Predictors of liver failure in primary biliary cirrhosis Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=iups20 Upsala Journal of Medical Sciences ISSN: 0300-9734 (Print) 2000-1967 (Online) Journal homepage: https://www.tandfonline.com/loi/iups20 Predictors of liver failure in primary biliary cirrhosis Pan Zhao, Wei-wei Liu, Jin-feng Li, Chun-ya Wang, Hao Wang, Jun Xu, Rui- fang Wang, Hao-zhen Yang, Cheng Jin & Zhen-man Wei To cite this article: Pan Zhao, Wei-wei Liu, Jin-feng Li, Chun-ya Wang, Hao Wang, Jun Xu, Rui-fang Wang, Hao-zhen Yang, Cheng Jin & Zhen-man Wei (2015) Predictors of liver failure in primary biliary cirrhosis, Upsala Journal of Medical Sciences, 120:1, 47-51, DOI: 10.3109/03009734.2014.985763 To link to this article: https://doi.org/10.3109/03009734.2014.985763 © Informa Healthcare Published online: 28 Nov 2014. Submit your article to this journal Article views: 553 View related articles View Crossmark data Citing articles: 3 View citing articles https://www.tandfonline.com/action/journalInformation?journalCode=iups20 https://www.tandfonline.com/loi/iups20 https://www.tandfonline.com/action/showCitFormats?doi=10.3109/03009734.2014.985763 https://doi.org/10.3109/03009734.2014.985763 https://www.tandfonline.com/action/authorSubmission?journalCode=iups20&show=instructions https://www.tandfonline.com/action/authorSubmission?journalCode=iups20&show=instructions https://www.tandfonline.com/doi/mlt/10.3109/03009734.2014.985763 https://www.tandfonline.com/doi/mlt/10.3109/03009734.2014.985763 http://crossmark.crossref.org/dialog/?doi=10.3109/03009734.2014.985763&domain=pdf&date_stamp=2014-11-28 http://crossmark.crossref.org/dialog/?doi=10.3109/03009734.2014.985763&domain=pdf&date_stamp=2014-11-28 https://www.tandfonline.com/doi/citedby/10.3109/03009734.2014.985763#tabModule https://www.tandfonline.com/doi/citedby/10.3109/03009734.2014.985763#tabModule Upsala Journal of Medical Sciences. 2015; 120: 47–51 ORIGINAL ARTICLE Predictors of liver failure in primary biliary cirrhosis PAN ZHAO1,8, WEI-WEI LIU2, JIN-FENG LI3, CHUN-YA WANG4, HAO WANG5, JUN XU6, RUI-FANG WANG7, HAO-ZHEN YANG8, CHENG JIN1 & ZHEN-MAN WEI1 1Clinical Trial Center, Beijing 302 Hospital (PLA 302 Hospital), Beijing 100039, China, 2Postgraduate Division, Academy of Military Medical Science, Beijing 100850, China, 3Radiology Department, PLA General Hospital, Beijing 100853, China, 4Emergency & Critical Care Center, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China, 5Medical Information Center, Beijing 302 Hospital (PLA 302 Hospital), Beijing 100039, China, 6Clinical Laboratory, Beijing 302 Hospital (PLA 302 Hospital), Beijing 100039, China, 7Ultrasonography Department, Beijing 302 Hospital (PLA 302 Hospital), Beijing 100039, China, and 8Liver Failure Therapy and Research Center, Beijing 302 Hospital (PLA 302 Hospital), Beijing 100039, China Abstract Background. The disease progression of patients with primary biliary cirrhosis (PBC) varies significantly, and the prognostic markers that identify those patients who will develop liver failure have been scarcely studied from a Chinese cohort. Aims. We aimed to determine the predictive factors of liver failure in patients with PBC. Methods. Patients who were first diagnosed as PBC with hepatic compensation between January 2007 and December 2009 were enrolled in this cohort study. Results. Altogether 398 patients were finally included. Of these patients, 80% were women, 98% had positive antimitochondrial antibodies, and 45% had positive antinuclear antibodies (ANA). To December 2012, a total of 38 patients developed liver failure. According to the outcome, patients who developed liver failure had had higher serum concentration of baseline total bilirubin (TBil) (p = 0.013) and total bile acid (TBA) (p < 0.001), and lower concentrations of baseline total cholesterol (Tch) (p = 0.008), than patients who did not develop liver failure. Additionally, the proportion of ANA positivity was statistically different between the two groups (p = 0.009). In the established model for predicting liver failure in PBC, three variables were finally selected out, including Tch (odds ratio (OR) 0.552, 95% confidence interval (CI) 0.394–0.774, p < 0.001), TBA (OR 1.006, 95% CI 1.002–1.010, p = 0.002), and ANA (+ versus –, OR 5.518, 95% CI 1.155–26.376, p = 0.032). Conclusions. ANA, Tch, and TBA are predictors of liver failure in PBC. Key words: Primary biliary cirrhosis, liver failure, predictor Introduction Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by the destruction of intra- hepatic bile ducts, which can lead to hepatic cirrhosis and eventually liver failure and death (1,2). Urso- deoxycholic acid (UDCA) is the only drug accepted internationally for the treatment of PBC (3-5). How- ever, a recent meta-analysis of 16 randomized clinical trials demonstrated no significant benefits of UDCA on all-cause mortality or liver transplantation in patients with PBC (6). In fact, the disease progression varies markedly among patients with PBC (7); more- over, substantial divergences of clinical characteristics exist because of variations in the populations under different studies (8,9). Thus, it is necessary in the early stage to determine the prognostic variables asso- ciated with the development of end-stage liver disease, so that physicians can closely monitor the disease progress and adjust treatment measures in a timely manner before fatal events occur. In the present study, we aim to study the clinical characteristics Correspondence: Zhen-man Wei, No. 100 of West Fourth Ring Middle Road, Beijing, China. E-mail: weizhenman@sina.com (Received 21 May 2014; accepted 4 November 2014) ISSN 0300-9734 print/ISSN 2000-1967 online � 2014 Informa Healthcare DOI: 10.3109/03009734.2014.985763 http://informahealthcare.com/journal/ups mailto:weizhenman@sina.com and risk factors associated with the development of liver failure in a prospective cohort with PBC. Patients and methods Patients Patients who were first diagnosed as PBC with hepatic compensation between January 2007 and December 2009 in Beijing 302 Hospital were enrolled in this cohort study. All of these included patients had received UDCA therapy at the initial diagnosis of PBC. Exclusion criteria included the concurrence of autoimmune hepatitis or extra-hepatic autoim- mune diseases; infection with hepatitis A, B, C, D, E, Epstein–Barr virus, cytomegalovirus, or human immunodeficiency virus; the presence of other forms of liver diseases such as alcoholic liver disease, drug- induced hepatitis, or Wilson’s disease; the use of corticosteroids or immunosuppressive drugs for a period of more than 2 weeks; and UDCA non-respon- ders. Liver failure in this study was defined as coagulopathy (prothrombin activity (PTA) £40% or international normalized ratio (INR) ‡1.5) and jaun- dice (serum total bilirubin (TBil) ‡171 mmol/L or a daily increase ‡17.1 mmol/L). The study was performed in accordance with the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the ethics committee of Beijing 302 Hospital. Laboratory tests Biochemical profiles, including alanine aminotrans- ferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), albumin, total choles- terol (Tch), and total bile acid (TBA) were measured using standard laboratory procedures. Normalized serum concentrations of ALT, AST, TBil, GGT, ALP, albumin, Tch, and TBA were, respectively, <40 U/L, <40 U/L, <17.1 mmol/L, 7–32 U/L, 40–150 U/L, 35–55 g/L, 2.8–5.2 mmol/L, and 0–10 mmol/L. Serum autoantibodies, including antimitochondrial antibodies (AMA) and antinuclear antibodies (ANA), were tested using indirect immunofluorescence with standardmethods(EuroimmunMedizinnischeLabor- diagnostika AG, Lubeck, Germany), and sera were consideredtobepositivewhentheyproducedareaction at a dilution of ‡1:100. Immunoglobulin (Ig) was assayed by means of immunological turbidometry (Diasys Diagnostic Systems, Shanghai, China). Normal serum concentrations of IgA, IgG, and IgM were 0.69–3.28 g/L, 7.23–16.6 g/L, and 0.63–2.77 g/L, respectively. Statistical analysis Data analyses were performed using SAS 9.2 software (SAS Institute Inc., Cary, NC, USA). Continuous data were expressed as medians (interquartile range). Categorical data were expressed as the number of subjects. Group comparisons were performed using the Wilcoxon rank sum test for continuous variables, and chi-square test or Fisher exact test for categorical variables. Logistic regression was used for evaluating prognostic predictors of liver failure. A probability (p) value of less than 0.05 was considered statistically significant. Results Demographic and clinical characteristics Finally, 398 patients were included. In these patients, 317 (80%) were female and 81 (20%) were male. The average age was 57 (12) years. A total of 389 patients had positive AMA, and 9 had negative AMA; 182 patients had positive ANA, and 216 had negative ANA. In the years 2007, 2008, and 2009, 80, 147, and 171 patients were enrolled (Figure 1). To December 2012, a total of 38 patients had developed liver failure (Figure 2). Univariate analysis for baseline variables in PBC According to the outcome, patients who developed liver failure had had higher serum concentrations of baseline TBil (43.7 mmol/L versus 23.2 mmol/L, p = 0.013) and TBA (92.5 mmol/L versus 46.0 mmol/L, p < 0.001) and lower serum concentra- tions of baseline Tch (3.09 mmol/L versus 4.52 mmol/L, p = 0.008) than patients who did not develop liver failure (Table I). In addition, the pro- portion of ANA positivity differed between the two groups. Thus, a majority of the patients who devel- oped liver failure had positive ANA (65.79% versus 43.61%, p = 0.009). Predictors of liver failure in PBC Three variables were eventually selected out to predict the development of liver failure in PBC using logistic regression, including Tch (odds ratio (OR) 0.552, 95% confidence interval (CI) 0.394–0.774, p < 0.001), TBA (OR 1.006, 95% CI 1.002–1.010, p = 0.002), and ANA (+ versus –, OR 5.518, 95% CI 1.155–26.376, p = 0.032) (Table II). 48 P. Zhao et al. Discussion PBC is a chronic and progressive cholestatic disease, and its pathogenesis remains unclear (10-12). Due to lack of curative therapeutics, liver failure is an evitable severe outcome in the majority of such patients. So, studying factors associated with the development of liver failure has vital and practical value. Beijing 302 Hospital is the largest hospital specializing in hepatology in China. Therefore, such an investigation on the risk of incipient liver failure in a large number of PBC patients possesses certain representativeness. Previous studies have shown that patients with PBC often have higher serum concentrations of cholesterol (13-15). Because the synthetic and metabolic process of cholesterol is closely associated with the function of the liver, the development and progression of liver diseases can influence the serum concentrations of cholesterol. In our study, patients with lower total serum cholesterol concentrations were more likely to develop liver failure than patients with higher concentrations. TBA has been less studied than other serum mar- kers in the evaluation of the prognosis of PBC. Based on our study, it was an independent risk factor for liver failure in PBC. As previously shown, cholestasis is a main physiopathological characteristic of PBC. It can cause the accumulation of hydrophobic bile acids in the liver, which are toxic to cellular membranes (16,17). So, an increase of serum TBA may mirror the disease severity in PBC. It has been reported that ANA can be found in 30%–50% of all PBC patients, and disease-specific ANA are associated with a more severe and rapidly progressing disease (18-20). In the present study, ANA were detected in 46% of the patients and proved to be related to the occurrence of liver failure. Regard- ing other early variables, such as ALP, GGT, and IgM, no correlations with the development of liver Year C u m u la ti v e i n c id e n c e o f li v e r fa il u re ( % ) 2007 2008 2009 2010 2011 2012 10 8 6 4 2 0 Figure 2. Cumulative incidence of liver failure in patients with primary biliary cirrhosis during follow-up. Evaluation of clinical information at entry Exclusion criteria: (I) Concurrence of autoimmune hepatitis or extra-hepatic autoimmune diseases; (II) Infection with hepatitis A, B, C, D, E, Epstein-bar virus, cytomegalovirus or human immunodeficiency virus; (III) Presence of other forms of liver diseases such as alcoholic liver disease, drug-induced hepatitis or Wilson’s disease; (IV) Use of corticosteroids or immunosuppressive drugs (≥ 2weeks); (V) Non-responders to ursodeoxycholic acid 398 patients with hepatic compensation were enrolled, including 80 in the year of 2007, 147 in 2008 and 171 in 2009 Follow-up: check-up in hospital pr telephone interview A total of 38 patients developed liver failure to December 2012 Figure 1. Patient enrollment. Predictors of liver failure in primary biliary cirrhosis 49 failure were observed, though some of them had definitely diagnostic value. In conclusion, ANA positivity, a lower serum con- centration of Tch, and higher serum concentration of TBA are all associated with the development of liver failure in PBC. Acknowledgements We are grateful to Professor Yu-kun Han and Dr Xin-ying Liu for their great help in the patient enrollment. Zhen-man Wei was the guarantor; Pan Zhao designed the study; Wei-wei Liu, Jin-feng Li, and Pan Zhao analyzed the data; Hao-zhen Yang and Pan Zhao enrolled the patients; Pan Zhao, Hao Wang, Jun Xu, Rui-fang Wang, and Cheng Jin collected the data; Pan Zhao and Chun-ya Wang wrote the manuscript. All authors read and approved the final manuscript. Pan Zhao, Wei-wei Liu, Jin-feng Li and Chun-ya Wang contributed equally to this work. Declaration of interest: This work was partly supported by the 302 Hospital Research Project (YNKT2013009). The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References 1. Czul F, Peyton A, Levy C. 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