Changes in Circulating Lysyl Oxidase-Like-2 (LOXL2) Levels, HOMA, and Fibrosis after Sustained Virological Response by Direct Antiviral Therapy

Abstract

Background: we aimed to assess the influence of metabolic syndrome on fibrosis regression (using liver-stiffness measurement (LSM) and serological scores) and the relationship with the expression of lysyl oxidase-like-2 as a potential goal of antifibrotic therapy. Methods: We included 271 patients treated with Direct Antiviral Therapy (DAAs) in our hospital who achieved a sustained virological response (SVR); physical examination, blood tests, and LSM were made at baseline (B) and 24 months (24 M) after SVR. Hemodynamic studies and transjugular liver biopsies were performed on 13 patients. Results: At B, 68 patients were F1 (25.1%); F2 n = 59 (21.7%); F3 n = 44 (16.05%); and 100 were F4 (36.9%). Although the LSM (absolute value) improved in 82% of patients (n = 222), it progressed in 17.5% of patients (n = 48). At 24 M, 48 patients met the metabolic syndrome (MetS) criteria and there was an increase in patients with a BMI of >25 kg/m2 (p < 0.001). At B and 24 M, a BMI of >25 kg/m2 is a risk factor for significant fibrosis or steatosis at 24 M (p < 0.05) and progression on LSM (p < 0.001), as well as MetS at B and 24 M (OR 4.1 IC (1.4–11.7), p = 0.008; and OR 5.4 IC (1.9–15.4), p = 0.001, respectively). Regarding the correlation between LSM and the liver biopsy, we found that only six out of 13 patients had a matching LSM and biopsy. We found a statistically significant decrease in LOXL2 levels at 24 M with respect to B (p < 0.001) with higher serological value in patients with elastography of >9 kPa vs. <9 kPa (p = 0.046). Conclusion: Regression of LSM was reached in 82% of patients. Downregulated LOXL2 was demonstrated post-SVR, with overexpression in cirrhotic patients being a potential therapy goal in selected patients.

Lysyl Oxidase (LOX) Family Members: Rationale and Their Potential as Therapeutic Targets for Liver Fibrosis

“…(32,33) Moreover, in a small cohort of pretreatment HCV patients with cirrhosis, hepatic LOXL2 expression was correlated with LOXL2 serum levels, but not with fibrosis stage, posttreatment. (31,32) We previously showed that in advanced CCl 4 -induced LF, LOX and LOXL1 transcripts were up-regulated 3-and 34-fold, respectively, whereas LOXL2 and LOXL3 expression remained unchanged and LOXL4 transcripts were even down-regulated. (12) These findings are in line with data by Perepelyuk et al, (34) tissues across humans and mice, regardless of the underlying etiology; however, the extent of mRNA expression changes of LOXL2, LOXL3, and LOXL4 vary among different studies, which requires further confirmation (Table 1).…”

“…The latter is a misconception in human trials, which interpreted serum LOXL2 levels as surrogate pharmacodynamic efficacy markers instead of assessing the actual target engagement within the liver ECM. In a small study of 8 HCV-infected patients, serum LOXL2 levels showed a good correlation with LOXL2 expression in the liver, but a high variability between patients with the same fibrosis stage (31,32) ; this may suggest that LOXL2 inhibition may achieve best clinical results in patients with higher serum LOXL2 levels. The unfortunate outcome has been a (temporary) loss of enthusiasm among clinicians and drug developers for targeting LOXL2 and the entire LOX family.…”

“…There are several other potential reasons for the lack of efficacy observed in the simtuzumab trial, in stark contrast to strong data supporting an important role of LOXL2 in fibrosis, (29,30,32) including a reasonable efficacy profile of anti-LOXL2 mAb in preclinical models. (14,42,45,46) Thus, there appears to be a problem with the drug in relation to its target, given that the simtuzumab antibody itself is only a weak LOXL2 antagonist because of its indirect, allosteric mechanism of action, achieving only 50% inhibition of enzymatic activity in vitro.…”

“…(19) Serum LOXL2 levels were also reported to be positively correlated with liver stiffness measured by transient elastography in HCV patients with cirrhosis with a sustained virological response to antiviral therapy at both baseline and at the end of follow-up, (30) decreasing after viral eradication. (31,32) Great variability in serum LOXL2 was found among fibrotic patients, possibly attributable to the involvement of LOXL2 in multiple processes, apart from fibrogenesis, such as promoting tumor growth and metastatic niche formation in HCC. (32,33) Moreover, in a small cohort of pretreatment HCV patients with cirrhosis, hepatic LOXL2 expression was correlated with LOXL2 serum levels, but not with fibrosis stage, posttreatment.…”

“…(31,32) Great variability in serum LOXL2 was found among fibrotic patients, possibly attributable to the involvement of LOXL2 in multiple processes, apart from fibrogenesis, such as promoting tumor growth and metastatic niche formation in HCC. (32,33) Moreover, in a small cohort of pretreatment HCV patients with cirrhosis, hepatic LOXL2 expression was correlated with LOXL2 serum levels, but not with fibrosis stage, posttreatment. (31,32) We previously showed that in advanced CCl 4 -induced LF, LOX and LOXL1 transcripts were up-regulated 3-and 34-fold, respectively, whereas LOXL2 and LOXL3 expression remained unchanged and LOXL4 transcripts were even down-regulated.…”