Soluble Klotho: a possible predictor of quality of life in acromegaly patients

Abstract

Purpose Although quality of life (QoL) is improved in patients with acromegaly after disease control, QoL correlates only weakly with traditional biomarkers. Our objective is to investigate a potential relation between the new serum biomarker soluble Klotho (sKlotho), GH and insulin-like growth factor 1 (IGF-1) levels, and QoL. Methods In this prospective cohort study, we investigated 54 acromegaly patients biochemically well-controlled on combination treatment with first-generation somatostatin receptor ligands (SRLs) and pegvisomant (PEGV) at baseline and 9 months after switching to pasireotide LAR (PAS-LAR; either as monotherapy, n = 28; or in combination with PEGV, n = 26). QoL was measured by the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) and Acromegaly Quality of Life (AcroQoL) questionnaire. Results Switching to PAS-LAR treatment significantly improved QoL without altering IGF-1 levels. QoL did not correlate with GH or IGF-1 levels, but sKlotho correlated with the observed improvements in QoL by the AcroQoL global (r = −0.35, p = 0.012) and physical subdimension (r = −0.34, p = 0.017), and with PASQ headache (r = 0.28, p = 0.048), osteoarthralgia (r = 0.46, p = 0.00080) and soft tissue swelling score (r = 0.29, p = 0.041). Parallel changes in serum sKlotho and IGF-1 (r = 0.31, p = 0.023) suggest sKlotho and IGF-1 to be similarly dependent on GH. Comparing the PAS-LAR combination therapy and the monotherapy group we did not observe a significant difference in improvement of QoL. Conclusions Patients experienced improved QoL during PAS-LAR, either as monotherapy or in combination with PEGV. Soluble Klotho concentrations appear to be a useful marker of QoL in acromegaly patients but the underlying mechanisms remain to be investigated.

A Pituitary Society update to acromegaly management guidelines

“…Other markers of GH action such as IGF binding protein 3 or acid-labile subunit have been suggested to assess discrepant GH and IGF-I results [ 46 ]. Soluble Klotho, predominantly expressed in the kidney [ 47 ], correlates with GH levels over a wide concentration range [ 48 ], and has been suggested to correlate with QOL improvements [ 49 ].…”

“…Additional analyses of PAPE data focused on predictors of treatment benefit. Neither GH nor IGF-I correlated with improved QOL observed after switching combination therapy regimens [ 49 ]. Somatostatin receptor SST2, but not SST5, expression, correlated with lower IGF-I levels [ 89 ].…”

Approach to the Patient With Treatment-resistant Acromegaly

“…In 33 of the 45 patients from the PAPE study, tumor volume decreased but this decrease was clinically significant (≥25%) in 15 cases only (33%) ( 36 ). In both treatment groups significant improvements in quality of life were observed after switching to pasireotide LAR ( 37 ). However, we should acknowledge that assessing a difference in quality of life between monotherapy and combination therapy was not a primary endpoint of this study, and it was underpowered to detect a significant difference.…”

Soluble Alpha Klotho in Acromegaly: Comparison With Traditional Markers of Disease Activity

“…It is noteworthy that in all the remaining 4 discordant cases, where sαKL remained elevated after treatment, IGF-I also remained elevated (despite normal GH random ), and all 4 patients reported severe symptoms, including headache, and had a worse quality of life compared with patients with normal sαKL. This is of interest since a recent study ( 29 ) had reported that changes in sαKL during successful treatment correlate with improvements particularly in quality of life and headache. The mechanisms are unclear, but it seems that sαKL could have particular relevance as a biomarker of central effects of GH excess.…”