Browsing by Author "Econs, Michael"

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    Hyperphosphatemic Tumoral Calcinosis With Pemigatinib Use
    (Elsevier, 2022-07-16) Puar, Akshan; Donegan, Diane; Helft, Paul; Kuhar, Matthew; Webster, Jonathan; Rao, Megana; Econs, Michael; Medicine, School of Medicine
    Background/objective: Pemigatinib, a fibroblast growth factor receptor (FGFR) 1-3 inhibitor, is a novel therapeutic approach for treating cholangiocarcinoma when an FGFR fusion or gene rearrangement is identified. Although the most reported side effect of pemigatinib is hyperphosphatemia, tumoral calcinosis with soft tissue calcifications is not widely recognized as a complication. We report a case of patient with hyperphosphatemic tumoral calcinosis on pemigatinib. Case report: A 59-year-old woman with progressive metastatic cholangiocarcinoma, despite receiving treatment with cisplatin and gemcitabine for 7 months, was found to have an FGFR2-BICC1 fusion in the tumor on next-generation sequencing. Pemigatinib was, therefore, initiated. Four months into the therapy, multiple subcutaneous nodules developed over the lower portion of her back, hips, and legs. Punch biopsies revealed deep dermal and subcutaneous calcifications. Investigations revealed elevated serum phosphorus (7.5 mg/dL), normal serum calcium (8.7 mg/dL), and elevated intact fibroblast growth factor-23 (FGF23, 1216 pg/mL; normal value <59 pg/mL) levels. Serum phosphorus levels improved with a low-phosphorus diet and sevelamer. Calcifications regressed with pemigatinib discontinuation. Discussion: Inhibition or deficiency of FGF-23 results in hyperphosphatemia and can lead to ectopic calcification. Pemigatinib, a potent inhibitor of FGFR-1-3, blocks the effect of FGF-23 leading to hyperphosphatemia and tumoral calcinosis as observed in our case. Treatment is aimed primarily at lowering serum phosphate levels through dietary restriction or phosphate binders; however, the regression of tumoral calcinosis can occur with pemigatinib cessation, as seen in this case. Conclusion: As the use of FGFR 1-3 inhibitors becomes more prevalent, we aim to raise attention to the potential side effects of tumoral calcinosis.
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    Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry
    (Wiley, 2019-07) Hsu, Yi-Hsiang; Estrada, Karol; Evangelou, Evangelos; Ackert-Bicknell, Cheryl; Akesson, Kristina; Beck, Thomas; Brown, Suzanne J.; Capellini, Terence; Carbone, Laura; Cauley, Jane; Cheung, Ching-Lung; Cummings, Steven R.; Czerwinski, Stefan; Demissie, Serkalem; Econs, Michael; Evans, Daniel; Farber, Charles; Gautvik, Kaare; Harris, Tamara; Kammerer, Candace; Kemp, John; Koller, Daniel L.; Kung, Annie; Lawlor, Debbie; Lee, Miryoung; Lorentzon, Mattias; McGuigan, Fiona; Medina-Gomez, Carolina; Mitchell, Braxton; Newman, Anne; Nielson, Carrie; Ohlsson, Claes; Peacock, Munro; Reppe, Sjur; Richards, J. Brent; Robbins, John; Sigurdsson, Gunnar; Spector, Timothy D.; Stefansson, Kari; Streeten, Elizabeth; Styrkarsdottir, Unnur; Tobias, Jonathan; Trajanoska, Katerina; Uitterlinden, André; Vandenput, Liesbeth; Wilson, Scott G.; Yerges-Armstrong, Laura; Young, Mariel; Zillikens, Carola; Rivadeneira, Fernando; Kiel, Douglas P.; Karasik, David; Medicine, School of Medicine
    Hip geometry is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16 to 93 years. Association analyses were performed with ∼2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p ≤ 2.6 × 10-8 ) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 × 10-5 ). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p = 0.0007), and rs6556301 (intergenic, chr.5 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility.
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    OR13-3 Effects of Iron Isomaltoside versus Ferric Carboxymaltose on Hormonal Control of Phosphate Homeostasis: The PHOSPHARE-IDA04/05 Randomized Controlled Trials
    (Oxford University Press, 2019-04-15) Wolf, Myles; Rubin, Janet; Achebe, Maureen; Econs, Michael; Peacock, Munro; Imel, Erik; Thomsen, Lars; Carpenter, Thomas; Weber, Thomas; Zoller, Heinz; Medicine, School of Medicine
    Iron isomaltoside (IIM) and ferric carboxymaltose (FCM) are newer intravenous iron preparations that can be administered in high-doses to rapidly correct iron deficiency anemia (IDA). FCM can cause hypophosphatemia due to fibroblast growth factor 23 (FGF23) mediated renal phosphate wasting, which has been associated with osteomalacia, but the comparative effects of IIM are unknown. In two separate, identically designed, open label randomized controlled trials, we 1:1 randomized 245 adults with IDA to receive IIM (single infusion of 1000 mg) or FCM (FDA-approved dosing schedule: 2 infusions of 750 mg administered 1 week apart). We compared the incidence, severity and duration of hypophosphatemia, and effects on renal phosphate excretion, FGF23, PTH, vitamin D, and biomarkers of bone turnover measured in blood and urine samples collected at study visits at baseline (day 0) and on days 1, 7, 8, 14, 21, and 35. In pooled analyses of both trials, the incidence of hypophosphatemia <2 mg/dL was higher in the FCM versus IIM group (74.4% versus 8.0%, p<0.0001). Hypophosphatemia persisted at day 35 in 43.0% of FCM-treated patients compared to 0.9% of IIM-treated patients (p<0.0001). Severe hypophosphatemia ≤1 mg/dL occurred in 11.3% of FCM-treated patients compared to 0.0% of IIM-treated patients (p<0.0001). FCM significantly increased intact FGF23 compared to IIM (p<0.0001): on day 1, which was one day after the first infusion, FCM increased mean intact FGF23 from 49.9 pg/mL at baseline to 149.5 pg/mL; by day 8, which was one day after the second infusion, FCM increased intact FGF23 to 327.9 pg/mL; the corresponding figures for IIM were 59.9 pg/mL at baseline, 58.3 pg/mL by day 1 and 66.9 pg/mL by day 8. Compared to treatment with IIM, FCM significantly: increased urinary fractional phosphate excretion; decreased serum 1,25-(OH)2 vitamin D; decreased ionized calcium; and increased PTH, which persisted through day 35. These changes after FCM treatment were accompanied by significant increases in both total and bone specific alkaline phosphatase that also persisted through day 35. Correction of IDA was comparable between the two treatments. Serious or severe hypersensitivity reactions occurred in 0.8% in the IIM group and 1.7% in the FCM group. Compared to IIM, FCM induced high rates of FGF23-mediated hypophosphatemia, which was frequently severe and often persisted for >35 days. FCM but not IIM also induced changes in vitamin D and calcium homeostasis that triggered secondary hyperparathyroidism, which likely contributed to persistence of hypophosphatemia. Consistent with case reports of pathological fractures following FCM use, FCM also induced significant elevations of biomarkers of bone turnover that are associated with osteomalacia.
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    Severe FGF23-based hypophosphataemic osteomalacia due to ferric carboxymaltose administration
    (BMJ Publishing Group, 2018-01-03) Klein, Klara; Asaad, Shonda; Econs, Michael; Rubin, Janet E.; Biochemistry and Molecular Biology, School of Medicine
    Ferric carboxymaltose (FCM) is a novel iron formulation increasingly prescribed due to its effectiveness and fast infusion time. FCM administration can cause an asymptomatic hypophosphataemia secondary to fibroblast growth factor 23 (FGF23) dysregulation. In patients with chronic iron needs, however, a severe, long-lasting hypophosphataemia can lead to osteomalacia with associated bone pain. Lack of awareness of this complication results in delayed time to diagnosis and significant morbidity. We report a case of a patient with Crohn’s disease and chronic iron-deficiency anaemia receiving multiple doses of FCM who developed severe hypophosphataemic osteomalacia with urinary phosphate loss and increased FGF23. FGF23 excess and osteomalacia resolved only months after FCM discontinuation and aggressive phosphate repletion. Potential mechanisms of FGF23 dysregulation are discussed, with the aim of raising awareness of this significant side effect for prescribers of chronic intravenous iron supplementation, and to help guide future studies to determine the safety of FCM in all patient populations.