Clinical utility of diagnostic guidelines and putative biomarkers in lymphangioleiomyomatosis

Abstract

BackgroundLymphangioleiomyomatosis is a rare disease occurring almost exclusively in women. Diagnosis often requires surgical biopsy and the clinical course varies between patients with no predictors of progression. We evaluated recent diagnostic guidelines, clinical features and serum biomarkers as diagnostic and prognostic tools.MethodsSerum vascular endothelial growth factor-D (VEGF-D), angiotensin converting enzyme (ACE), matrix metalloproteinases (MMP) -2 and -9, clinical phenotype, thoracic and abdominal computerised tomography, lung function and quality of life were examined in a cohort of 58 patients. 32 healthy female controls had serum biomarkers measured.ResultsSerum VEGF-D, ACE and total MMP-2 levels were elevated in patients. VEGF-D was the strongest discriminator between patients and controls (median = 1174 vs. 332 pg/ml p < 0.0001 with an area under the receiver operating characteristic curve of 0.967, 95% CI 0.93-1.01). Application of European Respiratory Society criteria allowed a definite diagnosis without biopsy in 69%. Adding VEGF-D measurement to ERS criteria further reduced the need for biopsy by 10%. VEGF-D was associated with lymphatic involvement (p = 0.017) but not the presence of angiomyolipomas.ConclusionsCombining ERS criteria and serum VEGF-D reduces the need for lung biopsy in LAM. VEGF-D was associated with lymphatic disease but not lung function.

A 2-year randomised placebo-controlled trial of doxycycline for lymphangioleiomyomatosis

“…Since MMPs are secreted as inactive zymogens, which require proteolytic cleavage for activation, we measured pro-and activated MMP-9 in serum and urine using gelatin zymography as previously described [12,22].…”

“…Matrix metalloproteinases (MMPs), can degrade extracellular matrix, and can affect cell growth, invasion, angiogenesis and inflammation [10]. MMP-2 and -9 are overexpressed in the serum of females with LAM [11,12] and MMP-1, -2, -9 and -14 are strongly expressed in the lungs of patients, particularly adjacent to cysts where disrupted collagen and elastic fibres are observed [13,14]. Therefore, inhibition of MMP activity could reduce lung destruction in LAM.…”

Treatment of lymphangioleiomyomatosis: building evidence in orphan diseases

“…Matrix metalloproteinases (MMPs), which can degrade extracellular matrix, are produced by LAM cells and have been implicated in the formation of lung cysts in LAM, especially MMP-1, MMP-2, MMP-9 and MMP-14, which are elevated in the serum and/or expressed in lung tissue adjacent to cysts [32][33][34][35]. Furthermore, MMPs are known to affect cell growth, invasion, inflammation and angiogenesis [36].…”

Doxiciclina em pacientes com linfangioleiomiomatose: biomarcadores e resposta funcional pulmonar

“…These findings are concordant with those of previous studies that found no association between VEGF-D levels and lung function impairment. ( 38 - 40 ) …”