High neutrophil-lymphocyte ratio indicates a worse response to ursodeoxycholic acid in primary biliary cholangitis: a retrospective cohort study

Primary biliary cholangitis (PBC, formerly known as primary biliary cirrhosis) is a chronic and cholestatic autoimmune liver disease characterized by the destruction of intrahepatic small bile ducts, leading to inflammation, fibrosis, hepatic failure, and, in some cases, hepatocellular carcinoma [1, 2] The serologic hallmark of PBC is the anti-mitochondrial antibody (AMA), especially the AMA-M2 subtype, which is a highly disease-specific autoantibody in PBC patients [3]. The presence of this antoantibody has also been shown to precede biochemically apparent liver injury by several years [4]. Antinuclear autoantibodies might be positive in patients with PBC, more specifically antiglycoprotein 210 (anti-gp210) and anti-sp100 [5]. Interestingly, its worldwide prevalence has recently been increasing, and the prevalence has risen to 19.1 cases per 100,000 in Chinese individuals [6, 7]. The first-line therapy in PBC is ursodeoxycholic acid (UDCA) at a dose of 13–15 mg/kg/day, which can significantly improve liver biochemistry, delay histological progression, and improve liver-transplantation-free survival [8]. However, approximately 40% of patients have an inadequate response to UDCA treatment [9]. Compared to responders to UDCA, these patients are at a greater risk of hepatic complications such as ascites, variceal bleeding, and hepatic encephalopathy [10]. At present, there are no reliable clinical approaches to identify UDCA-non-responsive patients before treatment. Therefore, identifying optional biomarkers that can predict either responders or nonresponders to UDCA in early stage have been of tremendous importance to improve clinical decision making. The neutrophil to lymphocyte ratio(NLR) is an easily obtained serum measure that corresponds to systemic inflammation and has been demonstrated to be a valuable prognostic indicator in different types of malignancies [11, 12], inflammatory disease [13], and chronic liver diseases [14‐16], However, it is not yet clear whether NRL is associated with poor therapeutic response in PBC patients. Our study aimed to evaluate the relationship between NRL and the response to UDCA treatment in PBC patients.

In this retrospective study, we adopted multivariate analysis and adjusted confounding factors to identify the risk factors of UDCA nonresponse. We found that NLR was an independent risk factor for incomplete response to UDCA treatment in PBC patients. In addition, the NLR is advantageous due to its simple and rapid determination. To our knowledge, this report is the first to provide evidence that a high NLR level at baseline is associated with a future risk of poor response to UDCA treatment.

In our study, we adjusted for age, sex, BMI, hypertension, arterial plaque, thyroid disease, jaundice, albumin, globulin, total bile acid, total bilirubin, ALP, GGT, HDLC, LDLC, total cholesterol, triglycerides, and APTT. The baseline NLR (OR:1.442, 95% CI:1.040–2.00, P = 0.013) levels were risk factors for the lack of response to UDCA treatment. The NLR is a composite marker of absolute peripheral neutrophil and lymphocyte counts. Elevated NLR which implies higher inflammatory burden signifies high neutrophil count due to active inflammation and a low lymphocyte count correlates with defective response to the inflammatory process [19]. Neutrophil levels are associated with inflammation, whereas lymphocytes are indispensable for immunosurveillance and immunoediting [20]. Therefore, analysing them apart may miss the interactions between these subtypes. Multiple previous studies have suggested that the NLR is a value that has been recently identified in relation to systemmation, and has been extensively studied in cardiovascular, malignancy, and pancreatitis [21‐23]. A high NLR that may be predictive for primary liver cancer invasion and metabasis indicates a poor prognosis for patients with primary liver cancer [24]. Meanwhile, NLR as an advanced histological or prognostic predictor in hepatitis B and C and nonalcoholic fatty liver disease has been reported previously [25‐27]. More importantly, a cohort study established the value that a high NLR was associated with a poorer long-term prognosis (15 years) in the PBC patients [28]. The results of this study are consistent with our findings. Currently, there are still no studies that prove whether a high NLR is correlated with worse response to UDCA therapy.

It is worth mentioning that inflammation is one of the major pathophysiological mechanisms for the development and progression of PBC [29]. Immune cells, inflammatory cytokines, and chemokines have been found to be involved in the pathogenesis of PBC [30]. Neutrophils have been described as a major target of IL-8. In a previous study, high positive expression of IL-8 was observed in small bile ducts of PBC, especially in end-stage cirrhosis [31‐33]. However, in the early stages of PBC and PSC, IL-8-positive bile ductules were relatively infrequent or completely absent [31]. Therefore, we speculate that neutrophilic infiltration could be related to the IL-8 expression in bile ductular epithelia. A previous study revealed that CD8+ and CD4+ lymphocytes were the predominant cell types among inflammatory cells within the portal area in PBC [34]. Compared to peripheral blood, liver tissue is a 100-fold enrichment of CD4 + T cells and a 10-fold enrichment of CD8 + T cells [35]. Previous studies have shown that UDCA responsders exhibited significantly less CD4 + T cell infiltration after UDCA treatment than before in PBC liver specimens [36]. Therefore, a decrease in the number of liver-infiltrating lymphocytes (CD4+ Th1 cells) is associated with a good response of patients to UDCA treatment. Besides, available data suggest that risk factors for nonresponse among patients of UDCA treatment include male sex, age at diagnosis, increased titers of IgG, AIH features, and vitamin D deficiency [37‐39]. It is worth noting that some patients with PBC who do not respond to ursodeoxycholic acid therapy may be combined with autoimmune hepatitis. The overlap syndrome of PBC and AIH patients characterized with high IgG, ALT, or AST level and interface hepatitis, is also associated with the poor response and prognosis [38, 40]. It is well known that when patients are diagnosed with PBC-AIH overlap syndrome (OS), immunosuppressive therapy is necessary in addition to treatment with UDCA. Besides, some studies suggest that patients with a symptomatic presentation (fatigue and/or pruritus) may have a poorer response to UDCA therapy, and a worse prognosis than asymptomatic patients [41, 42]. Because fatigue and pruritus are extremely subjective symptoms, patients are often unable to report precisely in the everyday clinical practice, and records with unsatisfactory data were not excluded in our study. In clinical practice, if patients are intolerant to UDCA or do not have a sufficient biochemical response to treatment, a second-line therapy in the form of added obeticholic acid can be considered. Fibrates (fenofibrate and bezafibrate), which are not approved for PBC treatment are also used in some countries because of evidence of their beneficial effects [43]. Currently, there are no available biomarkers to identify the patients who are unlikely to respond to UDCA and who might benefit from early introduction of second-line therapy.

This retrospective cohort study established a relatively good predictor for the inadequate response of UDCA treatment. However, our current study has some inevitable limitations. First, this was a single-center study that needed more centers and more samples to further test. Second, because of the short-term follow-up duration, we also could not identify the predictive value for long-term outcomes. Third, the subjective feelings of fatigue and pruritus at the baseline were difficult to obtain precisely.

In conclusion, our findings suggest that the NLR is an independent risk factor for non-response to UDCA treatment in PBC patients.