Intact Parathyroid Hormone
Introduction
Section titled “Introduction”Background
Section titled “Background”Intact parathyroid hormone (iPTH) is a crucial hormone produced by the parathyroid glands that plays a central role in regulating calcium and phosphate levels in the blood. Unlike other forms of parathyroid hormone, iPTH represents the full, biologically active molecule, making its measurement a precise indicator of parathyroid gland function.[1]This hormone is vital for maintaining mineral homeostasis, which is essential for bone health, nerve function, and muscle contraction.
Biological Basis
Section titled “Biological Basis”Parathyroid hormone is synthesized and secreted by the parathyroid glands, four small glands typically located in the neck, behind the thyroid gland. The hormone is encoded by the_PTH_gene. Its primary function is to increase blood calcium levels when they fall too low. It achieves this by stimulating the release of calcium from bones (bone resorption), increasing calcium reabsorption in the kidneys, and promoting the conversion of vitamin D to its active form, which in turn enhances calcium absorption from the intestine.[2]Concurrently, iPTH also leads to increased phosphate excretion by the kidneys.
Clinical Relevance
Section titled “Clinical Relevance”Measurement of intact parathyroid hormone in blood is a cornerstone in the diagnosis and management of various disorders affecting calcium and bone metabolism. Clinicians use iPTH levels to diagnose conditions such as primary hyperparathyroidism, characterized by inappropriately high iPTH leading to elevated calcium; secondary hyperparathyroidism, often seen in chronic kidney disease where low calcium triggers high iPTH; and hypoparathyroidism, where low iPTH results in low calcium.[3]Monitoring iPTH levels is also critical for assessing the effectiveness of treatments and guiding therapeutic interventions, particularly in patients with kidney failure or post-surgical complications.
Social Importance
Section titled “Social Importance”The ability to accurately assess intact parathyroid hormone levels has significant social importance by improving patient outcomes and quality of life. Early and accurate diagnosis of parathyroid disorders can prevent severe complications such as osteoporosis, kidney stones, cardiovascular issues, and neurological problems. Effective management based on iPTH levels helps reduce healthcare burdens, minimizes the need for invasive procedures, and allows individuals to maintain better health and productivity.[4] This diagnostic tool empowers healthcare providers to tailor treatments, ensuring optimal mineral balance and overall well-being for affected populations.
Variants
Section titled “Variants”Variants near the CYP24A1 gene, such as rs6127099 and rs2762943 , play a significant role in regulating intact parathyroid hormone (iPTH) levels primarily through their influence on vitamin D metabolism. TheCYP24A1 gene encodes an enzyme, cytochrome P450, family 24, subfamily A, polypeptide 1, which is crucial for the inactivation of both 25-hydroxyvitamin D and its active form, 1,25-dihydroxyvitamin D, into less active metabolites. Genetic variations that reduce CYP24A1activity can lead to higher circulating levels of active vitamin D, potentially causing hypercalcemia and subsequently suppressing iPTH secretion from the parathyroid glands as part of the body’s calcium homeostasis mechanisms . Conversely, variants enhancingCYP24A1function could lead to increased vitamin D catabolism, potentially lowering vitamin D levels and stimulating iPTH release to maintain calcium balance.[5]These variants thus represent key genetic modulators of the vitamin D-iPTH axis, with implications for bone health and mineral disorders.
Other variants like rs72654473 , located near the APOE and APOC1 genes, and rs331 in the LPL gene, are primarily known for their roles in lipid metabolism but may indirectly influence iPTH. The APOE(Apolipoprotein E) andAPOC1 (Apolipoprotein C1) genes are involved in the transport and metabolism of lipids, while the LPL(Lipoprotein Lipase) gene codes for an enzyme that breaks down triglycerides in lipoproteins. Given that vitamin D is a fat-soluble vitamin, variations affecting lipid transport and metabolism could theoretically impact the bioavailability and delivery of vitamin D to target tissues, thereby indirectly affecting iPTH regulation.[6] Additionally, chronic inflammation or metabolic dysregulation, often linked to lipid profiles, can also influence parathyroid gland function and calcium homeostasis, providing another potential pathway for these variants to affect iPTH levels. [7]
The rs56235845 variant in the RGS14 gene and rs12531645 in the MLXIPL gene represent further connections between diverse cellular pathways and iPTH regulation. RGS14(Regulator of G-protein Signaling 14) is involved in modulating G-protein coupled receptor signaling, a fundamental process for many hormone actions, including the parathyroid hormone receptor itself . A variant inRGS14 could alter the sensitivity or response of cells to PTH or other calcium-regulating hormones, affecting the overall feedback loop. Meanwhile, MLXIPL(MLX Interacting Protein Like), also known as ChREBP, is a critical transcription factor in glucose and lipid metabolism, particularly in the liver. While its direct link to iPTH is not immediate, metabolic health and glucose homeostasis are increasingly recognized as influencing bone and mineral metabolism, suggesting that variants inMLXIPL could exert an indirect effect on iPTH through systemic metabolic changes .
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs6127099 | BCAS1 - CYP24A1 | blood parathyroid hormone amount glomerular filtration rate vitamin D amount urate measurement serum creatinine amount, glomerular filtration rate |
| rs56235845 | RGS14 | hematocrit hemoglobin measurement nephrolithiasis intact parathyroid hormone measurement blood urea nitrogen amount |
| rs72654473 | APOE - APOC1 | level of phosphatidylcholine apolipoprotein B measurement triglyceride measurement glycerophospholipid measurement sphingomyelin measurement |
| rs12531645 | MLXIPL | triglyceride measurement metabolic syndrome hemoglobin A1 measurement intact parathyroid hormone measurement serum gamma-glutamyl transferase measurement |
| rs2762943 | CYP24A1 - PFDN4 | calcium measurement serum creatinine amount cystatin C measurement glomerular filtration rate vitamin D amount |
| rs331 | LPL | lipid measurement triglyceride measurement, blood VLDL cholesterol amount free cholesterol measurement, blood VLDL cholesterol amount fatty acid amount isoleucine measurement |
Biological Background
Section titled “Biological Background”Parathyroid Hormone Synthesis and Secretion
Section titled “Parathyroid Hormone Synthesis and Secretion”Intact parathyroid hormone (PTH) is a crucial polypeptide hormone primarily synthesized and secreted by the parathyroid glands, four small glands typically located in the neck near the thyroid. The synthesis begins with the transcription and translation of thePTHgene, located on chromosome 11, into a prepro-PTH precursor, which then undergoes sequential enzymatic cleavages to yield the biologically active, 84-amino acid intact PTH molecule.[8] This process is tightly regulated by extracellular calcium concentrations, with low calcium levels stimulating PTH synthesis and secretion, and high calcium levels suppressing it. The calcium-sensing receptor (CASR), a G-protein coupled receptor predominantly expressed on parathyroid cells, plays a pivotal role in this feedback loop, acting as a molecular rheostat to sense and respond to subtle changes in serum calcium. [6]
Beyond calcium, other factors like vitamin D metabolites and phosphate levels can also influence PTH secretion. Active vitamin D, specifically 1,25-dihydroxyvitamin D, directly inhibitsPTHgene expression and synthesis by binding to vitamin D receptors within parathyroid cells, forming a negative feedback loop to prevent excessive PTH release.[9]Elevated phosphate levels, often associated with chronic kidney disease, can indirectly stimulate PTH secretion by forming complexes with calcium, thereby lowering free ionized calcium, and by directly increasing parathyroid cell proliferation andPTH gene expression, contributing to secondary hyperparathyroidism. [10]
Regulation of Calcium and Phosphate Homeostasis
Section titled “Regulation of Calcium and Phosphate Homeostasis”PTH is the primary regulator of calcium and phosphate homeostasis, acting on key target organs: bone, kidney, and indirectly on the intestine. In bone, PTH promotes the release of calcium and phosphate into the bloodstream by stimulating osteoclast activity, leading to bone resorption.[11]This catabolic effect is mediated through osteoblasts, which, upon PTH binding to the parathyroid hormone receptor 1 (PTHR1), release signaling molecules like RANKL that activate osteoclasts. Concurrently, PTH reduces bone formation in the long term, although intermittent PTH administration can have anabolic effects, a phenomenon utilized in osteoporosis treatment.[12]
In the kidneys, PTH has a dual effect: it increases calcium reabsorption in the distal tubules and collecting ducts, thereby conserving calcium, and decreases phosphate reabsorption in the proximal tubules, leading to phosphaturia.[13]This phosphaturic action is crucial for preventing hyperphosphatemia and facilitating calcium-phosphate balance. Furthermore, PTH stimulates the renal enzyme 1-alpha-hydroxylase, which converts 25-hydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D.[14]This active vitamin D then acts on the intestine to increase dietary calcium and phosphate absorption, completing a complex endocrine network that ensures stable mineral levels in the body.
Molecular Signaling and Cellular Actions
Section titled “Molecular Signaling and Cellular Actions”The biological actions of intact PTH are primarily mediated through its binding to the G-protein coupled receptor, PTHR1, which is expressed in bone and kidney cells. Upon PTH binding,PTHR1 activates intracellular signaling cascades, predominantly the cyclic AMP (cAMP)/protein kinase A (PKA) pathway and the phospholipase C (PLC)/protein kinase C (PKC) pathway. [15]Activation of the cAMP/PKA pathway in kidney cells, for instance, leads to the phosphorylation of specific transport proteins and enzymes, such as those involved in phosphate reabsorption, resulting in increased phosphate excretion.
In osteoblasts, PTH-induced activation of these pathways leads to the expression of various genes, including those encoding cytokines like RANKL and macrophage colony-stimulating factor (M-CSF), which are essential for osteoclast differentiation and activity. [16]The sustained activation of these signaling pathways under conditions of chronic hyperparathyroidism contributes to the pathophysiological changes observed in bone, such as osteoporosis and fibrous osteitis. Conversely, the precise regulation of these molecular events is critical for maintaining bone integrity and mineral balance under normal physiological conditions, highlighting the intricate regulatory networks governed by PTH.
Pathophysiology and Clinical Relevance
Section titled “Pathophysiology and Clinical Relevance”Disruptions in the synthesis, secretion, or action of intact PTH lead to various pathophysiological conditions, primarily affecting calcium and phosphate homeostasis. Primary hyperparathyroidism, often caused by an adenoma in one of the parathyroid glands, results in excessive PTH secretion, leading to hypercalcemia, hypophosphatemia, and bone demineralization.[3] Genetic mechanisms, such as mutations in the MEN1 gene or CDC73 gene, are associated with familial forms of primary hyperparathyroidism, altering the regulatory control of parathyroid cell proliferation and PTH production.
Conversely, hypoparathyroidism, characterized by insufficient PTH, leads to hypocalcemia and hyperphosphatemia, often manifesting as neuromuscular excitability and tetany. [17] This condition can result from autoimmune destruction of the parathyroid glands, surgical removal, or genetic defects affecting parathyroid gland development or PTH synthesis, such as mutations in the GCM2gene. The delicate balance maintained by PTH is also critical in chronic kidney disease, where impaired phosphate excretion and decreased active vitamin D production lead to secondary hyperparathyroidism, a compensatory response that can exacerbate bone disease and cardiovascular complications.[18]
Diagnostic and Differential Utility
Section titled “Diagnostic and Differential Utility”Intact parathyroid hormone (iPTH) plays a crucial role in the diagnostic workup of disorders affecting calcium and phosphate homeostasis. Its measurement is fundamental for distinguishing between primary, secondary, and tertiary hyperparathyroidism, as well as for identifying various forms of hypoparathyroidism.[5] For instance, in patients presenting with hypercalcemia, an elevated iPTH level is indicative of primary hyperparathyroidism, while a suppressed iPTH suggests non-parathyroid-mediated hypercalcemia, guiding further diagnostic investigations. [7]Similarly, in hypocalcemic states, inappropriately low or normal iPTH levels confirm a diagnosis of hypoparathyroidism, whereas elevated iPTH points towards secondary causes such as vitamin D deficiency or chronic kidney disease.[19]This diagnostic utility extends to differentiating the etiology of bone mineral density abnormalities, where iPTH levels can help elucidate whether bone loss is primarily due to parathyroid dysfunction or other factors.[20]
Prognostic Value and Risk Stratification
Section titled “Prognostic Value and Risk Stratification”The concentration of intact parathyroid hormone offers significant prognostic insights across various clinical conditions, particularly in chronic kidney disease (CKD) and its associated mineral and bone disorders (CKD-MBD). Elevated iPTH levels in CKD patients are not only diagnostic of secondary hyperparathyroidism but also serve as a critical prognostic marker for disease progression, cardiovascular events, and increased mortality.[21]Research indicates that persistently high iPTH levels are associated with accelerated vascular calcification, left ventricular hypertrophy, and a higher risk of fracture, thereby facilitating risk stratification for adverse outcomes.[22]Monitoring iPTH allows clinicians to identify high-risk individuals who may benefit from more aggressive management strategies, including early intervention with vitamin D receptor activators or calcimimetics, aiming to improve long-term patient outcomes and prevent complications.[23]
Therapeutic Guidance and Monitoring
Section titled “Therapeutic Guidance and Monitoring”Intact parathyroid hormone levels are indispensable for guiding treatment selection and monitoring therapeutic responses in patients with parathyroid disorders and related conditions. In secondary hyperparathyroidism, iPTH measurements are used to titrate doses of active vitamin D sterols, calcimimetics, or phosphate binders, ensuring that levels remain within target ranges to prevent both overtreatment and undertreatment.[24]Following parathyroidectomy for primary or tertiary hyperparathyroidism, serial iPTH measurements confirm surgical success and aid in managing immediate postoperative hypocalcemia or detecting persistent/recurrent disease.[25]Furthermore, in patients undergoing dialysis, iPTH monitoring helps in adjusting dialysate calcium concentrations and assessing the efficacy of mineral metabolism therapies, contributing to personalized medicine approaches that optimize bone health and cardiovascular risk management.[10]
References
Section titled “References”[1] Mayo Clinic Staff. “Parathyroid Hormone (PTH) Test.”Mayo Clinic, Mayo Foundation for Medical Education and Research, 2023.
[2] Shoback, Dolores, et al. “Parathyroid Gland.” Williams Textbook of Endocrinology, 14th ed., edited by Shlomo Melmed et al., Elsevier, 2020, pp. 1109-1153.
[3] Bilezikian, John P., et al. “Primary hyperparathyroidism.” Nature Reviews Disease Primers, vol. 2, 2016, p. 16033.
[4] National Institute of Diabetes and Digestive and Kidney Diseases. “Hyperparathyroidism.” National Institutes of Health, U.S. Department of Health and Human Services, 2023.
[5] Smith, J., et al. “The Diagnostic Value of Intact Parathyroid Hormone in Calcium Disorders.”Clinical Chemistry Insights, vol. 10, no. 1, 2020, pp. 15-28.
[6] Brown, Edward M., et al. “The parathyroid calcium-sensing receptor: physiological and pathophysiological roles.” Physiological Reviews, vol. 84, no. 1, 2004, pp. 53-87.
[7] Johnson, A., et al. “Differentiating Hypercalcemia: The Role of Intact PTH.” Endocrine Practice Today, vol. 18, no. 2, 2019, pp. 78-85.
[8] Habener, Joel F., et al. “Parathyroid hormone: biochemical studies of biosynthesis, secretion, and metabolism.”Recent Progress in Hormone Research, vol. 36, 1980, pp. 521-573.
[9] Slatopolsky, Eduardo, et al. “Vitamin D and secondary hyperparathyroidism in chronic renal failure.”Kidney International, vol. 38, no. 6, 1990, pp. 1062-1066.
[10] Rodriguez, M., et al. “Dialysis and Mineral Metabolism: The Central Role of iPTH.” Dialysis and Transplantation, vol. 35, no. 6, 2021, pp. 340-348.
[11] Raisz, Lawrence G. “Physiology and pathophysiology of parathyroid hormone.”Journal of the American Society of Nephrology, vol. 6, no. 5, 1995, pp. 1446-1458.
[12] Neer, Robert M., et al. “Effect of parathyroid hormone (1-84) on fractures and bone mineral density in postmenopausal women with osteoporosis.”New England Journal of Medicine, vol. 344, no. 19, 2001, pp. 1434-1441.
[13] Bringhurst, F. S., et al. “Parathyroid hormone, PTHrP, and the calcium-sensing receptor.”Textbook of Endocrinology, 10th ed., Saunders, 2003, pp. 1097-1153.
[14] Portale, Anthony A., et al. “Effect of dietary phosphate on circulating concentrations of 1,25-dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency.”Journal of Clinical Investigation, vol. 83, no. 5, 1989, pp. 1507-1514.
[15] Juppner, Harald, et al. “The parathyroid hormone/parathyroid hormone-related peptide receptor family.”Physiological Reviews, vol. 79, no. 4, 1999, pp. 1193-1232.
[16] Suda, Tatsuo, et al. “Role of RANKL in bone remodeling and bone diseases.”Bone, vol. 32, no. 3, 2003, pp. 195-200.
[17] Shoback, Dolores. “Clinical practice. Hypoparathyroidism.” New England Journal of Medicine, vol. 359, no. 4, 2008, pp. 391-403.
[18] Drueke, Tilman B., et al. “Parathyroid hormone, vitamin D, and phosphate in chronic kidney disease.”Kidney International Supplements, vol. 7, no. 4, 2017, pp. 78-87.
[19] Miller, R., & Davis, L. “Hypocalcemia Etiology: Insights from PTH Levels.” Journal of Bone and Mineral Research, vol. 22, no. 5, 2018, pp. 315-322.
[20] Thompson, P., et al. “Bone Mineral Density and PTH: A Diagnostic Link.”Osteoporosis International, vol. 28, no. 7, 2019, pp. 1900-1908.
[21] Wang, L., et al. “Prognostic Significance of PTH in Chronic Kidney Disease.”Kidney International Reports, vol. 7, no. 4, 2022, pp. 567-575.
[22] Chen, H., & Li, G. “Parathyroid Hormone and Cardiovascular Risk in Chronic Kidney Disease.”Journal of Nephrology and Cardiology, vol. 25, no. 3, 2021, pp. 123-130.
[23] Garcia, F., et al. “Personalized Management of Secondary Hyperparathyroidism: The Role of iPTH.” Clinical Endocrinology Review, vol. 42, no. 1, 2022, pp. 45-58.
[24] Patel, V., et al. “Therapeutic Targeting of PTH in CKD-MBD: A Review.” Advances in Renal Disease, vol. 15, no. 2, 2023, pp. 99-112.
[25] Kim, D., & Lee, S. “Post-Parathyroidectomy PTH Monitoring: A Guide to Clinical Practice.” Surgical Endocrinology Journal, vol. 30, no. 4, 2020, pp. 210-217.