Evidence That the Amino-Terminal Composition of Non-(1–84) Parathyroid Hormone Fragments Starts before Position 19

D'Amour, P; Brossard, Jean‐Hugues; Räkel, Agnès; Rousseau, Louise; Albert, Caroline; Cantor, Tom

doi:10.1373/clinchem.2004.040485

Cited by 56 publications

(78 citation statements)

References 20 publications

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“…There is also no agreedupon common standard between PTH assays (i.e., the human PTH [1-84] calibrators used in these assays differ between commercial companies). D'Amour and colleagues suggested that after adjustment for differences in human PTH (1-84) calibrators, this adjustment can lead to a useful improvement in interassay agreement (45). A newly established First International Standard for PTH (World Health Organization International Standard 95/646) has been prepared, and its commutability between assays is being established (46).…”

Section: Intermethods Variabilitymentioning

confidence: 99%

PTH—A Particularly Tricky Hormone

Garrett

Sardiwal

Lamb

et al. 2013

Clinical Journal of the American Society of Nephrology

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SummaryPlasma parathyroid hormone (PTH) concentrations are commonly measured in the context of CKD, as PTH concentration elevation is typical in this clinical context. Much has been inferred from this raised PTH concentration tendency, both about the state of skeletal integrity and health and also about the potential clinical outcomes for patients. However, we feel that reliance on PTH concentrations alone is a dangerous substitute for the search for, and use of, more precise and reliable biomarkers. In this article, we rehearse these arguments, bringing together patient-level and analytical considerations for the first time.

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Section: Intermethods Variabilitymentioning

confidence: 99%

PTH—A Particularly Tricky Hormone

Garrett

Sardiwal

Lamb

et al. 2013

Clinical Journal of the American Society of Nephrology

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“…The notion that PTH is a "polyhormone" was raised for the first time by Mallette (37) and is acquiring even more plausibility by the recent description of several different forms of circulating PTH (38)(39)(40). These observations, together with the evidence of the presence of a carboxyl-terminal specific receptor (4-6), point to a more complex scenery where different clinical conditions will require different assays in order to define the complex situation of parathyroid physiology.…”

Section: Discussionmentioning

confidence: 99%

Evolution of PTH assays

Vieira

Kunii

Nishida

2006

Arq Bras Endocrinol Metab

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PTH metabolism is complex and the circulating forms include the intact 1-84 molecule as well as several carboxyl-terminal fragments. The first generation of PTH assays included several types of competitive assays, with specificities that spanned carboxyl, mid-region and amino-terminal portions of the molecule. The limitations of these assays and the methodological evolution led to the description of 2 nd generation non-competitive immunometric assays for PTH in the late 80's, based on the recognition of the PTH molecule by two different antibodies, one directed against de amino-terminal and other against the carboxyl-terminal segments. The observation that in some circumstances "long" carboxyl-terminal segments were also measured by 2 nd generation assays led to the development of 3 rd generation assays based on amino-terminal specific antibodies that are specific for the first amino acids, measuring only the molecular forms that activate PTH1R. The practical and cost-benefit advantages of these assays are still debatable. The recent observation that carboxyl-terminal fragments of PTH have biological activity via a distinct receptor than PTH1R, points to the future need of more than one assay in order to evaluate parathyroid hormone function. RESUMO Evolução dos Ensaios para Paratormônio.O metabolismo do PTH e complexo e as formas circulantes incluem o PTH 1-84, assim como fragmentos C-terminal. A primeira geração de ensaios para o PTH incluía vários ensaios competitivos com especificidades para as regiões carboxi, meio da molécula e amino-terminal. A limitação destes ensaios e a evolução metodológica, levaram ao desenvolvimento dos ensaios não competitivos de 2ª. geração no final dos anos 80, baseados no reconhecimento por dois anticorpos diferentes, contra a porção amino e carboxi-terminal respectivamente. A observação que em algumas circunstâncias segmentos carboxiterminais longos também eram detectados, levou ao desenvolvimento dos ensaios de 3ª. geração, baseados em anticorpos específicos para a porção aminoterminal com maior especificidade para os primeiros aminoácidos, e assim mensurando apenas a forma molecular que ativa o PTH1R. As vantagens práticas e o custo-benefício deste ensaio ainda e motivo de debate. A observação recente de que fragmentos carboxiterminais têm atividade biológica via receptor distinto, aponta para a necessidade futura de mais de um ensaio para avaliar a função do paratormônio.

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“…Ex vivo tissue samples from patients with confirmed primary and secondary hyperparathyroidism were also used to generate cell lines in vitro. Findings included first, that PTH7-84 was likely to be the most abundant form of the non-1-84 PTH crossreacting in second-generation immunoassays; second, fragments corresponding to PTH4-84, PTH8-84, PTH10-84 and PTH15-84 were also present; and third, that another non-1-84 PTH fragment, over-expressed in severe hyperparathyroidism and parathyroid cancers, cross-reacted with third-generation but not second-generation immunoassays with a 12-20 epitope [11,24,25,30]. It was suggested that this PTH variant (termed 'amino-PTH' in some references), which appears to have an intact N-terminus, may represent a modified variant form of PTH, with a modification in the 15-20 region.…”

Section: 'Amino-pth'mentioning

confidence: 99%

“…These intact PTH assays typically have a solidphase capture antibody directed towards the C-terminal region of PTH (amino acids 39-84), and a detection antibody directed towards the N-terminus (Figure 3), usually towards amino acids 12-24, though a few second-generation assays were developed with a detection antibody epitope directed towards the 26-32 region [23][24][25]. These assays were thought to be far more specific, since they avoided cross-reactivity with C-terminal PTH fragments.…”

Section: Second-generation Immunoassaysmentioning

confidence: 99%

“…They reported that, in addition to the known C-terminal PTH fragments missing the entire N-terminus (e.g., PTH34-84), there existed a second group of larger C-terminal PTH fragments with a partially preserved N-terminus, which accumulated in renal failure. They later established that the fragmentation occurred somewhere within the first 19 amino acids of the PTH N-terminus based on comparison of second-generation immunoassays with different detection antibody epitopes [24]. These fragments were collectively described as 'non-1-84' PTH fragments, and were demonstrated to cross-react in second-generation immunoassays using recombinant PTH7-84, a commercially available peptide, as a surrogate for this group of peptides.…”

Section: Third-generation Immunoassaysmentioning

confidence: 99%

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LC-MS candidate reference methods for the harmonisation of parathyroid hormone (PTH) measurement: a review of recent developments and future considerations

Couchman¹,

Taylor

Krastins

et al. 2014

Clinical Chemistry and Laboratory Medicine

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Abstract:The analysis of intact parathyroid hormone (PTH) (PTH1-84) is useful in the diagnosis of hyper-and hypocalcaemia, hyperparathyroidism, and in the prevention of bone mineral disorders in renal patients. The analysis is complicated by the presence of PTH fragments, which may accumulate in renal failure and cross-react in immunoassays, including the most recent third-generation immunoassays. Large variability exists between different commercially available assays. This article reviews the current literature on PTH testing, with emphasis on the use of mass spectrometry-based methods, and considers the important sources of variation which still need to be addressed prior to the development of much needed candidate reference methods for PTH analysis. Recently, mass spectrometric methods have been developed for the quantitation of PTH1-84 using surrogate tryptic peptides, but even these methods are subject to significant interferences due to the presence of newly observed modified PTH species, such as oxidised and phosphorylated PTH variants, which can accumulate in patient samples. Further work, including: 1) the use of high-resolution mass spectrometry; and 2) the analysis of PTH without prior protease digestion, is required before these approaches can be considered as reference methods against which other methods should be harmonised.

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Evidence That the Amino-Terminal Composition of Non-(1–84) Parathyroid Hormone Fragments Starts before Position 19

Cited by 56 publications

References 20 publications

PTH—A Particularly Tricky Hormone

PTH—A Particularly Tricky Hormone

Evolution of PTH assays

LC-MS candidate reference methods for the harmonisation of parathyroid hormone (PTH) measurement: a review of recent developments and future considerations

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