Hypothesis / aims of study
The diagnosis of interstitial cystitis/bladder pain syndrome (IC/BPS) is still difficult because it relies on subjective symptoms and nonspecific objective findings. Until now, biomarkers have been studied mainly in urine, but none of them has been developed for practical use. Thus, we conducted a comprehensive analysis to identify serum biomarkers of IC/BPS and validate their usefulness.
Study design, materials and methods
[Study 1] From January 2013 to February 2014, we sampled the blood from 25 patients with IC/BPS (4 men and 21 women; age: 63.2 ± 17.1 years), 10 age-matched subjects without lower urinary tract syndromes (LUTS; 10 women; age: 64.7 ± 6.8 years), and 15 younger subjects without LUTS (15 women; age: 35.5 ± 9.5 years). We used metabolomics to search for candidate substances in the serum. [Study 2] From August to December 2017, we sampled the blood from 5 female patients with Hunner-type IC (HIC; age: 58.2 ± 19.3 years) and 5 female subjects without LUTS and compared the concentration of candidate substances as a pilot prospective study. [Study 3] From January to February 2019, we sampled blood from 25 female patients with HIC (age: 70.4 ± 10.9 years) and 25 female subjects without LUTS (age: 66.1 ± 8.5 years) and compared the concentration of a candidate substance as a prospective study. In addition, the concentration of phospholipid was measured and the ratio of the candidate to phospholipid was calculated to improve the accuracy as a biomarker.
Results
[Study 1] We analyzed 678 metabolites; 58 metabolites were not significantly different among generations, but they were significantly different between patients with IC/BPS and the subjects without LUTS. We selected 1-linoleoylglycerophosphocholine (1-LPC 18:2; sensitivity, 80%; specificity, 70%) as a candidate biomarker. [Study 2] For the prospective study, we estimated the sample size to be ≥13 people in each group (type 1 error, 5%; power, 90%) because the concentration of 1-LPC 18:2 was 20.0 ± 7.0 and 31.0 ± 9.8 μg/mL in patients with HIC and subjects without LUTS, respectively. [Study 3] The concentrations of 1-LPC 18:2 were significantly different between patients with HIC and subjects without LUTS (27.9 ± 6.3 vs 40.4 ± 15.1 μg/mL, p < 0.0003). If we set the cutoff value of 1-LPC 18:2 at 28.4 μg/mL, the sensitivity and specificity would be 68% and 84%, respectively (Figure 1). The concentrations of phospholipid were significantly different between patients with HIC and subjects without LUTS (2146 ± 348.3 vs 2318 ± 277.5 μg/mL, p = 0.0366). The ratios of 1-LPC 18:2 to phospholipid were significantly different between patients with HIC and subjects without LUTS (13.1 ± 2.6 vs 17.4 ± 6.0 ‰ , p = 0.0013). If we set the cutoff value of the ratio at 15.7 ‰, the sensitivity and specificity would be 88% and 68%, respectively (Figure 2).
Interpretation of results
Lysophospholipids may be associated with the pathology of IC/BPS. In recent years, lysophospholipids have been recognized as the second lipid mediators next to prostaglandins and are next-generation drug targets. By focusing on lysophospholipids, it may be possible to elucidate the pathology and develop therapeutic drugs from a new perspective.