Lymphangioleiomyomatosis: circulating levels of FGF23 and pulmonary diffusion

Abstract

Objective: Lymphangioleiomyomatosis (LAM) is a rare, destructive disease of the lungs with a limited number of determinants of disease activity, which are a critical need for clinical trials. FGF23 has been implicated in several chronic pulmonary diseases. We aimed to determine the association between serum FGF23 levels and pulmonary function in a cohort of patients with LAM. Methods: This was a descriptive single-center study in which subjects with LAM and controls with unreported lung disease were recruited. Serum FGF23 levels were measured in all subjects. Clinical data, including pulmonary function testing, were retrospectively obtained from electronic medical records of LAM subjects. Associations between FGF23 levels and clinical features of LAM were explored via nonparametric hypothesis testing. Results: The sample comprised 37 subjects with LAM and 16 controls. FGF23 levels were higher in the LAM group than in the control group. In the LAM group, FGF23 levels above the optimal cutoff point distinguished 33% of the subjects who had nondiagnostic VEGF-D levels. Lower FGF23 levels were associated with impaired DLCO (p = 0.04), particularly for those with isolated diffusion impairment with no other spirometric abnormalities (p = 0.04). Conclusions: Our results suggest that FGF23 is associated with pulmonary diffusion abnormalities in LAM patients and elicit novel mechanisms of LAM pathogenesis. FGF23 alone or in combination with other molecules needs to be validated as a biomarker of LAM activity in future clinical research.

Lymphangioleiomyomatosis with Tuberous Sclerosis Complex—A Case Study

“…Since LAM occurs in approximately 30% of women with TSC alongside TSC1 and TSC2 tuberous sclerosis gene mutations, TSC genes play an important role in cell cycle regulation through the mammalian target rapamycin (mTOR) signaling pathway. Sirolimus, also called rapamycin (an mTOR inhibitor), blocks the mTOR signaling pathway and restores homeostasis in LAM cells [3,26]. Treatment with mTOR inhibitors results in significant improvement, primarily by resolving the chyloperitoneum.…”

“…Recent research suggests a novel biomarker, FGF23 (a thirty-two-kDa protein secreted by osteocytes), to measure LAM activity. The authors assessed FGF23's association with pulmonary diffusion abnormalities in LAM patients [3].…”

“…It mainly affects women of reproductive age and is a progressive disease [1,2]. LAM may occur as an isolated disease or coexist with tuberous sclerosis (TSC) [1,3]. The incidence of sporadic lymphangioleiomyomatosis (S-LAM) is unknown, but one study found that the sporadic form occurs in 1 in 400,000 adult women [4].…”

Lymphangioleiomyomatosis (LAM) with Tuberous Sclerosis Complex - A Case Study

“…Since LAM occurs in approximately 30% of women with TSC alongside TSC1 and TSC2 tuberous sclerosis gene mutations, TSC genes play an important role in cell cycle regulation through the mammalian target rapamycin (mTOR) signaling pathway. Sirolimus, also called rapamycin (an mTOR inhibitor), blocks the mTOR signaling pathway and restores homeostasis in LAM cells [3,19]. Treatment with mTOR inhibitors brought significant improvement, primarily by resolving the chyloperitoneum.…”

“…It mainly affects women of reproductive age and is a progressive disease [1,2]. LAM may occur as an isolated disease or coexist with tuberous sclerosis (TSC) [1,3]. Although LAM is not inherited, tuberous sclerosis is a hereditary condition and most women with TSC will develop LAM.…”