In people with HIV, the kynurenine/tryptophan (kyn/trp) ratio is elevated and is associated with greater liver fibrosis, according to data published in Open Forum Infectious Diseases.
The kyn/try ratio is a measure of tryptophan catabolism and has been associated with gut microbiota changes in patients with HIV. To investigate the association of the kyn/try ratio with liver fibrosis in women with and without HIV, researchers measured plasma kyn/trp ratios in 137 women in the Women’s Interagency HIV Study. Of these participants, 59 had HIV monoinfection, 42 had coinfection with HIV and hepatitis C virus (HCV), and 36 women were not infected with either virus. Liver fibrosis was estimated in all participants using FIB-4 and via vibration controlled transient elastography liver stiffness measurement in a subset of 83 patients.
The median kyn/try ratio in women who were HIV/HCV-coinfected, HIV-monoinfected, and not infected was 0.056 (interquartile [IQR] 0.045-0.066), 0.038 (IQR 0.032–0.046), and 0.031 (IQR 0.025-0.034), respectively (P <.001). After adjustments for demographic, lifestyle, and metabolic factors, coinfection with HIV/HCV, and HIV monoinfection were associated with 164% (95% CI, 100%-250%) and 37% (95% CI, 9%-73%) greater FIB-4 scores, respectively. In addition, older age was associated with a 30% greater FIB-4 score for every 10 years (95% CI, 16%-45%)
Higher kyn/trp ratio was associated with greater FIB-4 (27% per kyn/trp doubling; 95% CI, 5%-53%) when kyn/trp ratio was included, the associations of HIV monoinfection (29% per kyn/trp doubling; 95% CI, 2%-63%) and HIV/HCV coinfection (123% per kyn/trp doubling; 95% CI, 63%-203%) with greater FIB-4 were attenuated. Multivariable analysis in the elastography liver stiffness measurement subset found that higher a kyn/trp ratio was associated with greater elastography liver stiffness measurement (43% per kyn/trp doubling; 95% CI, 15%-79%).
As a result of the cross-sectional design of the study, the causality of the association between kyn/trp ratio and fibrosis could not be determined. Patients who achieved HCV treatment were also excluded from the study; therefore the effect of HCV cure in the cohort was not assessed. The investigators also noted that FIB-4, while well validated in HIV/HCV-coinfections, it is not validated in the absence of HCV or other known liver disease. The use of liver stiffness measurement is therefore more accurate, but when it was used as the fibrosis measure in HIV monoinfection the association with greater fibrosis disappeared. This may be a result of small sample sizes, lack of sufficient power or, because “[liver stiffness measurement] is a more accurate measure of fibrosis than FIB-4, which incorporates AST and ALT values and therefore may also reflect liver inflammation regardless of fibrosis,” according to the researchers. Also, as in all observational studies there exists the potential for residual or unmeasured confounders and because the study was performed only on women the results may not be generalizable to men.
Investigators concluded that, “these findings are among the first to provide evidence that tryptophan catabolism through the kynurenine pathway may be clinically relevant in liver fibrosis progression in the setting of HIV.”
Future prospective studies are needed to see if the pathway is casually associated with fibrosis. Researchers also believe that the data highlight the kyn/trp ratio as a potential noninvasive biomarker and therapeutic target in this population.
Kardashian A, Ma Y, Yin MT, et al. High kynurenine:tryptophan ratio is associated with liver fibrosis in HIV-monoinfected and HIV/Hepatitis C virus-coinfected women. Open Forum Infect Dis. 2019;6:ofz281.