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

Abstract

Context: Soluble alpha klotho (sαKL) has been linked to growth hormone (GH) action, but systematic evaluation and comparisons with traditional biomarkers in acromegaly are lacking.

Objective: To evaluate the potential of sαKL to aid classification of disease activity.

Methods: This retrospective study at 2 academic centers included acromegaly patients before surgery (A, n = 29); after surgery (controlled, discordant, or uncontrolled) without (B1, B2, B3, n = 28, 11, 8); or with somatostatin analogue treatment (C1, C2, C3, n = 17, 11, 5); nonfunctioning pituitary adenomas (n = 20); and healthy controls (n = 31). sαKL was measured by immunoassay and compared with traditional biomarkers (random and nadir GH, insulin-like growth factor I [IGF-I], IGF binding protein 3). Associations with disease activity were assessed.

Results: sαKL was correlated to traditional biomarkers, particularly IGF-I (rs=0.80, P <0.0001). High concentrations before treatment (A, median, interquartile range: 4.04 × upper limit of normal [2.26-8.08]) dropped to normal after treatment in controlled and in most discordant patients. A cutoff of 1548 pg/mL for sαKL discriminated controlled (B1, C1) and uncontrolled (B3, C3) patients with 97.8% (88.4%-99.9%) sensitivity and 100% (77.1%-100%) specificity. sαKL was below the cutoff in 84% of the discordant subjects. In the remaining 16%, elevated sαKL and IGF-I persisted, despite normal random GH. Sex, age, body mass index, and markers of bone and calcium metabolism did not significantly affect sαKL concentrations.

Conclusion: Our data support sαKL as a biomarker to assess disease activity in acromegaly. sαKL exhibits close association with GH secretory status, large dynamic range, and robustness toward biological confounders. Its measurement could be helpful particularly when GH and IGF-I provide discrepant information.

Keywords: biomarkers; discordant; growth hormone; insulin-like growth factor I; insulin-like growth factor-binding protein 3.

Figure 1.

A, GH_random concentrations (µg/L); B, IGF-I (× ULN); C, IGFBP-3 (× ULN); and D, sαKL (× ULN) represented by medians and interquartile range as well as minimum-maximum ranges in treatment-naïve patients with acromegaly before (A) and after surgery controlled without medication (B1), discordant (B2) and uncontrolled (B3) or on SSA controlled (C1), discordant (C2) and uncontrolled (C3), NFPA (D) and healthy controls (E). For reasons of readability, we only indicate the significance level one time if it was the same for different comparisons (* P < 0.05; ** P < 0.01; *** P < 0.001; **** P < 0.0001). Abbreviations: GH_random, random growth hormone; IGF-I, insulin-like growth factor I; IGFBP-3, insulin-like growth factor-binding protein 3; sαKL, soluble alpha klotho; ULN, upper limit of normal. We intentionally use an identical range and scale for the y-axis in B, C, and D to highlight the differences in the order of magnitude of the changes in the parameters. Graphs with optimized scales for each parameter are provided in Supplemental Fig. 2.

Figure 2.

A, Correlation between IGF-I (µg/L) and GH_random (µg/L) in all patients with acromegaly; r_s= 0.67, P < 0.0001; B, Correlation between sαKL (pg/mL) and GH_random (µg/L) in all patients with acromegaly; r_s= 0.68, P < 0.0001; C, Correlation between sαKL (pg/mL) and IGF-I (µg/L) in all patients with acromegaly; r_s= 0.80, P < 0.0001; D, Correlation between sαKL (pg/mL) and IGFBP-3 (µg/L) in all patients with acromegaly; r_s = 0.72, P < 0.0001. Abbreviations: GH_random, random growth hormone; IGF-I, insulin-like growth factor I; IGFBP-3, insulin-like growth factor-binding protein 3; sαKL, soluble alpha klotho.

Figure 3.

A, GH_random (µg/L); B, IGF-I (× ULN); C, sαKL (× ULN) and D, IGFBP-3 (× ULN) in patients with acromegaly (n = 11) before and after surgery. ** P < 0.01, **** P < 0.0001. Abbreviations: GH_random, random growth hormone; IGF-I, insulin-like growth factor I; IGFBP-3, insulin-like growth factor-binding protein 3; sαKL, soluble alpha klotho; ULN, upper limit of normal. We intentionally use an identical range and scale for the y-axis in B, C, and D to highlight the differences in the order of magnitude of the changes in the parameters.

Figure 4.

A, Soluble alpha klotho (sαKL) ROC curve: before surgery, treatment-naïve (A) vs healthy controls (E). Cutoff: 1641 pg/mL, AUC 0.98 (0.96-1.00), P < 0.0001. B, Soluble alpha klotho (sαKL) ROC curve: controlled (B1, C1) vs uncontrolled (B3, C3) acromegaly after surgery. Cutoff: 1548 pg/mL, AUC 0.99 (0.98-1.00), P < 0.0001. C, Soluble alpha klotho (sαKL) ROC curve: controlled acromegaly after surgery (B1, C1), NFPA (D) and healthy controls (E) vs uncontrolled patients before or after surgery (A, B3, C3). Cutoff: 1548 pg/mL, AUC 0.99 (0.98-1.00), P < 0.0001.