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

doi:10.21203/rs.3.rs-3342007/v1

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

https://doi.org/10.21203/rs.3.rs-3342007/v1

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published 17 Nov, 2023

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Background: Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by inflammation of the interlobular bile ducts. Ursodeoxycholic acid (UDCA) is the only FDA approved first-line therapy for PBC, but up to 40% of patients with PBC have an incomplete response to UDCA. Neutrophil-to-lymphocyte (NLR) has been used to predict prognosis in various liver diseases. There is limited evidence on the treatment response to UDCA in PBC patients. The aim of this study was to elucidate the changes in NLR in response to one-year UDCA treatment of PBC patients.

Methods:A total number of 257 primary biliary cholangitis (PBC) patients treated with UDCA (13–15 mg/kg/d) were enrolled in this retrospective study. The response to treatment was evaluated based on alkaline phosphatase levels < 1.67 times the upper limit of the normal value after 12 months of UDCA treatment. Multivariable logistic regression analysis was performed to investigate the association between NLR at baseline and the response to 12- month UDCA treatment after adjusting for important confounding variables. The quartiles of increased baseline NLR was assessed as a predictor of future nonresponse to UDCA treatment. The stability of the results was evaluated by unadjusted and adjusted models.

Results: The result of multiple regression analysis showed that NLR at baseline was positively associated with the nonresponse to UDCA treatment after adjustments for potential confounders (age, sex, BMI, hypertension, arterial plaque,thyroid disease, jaundice, albumin, globulin, total bile acid, ALP, GGT, LDLC, total cholesterol, hemoglobin, and APTT) (OR = 1.370, 95% CI 1.066-1.761). When NLR was translated into a categorical variable, the OR and 95% CI in the fourth quartile versus the first quartile was OR = 3.782, 95% CI 1.094-13.073, respectively (P for trend = 0.036). These results reveal that NLR is an independent risk factor of UDCA treatment nonresponse.

Conclusions: Our results suggest that NLR is an independent risk factor of UDCA treatment nonresponse.

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, a highly disease-specific autoantibody detected in PBC patients.³ Recently, with the increasing prevalence of PBC (39.2 per 100,000), the prevalence has risen up to 19.1 cases per 100,000 in chinese^4,5 The current standard treatment of PBC is ursodeoxycholic acid (UDCA), 13–15 mg/kg/day, which can significantly improve the clinical manifestations, serum profile, and histolagy⁶. However, approximately 40% of patients with PBC respond incompletely to UDCA treatment.⁷ Compared to responders to UDCA, these patients are at a greater risk of hepatic complications such as ascites, variceal bleeding, and hepatic encephalopathy.⁸ No clinical approaches exist for the identification of UDCA-non-responsive patients before treatment. Therefore, the establishment of factors which can predict the prognosis for PBC non-responders are of paramount importance for improving clinical decision making.

Recently, readily available parameters of routine complete blood count (CBC) have been investigated as potential biomarkers. Neutrophil-to-lymphocyte ratio (NRL) has been proposed as an indicator that can facilitate the diagnosis, early warning, and risk stratification of infectious diseases.^9,10 Accumulating evidence has suggested that increased NLR is associated with poor outcomes in different types of malignancies, infectious diseases, metabolic syndrome, cardiovascular disease, and other inflammatory diseases.^11–14 However, it is not yet clear whether NRL is associated with poor therapeutic response in PBC patients. The present study aimed to evaluate the relationship between NRL and the response to UDCA treatment in PBC patients.

Study patients

This single-center, retrospective cohort study was conducted at the Department of Gastroenterology, Second Affiliated Hospital of Kunming Medical University (Kunming, China). All patients (n = 732) were diagnosed with PBC on admission from December 2013 to September 2021, and their data were collected via the electronic medical record database. Patients who fulfilled the inclusion criteria were enrolled, and their demographics and clinical data were extracted from the individual medical records in a case report form. Summary statistical analyses were employed to examine the baseline demographics at their first diagnosis of PBC(Fig. 1).

The present study protocol was implemented in accordance with the ethical guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of the Second Affiliated Hospital of Kunming Medical University. Due to we collect already existing ordinary clinical data, ethical clearance of this retrospective study was obtained and the requirement for informed consent was waived(YJ-2023-96).

Diagnostic criteria

According to the Guideline of the American/European Association for the Study of Liver Disease, patients could be diagnosed with PBC when two of the following three criteria are fulfilled: (1) elevated ALP in the liver biochemical indicators; (2) positive serum AMA or the AMA-M2 subtype; and (3) manifestations of nonsuppurative cholangitis and intrahepatic interlobular bile duct destruction established through liver biopsy.^15,16

Inclusion criteria

The following inclusion criteria were applied: (1) patients who fulfilled the PBC diagnostic criteria; (2) patients with or without previous oral UDCA administration history, who began to take 13–15 mg/kg/d UDCA orally from the baseline date and received continuous and regular treatment; and (3) qualified patients with complete data at baseline and at least a 12-month follow-up period duration.

Exclusion criteria

Patients who fulfilled any one of the following criteria were excluded: evidence of hepatitis B or hepatitis C virus, primary sclerosing cholangitis or other liver disease, including Budd-Chiari syndrome, autoimmune hepatitis-primary biliary cholangitis (AIH-PBC) overlap syndrome, and intrahepatic or extrahepatic biliary obstruction, and patients who were followed up for less than 1 year. Initially, patients who fulfilled any of the exclusion criteria were also excluded from this study (n = 475). Finally, we retrospectively included 257 patients who met the inclusion criteria.

Data collection

All clinical and laboratory data were recorded upon patient enrollment, including demographic characteristics, basic disease, clinical symptoms, clinical data, and laboratory test data. Specifically, the course of disease, history of UDCA treatment, cirrhotic status, and comorbidities were recorded. Patients who had not used UDCA before and began to use it at baseline were defined as first-time users of UDCA (F-UDCA). The endpoint was UDCA response, defined as alkaline phosphatase < 1.67 times the upper limit of the normal value after 12 months of UDCA treatment. NLR was measured by dividing the absolute neutrophil count by the lymphocyte count.

Because the data contains patient information. The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Statistical analysis

All analysis adopted a significance level of 0.05 and were conducted in SPSS 26.0 software. Data with a normal distribution were expressed as mean ± SD, whereas those not conforming to a normal distribution were expressed as the median (IQR). Frequencies and percentages were used to express categorical qualitative variables. Data with a normal distribution with homogeneity of variance were compared using an independent sample t-test. Mann-Whitney’s nonparametric test was employed to compare non-normally distributed between groups. Non-parametric \({ \text{{\rm X}}}^{2}\)-test or Fisher’s exact test were implemented to compare categorical variables.

Variables that were identified as statistically significant by univariate analyses (P < 0.05) or clinically significant were entered into a multivariate logistic regression analysis to determine the contribution of NLR to the endpoint of UDCA response. Multiple logistic regression analysis was utilized to assess the specific relations between the neutrophil-to-lymphocyte (NLR) and outcome (1 year nonresponse of treatment of UDCA);odds ratio(OR) and 95% confidence interval(CI) were used to evaluate the risk.

Baseline characteristics of the study population

During the study period, 257 PBC patients met the inclusion criteria and were included in the study (Table 1). The average patient age was 56.20 ± 11.84 years, including 223 (86.80%) female patients. A number of 235 (91.40%) PBC patients were subjected to first UDCA treatment. A total number of 83 (31.90%) had cirrhosis at baseline. Additionally, 132 (51.40%) patients were positive for serum antimitochondrial antibody (AMA) or the M2 subtype.

We compared the clinical characteristics and parameters between the following groups: a response group (with ALP ≤ 1.67 times) and an inadequate response group (with ALP > 1.67 times the ULN). Overall, 170 (66.15%) patients did not response to UDCA treatment. BMI media (fist quartile; third quartile) of the responder group 22.60 (20.70–24.23) were slightly higher than those of the non-responder group 21.64 (19.56–24.23) at baseline (BMI:). Furthermore, the differences among groups in gender, age, with liver cirrhosis was not statistically significant (P > 0.05). Interestingly, the complications of PBC, including ascites and esophageal varices, were significantly more frequent in the non-responder group than in the responder group (P < 0.05). A more significant increase in ALT, AST, ALP, GGT, total bilirubin (TB), and NLR levels after 12-months of UDCA treatment were noted in the inadequate response group than in the response group (P < 0.05). The definitive diagnosis of 73 patients was made by liver biopsy, with histological Scheuer classification stages as follows: I (n = 5), II (n = 24), III (n = 25), and IV (n = 19) (data not shown).

Table 1

Baseline characteristics of the biochemical response in patients with PBC.
Characteristics	Total (n = 257)	Non-responders (n = 87)	Responders (n = 170)	P-value
Sex(female)	223 (86.80)	73 (83.90)	150 (88.20)	0.273
Age (years)	56.20 ± 11.84	55.23 ± 10.97	56.74 ± 12.31	0.336
BMI	22.22 (20.44–24.09)	21.64 (19.56–24.23)	22.60 (20.70-24.23)	0.026
F-UDCA	235 (91.40)	80 (92)	155 (91.20)	0.822
Cirrhosis	83 (31.90)	33 (37.90)	49 (28.80)	0.147
Comorbidities
Hypertension	29 (11.30)	5 (5.75)	24 (14.12)	0.043
Thyroid disease	50 (19.50)	11 (12.64)	39 (22.94)	0.046
Atherosis	5 (1.90)	4 (4.60)	1 (0.59)	0.028
Complications
Esophageal and gastric varices	46 (17.90)	23 (26.44)	23 (13.53)	0.011
Ascites	39 (15.20)	20 (22.99)	19 (11.18)	0.038
Laboratory date
Albumin (g/l)	36.90 (32.00-41.35)	33.80 (28.30–38.60)	38.20 (33.60-42.65)	< 0.001
Globulin (g/l)	35.13 ± 7.70	36.49 ± 7.80	34.45 ± 7.59	0.045
Total bilirubin (umol/l)	25.00 (15.5–49.30)	36.70 (24.40–70.10)	19.60 (13.60-34.35)	< 0.001
Alanine aminotransferase (×ULN)	60.00 (32.00-104.00)	75.00 (41.00-103.00)	51.00 (27.00-103.00)	0.019
Aspartate aminotransferase(×ULN)	69.00 (42.00-117.00)	88.00 (71.00-130.00)	54.00 (35.00-105.00)	0.010
Alkaline phosphatase (×ULN)	220.00 (132.00-347.50)	395.00 (259.00-549.00)	160.00 (113.00-233.50)	< 0.001
γ-Glutamyl transferase (×ULN)	206.00 (77.00-421.50)	400.00 (201.00-709.00)	159.00 (49.50–311.00)	< 0.001
Total cholesterol (mmol/l)	4.83 (3.90–6.06)	57.90 (24.10-170.60)	21.30 (8.35–68.80)	< 0.001
HDL-C (mmol/l)	1.28 (0.93–1.68)	1.29 (0.85–1.91)	1.26 (0.99–1.64)	0.676
LDL-C (mmol/l)	2.74 (2.09–3.64)	3.16 (2.32–4.72)	2.54 (1.95–3.33)	< 0.001
White blood cell (×10⁹/l)	4.88 (3.59–5.97)	4.85 (3.82–6.39)	4.88 (3.58–5.74)	0.287
Neutrophil counts (×10⁹/l)	2.75 (1.92–3.65)	2.91 (2.12–4.28)	2.58 (1.89–3.44)	0.017
Lymphocyte counts (10⁹/l)	1.48 (1.04–1.92)	1.38 (1.03–1.78)	1.53 (1.06–2.05)	0.070
Monocyte counts (×10⁹/l)	0.31 (0.23–0.40)	0.31 (0.23–0.41)	0.31 (0.24–0.40)	0.885
NLR	1.83 (1.27–2.76)	2.16 (1.43–3.33)	1.70 (1.18–2.53)	0.001
Platelet count (×10⁹/l)	150.00 (93.50–225.00)	150.00 (85.00-228.00)	153.00 (95.50–222.00)	0.722
International normalized ratio	1.05 ()0.95–1.19	1.02 (0.92–1.18)	1.05 (0.97–1.20)	0.076
APTT(s)	35.80 (31.70–39.70)	37.29 ± 7.29	34.76 ± 6.10	0.004
Serum creatinine (umol/l)	58.00 (50.00–66.00)	54.00 (46.00–62.00)	60.00 (54.00–66.00)	< 0.001
Serum sodium (mmol/l)	139.80 (137.73–14158)	139.10 (137.20–141.00)	140.30 (138.30–142.00)	0.008
Positive AMA-2	132 (51.40)	49 (56.32)	83 (48.82)	0.274

BMI, body mass index; NLR, neutrophil-to-lymphocyte ratio; AMA, antimitochondrial antibody; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; UDCA, ursodeoxycholic acid; APTT, activated partial thromboplastin time; ULN, upper limit of normal.

NLR is an independent risk factor for non-response to UDCA treatment in PBC patients: binary logistic regression model results

Univariate binary logistic regression analysis showed that globulin, total bile acid, Υ-glutamyl transferase (GGT), low-density lipoprotein (LDLC), total cholesterol (TC), neutrophils, APTT, NLR are risk factors for UDCA nonresponse (P < 0.05). In the multivariate binary logistic regression analysis, we developed three models adjusted for different covariates to confirm the stability of the results. Model A, which is adjusted for age, sex, and BMI, indicated that NLR is an independent risk factor for the lack of response to UDCA treatment (OR: 1.355, 95% CI: 1.132–1.622, P = 0.001). Model B, which was adjusted for age, sex, BMI, hypertension, arterial plaque, and thyroid disease suggested that hypertension (OR: 3.704, 95% CI:1.137–12.062, P = 0.030) and NLR (OR: 1.402, 95% CI: 1.169–1.683, P < 0.001) were risk factors for the lack of response. Model C, which was 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, showed that ALB(OR:0.883,95%CI:0.806–0.967) level was the protective factors of the response, wh ereas the baseline ALP(OR:1.013, 95%CI:1.009–1.018), and NLR (OR:1.442, 95% CI:1.040-2.00, P = 0.013) levels were also risk factors for the lack pof response to UDCA treatment (Table 2).

Table 2. Binary logistic regression analysis results of NLR and one-year lack of response to UDCA treatment in PBC patients.

Variable	Univariate analysis		Multivariate analysis
			Model A		Model B			Model C
	OR (95% CI)	P-value	OR (95% CI)	P-value	OR (95% CI)	P-value		OR (95% CI)	P-value
Age (years)	0.989 (0.968-1.011)	0.335	0.988 (0.966-1.011)	0.317	0.993 (0.970-1.018)	0.598		1.011(0.969-1.055)	0.606
Sex (male/female)	0.660 (0.314-1.391)	0.275	1.609 (0.749-3.454)	0.223	1.119 (0.495-2.532)	0.787		1.191(0.327-4.348)	0.791
BMI	0.940 (0.864-1.022)	0.144	0.947 (0.868-1.032)	0.211	0.972 (0.891-1.060)		0.520	1.038(0.914-1.180)	0.565
Hypertension	2.714 (0.998-7.385)	0.051			3.704 (1.137-12.062)		0.030	1.860(0.403-8.595)	0.427
Arterial plaque	8.096 (0.891-7.585)	0.063			0.101 (0.010-1.022)		0.052	0.427(0.032-5.732)	0.521
Thyroid disease	0.482 (0.233-0.998)	0.049			2.122 (0.965-4.666)		0.061	20639(0.869-8.013)	0.087
Jaundice	0.505 (0.258-0.988)	0.046						0.393(0.095-1.618)	0.196
Albumin (g/l)	0.903 (0.865-0.942)	0.000						0.883(0.806-0.967)	0.008
Globulin (g/l)	1.035 (1.000-1.071)	0.047						0.980(0.924-1.039)	0.489
Total bile acid (u/mol/L)	1.003 (1.001-1.005)	0.005						1.001(0.995-1.007)	0.759
Total bilirubin (umol/L)	1.003 (0.999-1.007)	0.129						0.986(0.972-1.001)	0.060
Alkaline phosphatase (u/l)	1.011 (1.008-1.014)	0.000						1.013(1.009-1.018)	<0.001
γ-Glutamyl transferase (u/l)	1.003 (1.002-1.004)	0.000						0.999(0.997-1.001)	0.212
HDL-C (mmol/l)	1.313 (0.851-2.025)	0.218						1.346(0.403-4.488)	0.629
LDL-C (mmol/L)	1.325 (1.110-1.582)	0.002						0.531(0.232-1.215)	0.134
Total cholesterol (mmol/L)	1.278 (1.117-1.461)	0.000						1.722(0.866-3.423)	0.121
Triglycerides (mmol/L)	1.127 (0.879-1.446)	0.346						1.316(0.649-2.671)	0.447
Neutrophils (×10⁹/l)	1.359 (1.127-1.638)	0.001						1.012(0.691-1.481)	0.951
APTT(s)	1.066 (1.019-1.116)	0.006						1.054(0.977-1.137)	0.175
NLR	1.325 (1.109-1.584)	0.002	1.321 (1.104-1.580)	0.002	1.369 (1.141-1.643)		0.001	1.442(1.040-2.000)	0.028

Model A: adjusted for age, sex, and BMI;

Model B: adjusted for age, sex, BMI, hypertension, arterial plaque, and thyroid disease;

Model C: 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.

In this study, we adopted univariate 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. Meanwhile, 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.

Multiple studies have suggested that NLR is a value that has been recently identified in relation to systemmation, and has been extensively studied in cardiovascular, malignancy, and pancreatitis.^17–19 A meta-analysis showed that a high NLR indicates a poor prognosis for patients with primary liver cancer and may also be predictive for primary liver cancer invasion and metabasis.²⁰ Neutrophil levels are associated with inflammation, whereas lymphocytes are indispensable for immunosurveillance and immunoediting.²¹ Thus, NLR might serve as a prognostic indicator in patients with primary liver cancer. Meanwhile, the potential of NLR as an advanced histological or prognostic predictor in hepatitis B and C and nonalcoholic fatty liver disease has been reported earlier.^22–24 A cohort study established the value of NLR for the prediction of long-term prognosis (15 years).¹⁰ However, no universal predictive cut-off NLR value has been proposed.

Inflammation is one of the major pathophysiological mechanisms for the development and progression of PBC.²⁵ Immune cells, inflammatory cytokines, and chemokines have been found to be involved in the pathogenesis of PBC.²⁶ There are studies findings the close relationship between periductular infiltration of neutrophils and IL-8 produced by ductular epithelial cells, high IL-8 mRNA levels were found in samples from cirrhotic livers (F4 fibrosis score), especially patients with primary biliary cirrhosis.²⁷ However, in the early stages of PBC and PSC, IL-8-positive bile ductules were relatively infrequent or completely absent.²⁸ Therefore, we speculate that IL-8 expression is correlated with different disease stages. In this study, patients with liver biopsy data available had more advanced liver disease. A previous study revealed that CD8 + and CD4 + lymphocytes were the predominant cell types among inflammatory cells within the portal area in PBC.²⁹ In another investigation, PBC liver compared to peripheral blood, there is a 100-fold enrichment of CD4 + T cells and a 10-fold enrichment of CD8 + T cells specific for the major PBC autoantigen.³⁰ Available data suggest that risk factors for nonresponse among patients include male sex, age at diagnosis, increased titers of IgG-AMA, AIH features, and vitamin D deficiency.^31–33 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 used in some countries for this purpose because of evidence of their beneficial effects.. However, it is unknown whether fibrates are suitable for the Chinese population, and this view needs to be validated by further research in the future.

This retrospective cohort study established a relatively good predictor for the inadequate response of UDCA treatment, but some limitations are to be mentioned. First, our sample size was small, which might have caused a selection bias. Second, because of the short-term follow-up duration, we also could not identify the predictive value for long-term outcomes.

Funding: This study was supported by National Natural Science Foundation of China (Grant No.81760383, 82160106); Second Affiliated Hospital clinical project of Kunming Medical University (ynllT2021001, ynllT2021009)

Author Contributions: Huiling Zhu and Mengyao Zheng designed the study and drafted the manuscript. Huiling Zhu collected the clinical data. Hongtao Lei and Haiyu He analysed the data. Jinhui Yang and Wenlin,Tai reviewed the data and revised the manuscript. All authors approved the final version.

Conflicts of Interest: The authors declare no conflict of interest.

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No competing interests reported.

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

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