Normalization of reversed bio-intact-PTH(1-84)/intact- PTH ratio after parathyroidectomy in a patient with severe secondary hyperparathyroidism

Tanaka, Motoko; Itoh, Kiichiro; Matsushita, Kanehiro; Fujii, Hideki; Fukagawa, Masafumi

doi:10.5414/cnp64069

Cited by 26 publications

(31 citation statements)

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“…We have described a similar lack of change in the PTH HPLC profile in a patient with severe PHPT who was treated with vitamin D and an intravenously administered bisphosphonate (4 ). In contrast, removal of the pathologic parathyroid gland appears to normalize the PTH HPLC profile, in both primary and secondary hyperparathyroidism (4,11 ). The HPLC profiles of healthy individuals and PHPT patients represent the mean of 6 HPLC profiles in each case.…”

Section: Discussionmentioning

confidence: 83%

An N-Terminal Molecular Form of Parathyroid Hormone (PTH) Distinct from hPTH(1–84) Is Overproduced in Parathyroid Carcinoma

et al. 2007

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Background:A new parathyroid hormone (PTH) species, the N-terminal PTH form (N-PTH), is distinct from intact human PTH of 84 amino acid residues [hPTH(1-84)] and is recognized in a 3rd-generation assay of "whole" PTH (wPTH; the 1-2 epitope) but not in a 2nd-generation assay of "total" PTH (tPTH; the 12-18 epitope). N-PTH usually represents <15% of wPTH but can be overproduced in severe primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism. We investigated whether N-PTH is also overproduced in parathyroid cancer and whether N-PTH concentration is influenced by calcimimetic therapy. Methods: We studied 8 patients with parathyroid carcinoma before and at week 16 of cinacalcet therapy, 6 patients with PHPT, and 6 control individuals. We fractionated sera with HPLC and analyzed fractions with the 2 assays to quantify hPTH(1-84), N-PTH, and non-(1-84) PTH fragments. Results: Half of parathyroid carcinoma patients had an increased wPTH:tPTH ratio [mean (SD), 1.35 (0.29)]; the others had a typical ratio [0.72 (0.12)]. HPLC fractionation of sera from 2 high-ratio patients confirmed N-PTH overproduction [65% (12%) of wPTH]. The N-PTH fraction was <15% of wPTH in PHPT and healthy individuals. Calcimimetic therapy appreciably reduced calcium concentrations in parathyroid carcinoma patients but had little influence on PTH concentration, the wPTH:tPTH ratio, or the PTH HPLC profile.

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Section: Discussionmentioning

confidence: 83%

An N-Terminal Molecular Form of Parathyroid Hormone (PTH) Distinct from hPTH(1–84) Is Overproduced in Parathyroid Carcinoma

et al. 2007

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“…This ratio can be reduced in severe secondary hyperparathyroidism by therapy with intravenous vitamin D analogues (22,23) but has not been modified by calcimimetic therapy (24). In a limited number of dialysis patients with severe secondary hyperparathyroidism, the ratio can be elevated to Ͼ100% (25) for reasons that remain unclear.…”

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confidence: 99%

Overproduction and Secretion of a Novel Amino-Terminal Form of Parathyroid Hormone from a Severe Type of Parathyroid Hyperplasia in Uremia

Arakawa¹,

D'Amour²,

Rousseau³

et al. 2006

Clinical Journal of the American Society of Nephrology

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Measurement of bioactive parathyroid hormone (PTH) is essential for optimal management of bone abnormalities in dialysis patients. This can be accomplished by PTH measurements using third-generation PTH assays, which detect more or less of the first six amino acids of the PTH structure. Such assays do not detect non-(1-84) PTH fragments, such as human PTH (7-84), which are recognized by the second-generation PTH assays that use a detection antibody that recognizes an epitope within the 13-34 region of the PTH structure. Therefore, third-generation PTH results are expected to be lower than those that are obtained with second-generation PTH assays. Rare exceptions to this rule have been reported for patients with severe primary hyperparathyroidism or parathyroid cancer. Sera and gland extracts were analyzed from a dialysis patient with high bone turnover disease and with surprising higher PTH levels by a third-generation assay than by a second-generation assay. This finding normalized after the surgical removal of an enlarged gland with a single nodule, an advanced type of nodular hyperplasia. HPLC fractionation of sera and gland extracts revealed the overproduction and secretion of a PTH molecule with an intact amino-terminus structure distinct from (1-84) PTH. This form of PTH was readily detectable by third-generation PTH assays but was poorly reactive in second-generation PTH assays. Therefore, parathyroid glands with advanced uremic nodular hyperplasia may overproduce and secrete a novel, biologically active form of PTH with an intact 1-6 region but a presumably modified 12-18 region required for the detection in second-generation PTH assays.

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“…In contrast, for others, (9,10,13) this ratio stays for whole PTH/iPTH. In the exceptional cases in which the PTH-(1-84) level is paradoxically higher than that of iPTH, it is obvious that one cannot calculate PTH- as the difference between iPTH and PTH-(1-84), because this would yield a negative value.…”

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confidence: 78%

“…Second-generation PTH assays recognize PTH fragments other than only large C-PTH fragments, and third-generation assays also seem to measure PTH moieties other than whole PTH-(1-84) alone. The occurrence of the latter, which is characterized by an abnormally high PTH-(1-84)/iPTH ratio (12), was recently demonstrated by Tanaka et al (10) and Arakawa et al (13) in association with severe secondary hyperparathyroidism and by Rubin et al (9) in association with parathyroid cancer.…”

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confidence: 94%

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Whole or Fragmentary Information on Parathyroid Hormone?

Drüeke

Fukagawa

2007

Clinical Journal of the American Society of Nephrology

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M ore than a decade ago, Brossard et al. (1) drew attention to the fact that the so-called "intact," second-generation parathyroid hormone (PTH) assays measured not only the PTH-(1-84) molecule but also large PTH fragments in patients with chronic kidney disease (CKD). One of the major problems is that the proportion of PTH-(1-84) and its fragments in the circulation changes in response to the serum level of ionized calcium; therefore, in presence of hypercalcemia, the parathyroid gland releases less PTH-(1-84) but more PTH fragments. The reverse is true in the presence of hypocalcemia, where more active PTH-(1-84) is needed. The difference is particularly striking in patients with CKD. When considering the potential biologic relevance of this finding, it is even more disturbing that at least one of the fragments, namely PTH-(7-84), has been shown to act as a partial antagonist of PTH-(1-84), with opposite biologic activities (2-4). Progressive awareness of these methodologic problems and the underlying biologic complexity went along with the development of thirdgeneration PTH assays that recognize only PTH-(1-84), also called "whole," "bio-intact," or "biologically active" PTH (5).Theoretically, the assessment of second-and third-generation PTH assays combined should reflect parathyroid activity more adequately than second-generation assays alone, reflecting the sum of potentially opposing effects of PTH-(1-84) and its fragments. Several authors explored changes of serum PTH levels, as measured with various assays, with progression of CKD and in response to medical interventions. Reduction in GFR is accompanied by a higher increase in large PTH-related C-terminal fragments than in PTH-(1-84) in patients with CKD (6,7). The administration of cinacalcet to patients with stage 5 CKD and secondary hyperparathyroidism (8) or to patients with parathyroid cancer (9) did not change the ratio between intact PTH (iPTH) and PTH-(1-84). This is somewhat surprising because cinacalcet reduces serum calcium, and hypocalcemia is associated with changes in the PTH ratio. In contrast, surgical parathyroidectomy, which often leads to profound hypocalcemia, has been shown to normalize the ratio (10).In an original article in this issue, Monier-Faugere et al. (11) report the effects of the administration to long-term hemodialysis patients of calcitriol, the most active metabolite of vitamin D, and its active derivative paricalcitol on circulating levels of PTH-(1-84), iPTH, large C-terminal PTH fragments (C-PTH), and the PTH-(1-84)/C-PTH fragment ratio, also called PTH-(1-84)/C-PTH-(7-84) ratio. They present results that were obtained first in a longitudinal, crossover design study that compared paricalcitol with calcitriol and second in a cross-sectional study that compared paricalcitol with no vitamin D treatment. In the longitudinal study, they observe a lower PTH ratio in response to calcitriol but a higher PTH ratio in response to paricalcitol, as compared with respective baseline values. In the cross-sectional study, they fi...

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Normalization of reversed bio-intact-PTH(1-84)/intact- PTH ratio after parathyroidectomy in a patient with severe secondary hyperparathyroidism

Cited by 26 publications

References 0 publications

An N-Terminal Molecular Form of Parathyroid Hormone (PTH) Distinct from hPTH(1–84) Is Overproduced in Parathyroid Carcinoma

An N-Terminal Molecular Form of Parathyroid Hormone (PTH) Distinct from hPTH(1–84) Is Overproduced in Parathyroid Carcinoma

Overproduction and Secretion of a Novel Amino-Terminal Form of Parathyroid Hormone from a Severe Type of Parathyroid Hyperplasia in Uremia

Whole or Fragmentary Information on Parathyroid Hormone?

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