never had documented hypercalcemia, and if all apparent causes of secondary hyperparathyroidism had been ruled out. Specifically, patients with impaired renal function, and those in whom vitamin D supplementation unmasked hypercalcemia, were excluded. Patients in whom elevated PTH levels decreased following treatment (vitamin D or calcium supplementation, or thiazides) were considered to have secondary hyperparathyroidism and thus were not eligible. We identified 32 patients who met these criteria. Serum calcium levels were determined on a Hitachi 747 random-access analyzer (Roche Diagnostics Boehringer Mannheim, Mannheim, Germany) or a Bayer Advia 1650 analyzer (Leverkusen, Germany) with identical analytical performances; the normal range was 8.5 to