Letter to Editor From McCarroll et al: “Approach to the Patient: Normocalcemic Primary Hyperparathyroidism”
Bibliographic record
Abstract
Dear Editor, We commend Liu et al, for their clear and comprehensive review of normocalcemic primary hyperparathyroidism (NPHPT) (1). One of the most important considerations in diagnosing NPHPT is the exclusion of other causes of secondary hyperparathyroidism (SHPT). While loop diuretics are known to cause SHPT, Liu et al report that thiazide diuretics are associated with elevated parathyroid hormone (PTH), though they point out that studies are conflicting. However, the evidence for thiazides causing elevations in PTH is sparse and we are inclined to agree with other authors that they should not be considered PTH-inducing drugs (2). The largest and most recent observational study (n = 4139) published this year, but not referenced by Liu et al, found no increased risk of SHPT in thiazide users, including in a subset (n = 2612) without significant chronic kidney disease (estimated glomerular filtration rate >60 mL/min) (3). Another observational study involving 1888 individuals identified lower PTH levels in thiazide users (4). Most compelling are the results of 2 double-blind randomized controlled trials in healthy postmenopausal women. One study (n = 265) identified no change in PTH after treatment with low-dose thiazides over 3 years while another (n = 188) found no change with high-dose thiazides over 2 years (5). Other small intervention trials identified no effect of thiazides on PTH, as previously reported (2, 4). While a small study identified an initial rise in PTH in postmenopausal women after thiazide initiation, this was only a 7-day trial and levels approached baseline at the end of the study (2). Several studies of patients with idiopathic hypercalciuria and some with primary hyperparathyroidism have also shown that thiazides lowered or had no effect on PTH levels (4). In the clinical case presented by Liu et al (1), SHPT in a patient on a thiazide diuretic also resolved after correcting low calcium intake. One medication not mentioned that may increase the risk of SHPT are proton pump inhibitors (PPIs) (4). A recent large observational study identified an increased risk of SHPT in users of PPIs who were taking calcium supplements (3). PPIs inhibit gastric acid secretion, which is required for the absorption of calcium carbonate (the most common form of calcium in supplements). To optimize absorption, calcium carbonate should be taken with food; however, calcium citrate, whose absorption is unaffected by gastric acid, may be preferable for PPI users with elevated PTH despite having no other causes for SHPT (6). Finally, one concern regarding the diagnosis of NPHPT that was not raised is the reliability of assays used to measure PTH. Immunoassays for PTH are susceptible to interference from heterophile antibodies and other proteins, with considerable variations between platforms (7). For this reason, it has been recommended to measure PTH using a different assay in cases of NPHPT with persistently elevated levels after excluding other causes (8). The authors have nothing to disclose. normocalcemic primary hyperparathyroidism proton pump inhibitors parathyroid hormone secondary hyperparathyroidism
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.024 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.003 | 0.002 |
| Scholarly communication | 0.003 | 0.003 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.036 | 0.028 |
| Insufficient payload (model declined to judge) | 0.006 | 0.005 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".