Hyperparathyroidism and parathyroidectomy in X-linked hypophosphatemia patients

DeLacey, Sean; Liu, Ziyue; Broyles, Andrea A.; El-Azab, Sarah A.; Guandique, Cristian F.; James, Benjamin C.; Imel, Erik A.

doi:10.1016/j.bone.2019.06.025

Cited by 32 publications

(33 citation statements)

References 28 publications

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“…(42) In adults with XLH, secondary hyperparathyroidism is common, ranging in prevalence from 15% to 67%. (14,18,43,44) In two recent large surveys of XLH, tertiary hyperparathyroidism was evident in 10% to 17% of cases. (18,44) Hyperparathyroidism, as a complication of treating XLH, should diminish given the success of blocking FGF23 activity with burosumab, which obviates the need for phosphate supplements in both children and adults.…”

Section: Discussionmentioning

confidence: 99%

“…(14,18,43,44) In two recent large surveys of XLH, tertiary hyperparathyroidism was evident in 10% to 17% of cases. (18,44) Hyperparathyroidism, as a complication of treating XLH, should diminish given the success of blocking FGF23 activity with burosumab, which obviates the need for phosphate supplements in both children and adults. (45,46) There are two other clinical circumstances where hyperparathyroidism in conjunction with FGF23 excess could exacerbate hypophosphatemia.…”

Section: Discussionmentioning

confidence: 99%

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Renal Phosphate Handling: Independent Effects of Circulating FGF23, PTH, and Calcium

et al. 2020

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Excess fibroblast growth factor 23 (FGF23), excess parathyroid hormone (PTH) and an increase in extracellular calcium cause hypophosphatemia by lowering the maximum renal phosphate reabsorption threshold (TmP/GFR). We recently reported two cases of X-linked hypophosphatemia (XLH) with severe tertiary hyperparathyroidism, who had normalization of TmP/GFR upon being rendered hypoparathyroid following total parathyroidectomy, despite marked excess in both C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23). We explored the effects of FGF23, PTH, and calcium on TmP/GFR in a cross-sectional study (n = 74) across a spectrum of clinical cases with abnormalities in TmP/GFR, PTH, and FGF23. This comprised three groups: FGF23-dependent hypophosphatemia (FDH) (n = 27); hypoparathyroidism (HOPT) (n = 17); and chronic kidney disease (CKD) (n = 30). Measurements included TmP/GFR, cFGF23, PTH, ionized calcium, vitamin D metabolites, and bone turnover markers. The effects of cFGF23, PTH and ionized calcium on TmP/GFR was modelled using hierarchical multiple regression and was probed by moderation analysis with PROCESS. Modeling analyses showed independent effects on TmP/GFR by cFGF23, PTH, and ionized calcium in conjunction with a weak but significant effect of the interaction term for PTH and FGF23; probing demonstrated that the effect was most prominent during PTH deficiency. Teriparatide 20 μg daily was self-administered for 28 days by one case of X-linked hypophosphatemia with hypoparathyroidism (XLH-HOPT) in order to assess the response of TmP/GFR, cFGF23, iFGF23, nephrogenous cyclic adenosine monophosphate (NcAMP), vitamin D metabolites and bone turnover markers. After 28 days, TmP/GFR was lowered from 1.10 mmol/L to 0.48 mmol/L; this was accompanied by an increase in NcAMP, ionized calcium and bone turnover markers. In conclusion, the effect of FGF23 excess on TmP/GFR is altered by parathyroid status such that the effect is ameliorated by hypoparathyroidism and the effect is augmented by hyperparathyroidism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Renal Phosphate Handling: Independent Effects of Circulating FGF23, PTH, and Calcium

et al. 2020

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“…Because FGF23 stimulates CYP24A1 and inhibits CYP27B1 (25-hydroxyvitamin D 3 -1α-hydroxylase) expression in both renal and extrarenal tissues ( 40 ), FGF23-mediated forms of hypophosphatemia are associated with low 1,25(OH) 2 D levels ( 41 ), secondary hyperparathyroidism ( 42 ), and low-normal to slightly decreased calcemia. However, 10-16.7% of adult XLH patients may exhibit tertiary (hypercalcemic) hyperparathyroidism, which is amenable to parathyroidectomy ( 42 , 43 ). The levels of 1,25(OH) 2 D are also decreased in patients with very severe 25(OH)D deficiency, those with chronic renal insufficiency or in rare cases of CYP27B1 mutations (vitamin D-resistant rickets type 1A).…”

Section: Resultsmentioning

confidence: 99%

“…It may be improved by partial or (sub)total parathyroidectomy, with or without ectopic parathyroid reimplantation. Clinicians should be aware that parathyroidectomy in these circumstances is usually followed by severe hungry bone syndrome with symptomatic hypocalcemia, which may require high doses of intravenous and oral calcium in combination with active vitamin D supplements ( 43 , 185 ).…”

Section: Resultsmentioning

confidence: 99%

Consensus Recommendations for the Diagnosis and Management of X-Linked Hypophosphatemia in Belgium

et al. 2021

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X-linked hypophosphatemia (XLH) is the most common genetic form of hypophosphatemic rickets and osteomalacia. In this disease, mutations in the PHEX gene lead to elevated levels of the hormone fibroblast growth factor 23 (FGF23), resulting in renal phosphate wasting and impaired skeletal and dental mineralization. Recently, international guidelines for the diagnosis and treatment of this condition have been published. However, more specific recommendations are needed to provide guidance at the national level, considering resource availability and health economic aspects. A national multidisciplinary group of Belgian experts convened to discuss translation of international best available evidence into locally feasible consensus recommendations. Patients with XLH may present to a wide array of primary, secondary and tertiary care physicians, among whom awareness of the disease should be raised. XLH has a very broad differential-diagnosis for which clinical features, biochemical and genetic testing in centers of expertise are recommended. Optimal care requires a multidisciplinary approach, guided by an expert in metabolic bone diseases and involving (according to the individual patient’s needs) pediatric and adult medical specialties and paramedical caregivers, including but not limited to general practitioners, dentists, radiologists and orthopedic surgeons. In children with severe or refractory symptoms, FGF23 inhibition using burosumab may provide superior outcomes compared to conventional medical therapy with phosphate supplements and active vitamin D analogues. Burosumab has also demonstrated promising results in adults on certain clinical outcomes such as pseudofractures. In summary, this work outlines recommendations for clinicians and policymakers, with a vision for improving the diagnostic and therapeutic landscape for XLH patients in Belgium.

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“…This was the case with our patient too. Parathyroidectomy in XLH is associated with a high rate of recurrence or persistence of tertiary hyperparathyroidism postoperatively [ 17 ], and it is likely that many patients may need a repeat surgery over their lifetimes.…”

Section: Discussionmentioning

confidence: 99%

Delayed Diagnosis, Difficult Decisions: Novel Gene Deletion Causing X-Linked Hypophosphatemia in a Middle-Aged Man with Achondroplastic Features and Tertiary Hyperparathyroidism

Chin

Zhao

Tay

et al. 2021

Case Reports in Endocrinology

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X-linked hypophosphatemia (XLH) is the most prevalent form of hereditary hypophosphatemic rickets associated with phosphate wasting. However, its diagnosis is often missed, resulting in patients presenting late in the course of the disease when complications such as tertiary hyperparathyroidism and renal failure have already set in. Phosphate and calcitriol replacement, both of which have undesirable consequences of their own, have historically been the main stay of therapy. We describe the case of a 57-year-old gentleman with tertiary hyperparathyroidism, who was mislabelled as having achondroplasia for many years before we made a diagnosis of XLH in him. His XLH was found to be due to a hereto unreported deletion of entire exon 14 with partial deletions of introns 13 and 14 of the PHEX gene. Perioperative management in him was fraught with surgical and medical difficulties including an operation that was technically complicated due to his multiple anatomical deformities. Our case also highlights the critical importance of timely recognition and accurate diagnosis of XLH, as well as the long-term multidisciplinary management that is needed for this disorder.

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Hyperparathyroidism and parathyroidectomy in X-linked hypophosphatemia patients

Cited by 32 publications

References 28 publications

Renal Phosphate Handling: Independent Effects of Circulating FGF23, PTH, and Calcium

Renal Phosphate Handling: Independent Effects of Circulating FGF23, PTH, and Calcium

Consensus Recommendations for the Diagnosis and Management of X-Linked Hypophosphatemia in Belgium

Delayed Diagnosis, Difficult Decisions: Novel Gene Deletion Causing X-Linked Hypophosphatemia in a Middle-Aged Man with Achondroplastic Features and Tertiary Hyperparathyroidism

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