Orchestration of Tryptophan‐Kynurenine Pathway, Acute Decompensation, and Acute‐on‐Chronic Liver Failure in Cirrhosis

Abstract

Systemic inflammation (SI) is involved in the pathogenesis of acute decompensation (AD) and acute‐on‐chronic liver failure (ACLF) in cirrhosis. In other diseases, SI activates tryptophan (Trp) degradation through the kynurenine pathway (KP), giving rise to metabolites that contribute to multiorgan/system damage and immunosuppression. In the current study, we aimed to characterize the KP in patients with cirrhosis, in whom this pathway is poorly known. The serum levels of Trp, key KP metabolites (kynurenine and kynurenic and quinolinic acids), and cytokines (SI markers) were measured at enrollment in 40 healthy subjects, 39 patients with compensated cirrhosis, 342 with AD (no ACLF) and 180 with ACLF, and repeated in 258 patients during the 28‐day follow‐up. Urine KP metabolites were measured in 50 patients with ACLF. Serum KP activity was normal in compensated cirrhosis, increased in AD and further increased in ACLF, in parallel with SI; it was remarkably higher in ACLF with kidney failure than in ACLF without kidney failure in the absence of differences in urine KP activity and fractional excretion of KP metabolites. The short‐term course of AD and ACLF (worsening, improvement, stable) correlated closely with follow‐up changes in serum KP activity. Among patients with AD at enrollment, those with the highest baseline KP activity developed ACLF during follow‐up. Among patients who had ACLF at enrollment, those with immune suppression and the highest KP activity, both at baseline, developed nosocomial infections during follow‐up. Finally, higher baseline KP activity independently predicted mortality in patients with AD and ACLF. Conclusion: Features of KP activation appear in patients with AD, culminate in patients with ACLF, and may be involved in the pathogenesis of ACLF, clinical course, and mortality.

Albumin in decompensated cirrhosis: new concepts and perspectives

“…Finally, a number of metabolites with well-known effects on the immune system, such as those belonging to the tryptophan–kynurenine pathway, mostly circulate bound to albumin. Therefore, their free serum levels in decompensated cirrhosis can be increased due to hypoalbuminaemia, structural changes of albumin or binding competition with endogenous and exogenous substances 63…”

pCLIF-SOFA is a reliable outcome prognostication score of critically ill children with cirrhosis: an ESPNIC multicentre study

“…Liver failure shares many similarities with sepsis with regard to acute inflammation and development of immunoparalysis [26]. Systemic inflammation may be involved in the pathogenesis of ACLF and be a prognostic factor for evolution towards ACLF in patients with acutely decompensated cirrhosis [27,28]. Although not analysed in detail, presence of comorbidities in our cohort was associated with all outcomes, but 28-day mortality.…”

Explorative study of serum biomarkers of liver failure after liver resection

“…The kynurenine pathway for tryptophan catabolism mainly occurs in the liver; however, tryptophan level varies depending on liver function and availability of the rate-limiting enzyme (indoleamine 2,3-dioxygenase) induced by inflammatory response and kidney function 28 . A recent prospective study revealed that, in the 70% resection model with compensated liver function, serum tryptophan level increased with normal or mildly elevated indoleamine 2,3-dioxygenase level 29 . Conversely, in the 90% resection model with decompensated liver function, tryptophan level decreased with increase in indoleamine 2,3-dioxygenase level induced by other organs such as the kidney 29 .…”

“…A recent prospective study revealed that, in the 70% resection model with compensated liver function, serum tryptophan level increased with normal or mildly elevated indoleamine 2,3-dioxygenase level 29 . Conversely, in the 90% resection model with decompensated liver function, tryptophan level decreased with increase in indoleamine 2,3-dioxygenase level induced by other organs such as the kidney 29 . Given the similar inflammatory states in the 70% and 90% resection models, it is unclear if compensation determines the tryptophan level 26,27,29 .…”