Please wait a minute...
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front Med    2013, Vol. 7 Issue (2) : 255-263     DOI: 10.1007/s11684-012-0227-1
Observation on therapeutic efficacy of ursodeoxycholic acid in Chinese patients with primary biliary cirrhosis: a 2-year follow-up study
Jiangyi Zhu1, Yongquan Shi1, Xinmin Zhou1, Zengshan Li2, Xiaofeng Huang2, Zheyi Han1, Jianhong Wang1, Ruian Wang2, Jie Ding1, Kaichun Wu1, Ying Han1(), Daiming Fan1()
1. State Key Laboratory of Cancer Biology, Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, ?China; 2. Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
Download: PDF(544 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

The efficacy of ursodeoxycholic acid (UDCA) on long-term outcome of primary biliary cirrhosis (PBC) has been less documented in Chinese cohort. We aimed to assess the therapeutic effect of UDCA on Chinese patients with PBC. In the present study, 67 patients with PBC were treated with UDCA (13–15 mg?kg-1?day-1) and followed up for 2 years to evaluate the changes of symptoms, laboratory values and histological features. As the results indicated, fatigue and pruritus were obviously improved by UDCA, particularly in patients with mild or moderate symptoms. The alkaline phosphatase and γ-glutamyl transpetidase levels significantly declined at year 2 comparing to baseline values, with the most profound effects achieved in patients at stage 2. The levels of alanine aminotransferase and aspartate aminotransferase significantly decreased whereas serum bilirubin and immunoglobulin M levels exhibited no significant change. Histological feature was stable in patients at stages 1–2 but still progressed in patients at stages 3–4. The biochemical response of patients at stage 2 was much better than that of patients at stages 3–4. These data suggest that, when treated in earlier stage, patients in long-term administration of UDCA can gain favorable results not only on symptoms and biochemical responses but also on histology. It is also indicated that later histological stage, bad biochemical response and severe symptom may be indicators of poor prognosis for UDCA therapy.

Keywords primary biliary cirrhosis      ursodeoxycholic acid      Chinese      biochemical response      therapeutic efficacy     
Corresponding Authors: Han Ying,; Fan Daiming,   
Issue Date: 05 June 2013
URL:     OR
Clinical stageHistological stage
Sex ratio(female: male)6∶019∶618∶215∶13∶09∶234∶412∶3
Age at diagnosis (year)38.33±16.2948.64±9.8150.76±7.1957.67±7.2143.00±13.2549.80±8.5351.29±7.6256.93±8.09
Tab.1  The baseline characteristic of PBC patients
Fig.1  The effects of UDCA on fatigue and pruritus of PBC patients. Sixty-seven PBC patients were administrated with UDCA for 2 years at the dose of 13-15 mg?kg?day. Before treatment, 43 and 35 patients presented fatigue (26 mild and moderate, 17 severe) and pruritus (23 mild and moderate, 12 severe) respectively. Fatigue and pruritus were scored as following: grade 1, none; grade 2, mild; grade 3, moderate; grade 4, severe and grade 5, permanent or tough. (A) The scores of fatigue and pruritus before (pre-treatment) and 2 years after treatment (post-treatment) were compared by Wilcoxon signed rank test. * <0.05 vs. pre-treatment. (B and C) Symptomatic patients were divided into 3 groups according to the extent of symptoms: mild (grade 2), moderate (grade 3) and severe (grades 4 and 5). Shown was the percentage of cases whose fatigure (B) or pruritus (C) was aggravated, unchanged or alleviated.
ClinicalstageVariables(normal range)Stage 1Stage 2Stage 3Stage 4
ALT(0-40 IU/L)21.83±7.4621.33±7.1689.63±39.7543.00±9.16*96.66±61.4757.37±33.52*55.33±32.4339.00±23.38
AST(0-40 IU/L)18.75±5.8320.67±5.5991.27±66.5839.66±5.77*92.79±44.6149.50±29.15*76.07±36.1145.01±17.07*
ALP(15-121 IU/L)54.00±10.1544.82±13.99272.09±138.79124.67±28.77*455.73±269.24205.50±72.89*392.07±296.08137.50±43.13*
γ-GT(8-52 IU/L)31.67±12.5529.98±17.20253.45±92.9456.33±34.01*420.91±245.36195.30±108.09*234.67±124.8878.50±60.40*
Albumin(37-55 g/L)43.56±3.7741.91±2.9041.08±2.6638.40±2.3841.50±2.7939.78±4.2836.15±5.6733.13±4.33
Bilirubin(3.4-20.5 μmol/L)10.17±4.4012.63±5.7513.87±5.1412.1±8.0244.74±50.7228.47±14.3541.27±26.0834.73±6.49
Cholesterol(3.5-6.5 mmol/L)4.69±1.574.92±1.565.80±1.526.03±1.676.87±3.806.47±2.164.49±1.193.79±1.02
Prothrombin index(80%-120%)118.67±26.09121.16±24.26125.41±26.87116.86±33.65116.87±27.56107.25±31.2576.78±18.5484.67±21.54
Immunoglobulin M(0.5-3.0 g/L)1.34±0.871.52±0.735.21±3.483.94±2.756.76±6.364.73±2.316.17±5.254.21±2.13
Tab.2  Changes in laboratory variables in patients throughout the study
Fig.2  The dynamic changes of ALP and γ-GT of PBC patients treated with UDCA. Sixty-seven PBC patients were administrated with UDCA for 2 years at the dose of 13-15 mg?kg?day. The ALP (A) and γ-GT (B) levels were measured at the indicated time points during 2-year follow-up and plotted according to the clinical stages. The dotted lines represented upper limit of normal ranges.
Histological stageClinical stagePre-treatmentPost-treatment
Stage 1Stage 2Stage 3Stage 4Stage 1Stage 2Stage 3Stage 4
Stage 12---2---
Stage 2121--31-
Stage 3-221-113
Stage 4--12--03
Tab.3  The stage distribution of PBC patients before and after UDCA treatment
Pre-treatmentPost-treatmentStatistic valueP value
Portal inflammation2.64±0.492.07±0.62-2.4190.016*
Piecemeal necrosis2.00±1.041.64±1.01-1.0360.300
Lobular necrosis2.07±1.211.43±1.02-1.6990.089
Ductular proliferation2.00±1.171.14±0.81-1.9160.068
Bridging fibrosis0.86±0.771.79±1.31-2.2840.031*
Tab.4  The histological feature of PBC patients before and after UDCA treatment
Fig.3  Effect of UDCA treatment on histological characteristics. Fourteen PBC patients received liver biopsy before and 2 years after UDCA treatment. Shown are typical cases. (A and C) Before treatment. (B and D) 2 years after treatment. One patient at stage 2 got paired-biopsy pre-(A) and post-treatment (B). Portal inflammatory infiltration lessened significantly after 2-year treatment. Another patient at stage 4 got paired-biopsy pre-(C) and post-treatment (D). Before treatment, bile duct proliferation (arrowhead in C) and inflammatory infiltration was seen in the portal and bridging necrosis formed. After treatment, bile duct proliferation (arrowhead in D) and portal inflammation were significantly alleviative but bridging fibrosis had still progressed 2 years after treatment.
Clinical stageStage 2n/N (%)Stage 3n/N (%)Stage 4n/N (%)Total rate
Paris criteria21/25 (84%) * D12/20 (60%) #7/16 (44%)65.6%
Barcelona criteria22/25 (88%) * D14/20 (70%) #9/16 (56.3%)73.8%
Tab.5  Status of biochemical response in different clinical stages by two criteria
1 Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol 2010; 52(5): 745–758
doi: 10.1016/j.jhep.2009.11.027 pmid:20347176
2 Prince M, Chetwynd A, Newman W, Metcalf JV, James OF. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterology 2002; 123(4): 1044–1051
doi: 10.1053/gast.2002.36027 pmid:12360466
3 Jackson H, Solaymani-Dodara M, Card TR, Aithal GP, Logan R, West J. Influence of ursodeoxycholic acid on the mortality and malignancy associated with primary biliary cirrhosis: a population-based cohort study. J Hepatol 2007; 46: S252–S253
doi: 10.1016/S0168-8278(07)62265-X
4 Poupon R, Chrétien Y, Poupon RE, Ballet F, Calmus Y, Darnis F. Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis? Lancet 1987; 329(8537): 834–836
doi: 10.1016/S0140-6736(87)91610-2 pmid:2882236
5 Lazaridis KN, Talwalkar JA. Clinical epidemiology of primary biliary cirrhosis: incidence, prevalence, and impact of therapy. J Clin Gastroenterol 2007; 41(5): 494–500
doi: 10.1097/01.mcg.0000225653.07932.8f pmid:17450033
6 Poupon RE, Lindor KD, Parés A, Chazouillères O, Poupon R, Heathcote EJ. Combined analysis of the effect of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis. J Hepatol 2003; 39(1): 12–16
doi: 10.1016/S0168-8278(03)00192-2 pmid:12821038
7 Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology 2000; 32(6): 1196–1199
doi: 10.1053/jhep.2000.20240 pmid:11093724
8 van Os E, van den Broek WW, Mulder PG, ter Borg PC, Bruijn JA, van Buuren HR. Depression in patients with primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol 2007; 46(6): 1099–1103
doi: 10.1016/j.jhep.2007.01.036 pmid:17399846
9 Jones DE, Al-Rifai A, Frith J, Patanwala I, Newton JL. The independent effects of fatigue and UDCA therapy on mortality in primary biliary cirrhosis: results of a 9 year follow-up. J Hepatol 2010; 53(5): 911–917
doi: 10.1016/j.jhep.2010.05.026 pmid:20800924
10 Goldblatt J, Taylor PJ, Lipman T, Prince MI, Baragiotta A, Bassendine MF, James OF, Jones DE. The true impact of fatigue in primary biliary cirrhosis: a population study. Gastroenterology 2002; 122(5): 1235–1241
doi: 10.1053/gast.2002.32993 pmid:11984509
11 Goulis J, Leandro G, Burroughs AK. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis. Lancet 1999; 354(9184): 1053–1060
doi: 10.1016/S0140-6736(98)11293-X pmid:10509495
12 Papatheodoridis GV, Hadziyannis ES, Deutsch M, Hadziyannis SJ. Ursodeoxycholic acid for primary biliary cirrhosis: final results of a 12-year, prospective, randomized, controlled trial. Am J Gastroenterol 2002; 97(8): 2063–2070
doi: 10.1111/j.1572-0241.2002.05923.x pmid:12190178
13 Heathcote EJ. Management of primary biliary cirrhosis. The American association for the study of liver disease practice guidelines. Hepatology 2000; 31(4): 1005–1013
doi: 10.1053/he.2000.5984 pmid:10733559
14 Selmi C, Bowlus CL, Gershwin ME, Coppel RL. Primary biliary cirrhosis. Lancet 2011; 377(9777): 1600–1609
doi: 10.1016/S0140-6736(10)61965-4 pmid:21529926
15 Macaluso FS, Licata A, Costantino A, Alessi N, Maida MF, Craxì A, Almasio PL. Natural history of primary biliary cirrhosis: experience from single center in southern Italy. Dig Liver Dis 2012; 44(Supplement 2): S104
doi: 10.1016/S1590-8658(12)60282-5
16 Corpechot C, Abenavoli L, Rabahi N, Chrétien Y, Andréani T, Johanet C, Chazouillères O, Poupon R. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology 2008; 48(3): 871–877
doi: 10.1002/hep.22428 pmid:18752324
17 Parés A, Caballería L, Rodés J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology 2006; 130(3): 715–720
doi: 10.1053/j.gastro.2005.12.029 pmid:16530513
18 Beuers U, Lindor KD. A major step towards effective treatment evaluation in primary biliary cirrhosis. J Hepatol 2011; 55(6): 1178–1180
doi: 10.1016/j.jhep.2011.04.012 pmid:21703168
19 Dilger K, Hohenester S, Winkler-Budenhofer U, Bastiaansen BA, Schaap FG, Rust C, Beuers U. Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and heath. J Hepatol 2012; 57(1): 133–140
doi: 10.1016/j.jhep.2012.02.014 pmid:22414767
20 Duan MQ, Hen F, Wang ZS, Wu ZC, Liu WS. One-year summary report on UDCA treatment for PBC. J Clin Hepatol (Shi Yong Gan zang bing Za zhi) 2009; 12: 50–52 (in Chinese)
21 Eriksson LS, Olsson R, Glauman H, Prytz H, Befrits R, Rydén BO, Einarsson K, Lindgren S, Wallerstedt S, Wedén M. Ursodeoxycholic acid treatment in patients with primary biliary cirrhosis. A Swedish multicentre, double-blind, randomized controlled study. Scand J Gastroenterol 1997; 32(2): 179–186
doi: 10.3109/00365529709000190 pmid:9051880
22 Parés A, Caballería L, Rodés J, Bruguera M, Rodrigo L, García-Plaza A, Berenguer J, Rodríguez-Martínez D, Mercader J, Velicia R. Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. J Hepatol 2000; 32(4): 561–566
doi: 10.1016/S0168-8278(00)80216-0 pmid:10782903
23 Corpechot C, Chrétien Y, Chazouillères O, Poupon R. Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis. J Hepatol 2010; 53(1): 162–169
doi: 10.1016/j.jhep.2010.02.019 pmid:20471130
24 Ma X, Idle JR, Gonzalez FJ. The pregnane X receptor: from bench to bedside. Expert Opin Drug Metab Toxicol 2008; 4(7): 895–908
doi: 10.1517/17425255.4.7.895 pmid:18624678
25 Zollner G, Wagner M, Trauner M. Nuclear receptors as drug targets in cholestasis and drug-induced hepatotoxicity. Pharmacol Ther 2010; 126(3): 228–243
doi: 10.1016/j.pharmthera.2010.03.005 pmid:20388526
26 Kuiper EM, Hansen BE, de Vries RA, den Ouden-Muller JW, van Ditzhuijsen TJ, Haagsma EB, Houben MH, Witteman BJ, van Erpecum KJ, van Buuren HR; Dutch PBC Study Group. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology 2009; 136(4): 1281–1287
doi: 10.1053/j.gastro.2009.01.003 pmid:19208346
27 Corpechot C, Carrat F, Bahr A, Chrétien Y, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology 2005; 128(2): 297–303
doi: 10.1053/j.gastro.2004.11.009 pmid:15685541
28 Wong GL, Hui AY, Wong VW, Chan FK, Sung JJ, Chan HL. A retrospective study on clinical features and prognostic factors of biopsy-proven primary biliary cirrhosis in Chinese patients. Am J Gastroenterol 2005; 100(10): 2205–2211
doi: 10.1111/j.1572-0241.2005.50007.x pmid:16181370
29 Kim WR, Lindor KD, Locke GR 3rd, Therneau TM, Homburger HA, Batts KP, Yawn BP, Petz JL, Melton LJ 3rd, Dickson ER. Epidemiology and natural history of primary biliary cirrhosis in a US community. Gastroenterology 2000; 119(6): 1631–1636
doi: 10.1053/gast.2000.20197 pmid:11113084
30 Locke GR 3rd, Therneau TM, Ludwig J, Dickson ER, Lindor KD. Time course of histological progression in primary biliary cirrhosis. Hepatology 1996; 23(1): 52–56
doi: 10.1002/hep.510230108 pmid:8550048
31 Kuiper EMM, Hansen BE, Lesterhuis W, Robijin RJ, Thijs JC, Engels LG, Koek G, Aparicio MN, Kerbert-Dreteler MJ, van Buuren HR; Dutch PBC Study Group. The long-term effect of ursodeoxycholic acid on laboratory liver parameters in ciochemically non-advanced primary biliary cirrhosis. Clin Res Hepatol Gastroenterol 2011; 35(1): 29–33
doi: 10.1016/j.gcb.2010.07.018 pmid:20810227
32 Corpechot C, Chazouillères O, Poupon R. Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome. J Hepatol 2011; 55(6): 1361–1367
doi: 10.1016/j.jhep.2011.02.031 pmid:21703194
33 Donaldson PT, Baragiotta A, Heneghan MA, Floreani A, Venturi C, Underhill JA, Jones DE, James OF, Bassendine MF. HLA class II alleles, genotypes, haplotypes, and amino acids in primary biliary cirrhosis: a large-scale study. Hepatology 2006; 44(3): 667–674
doi: 10.1002/hep.21316 pmid:16941709
34 Hirschfield GM, Liu X, Xu C, Lu Y, Xie G, Lu Y, Gu X, Walker EJ, Jing K, Juran BD, Mason AL, Myers RP, Peltekian KM, Ghent CN, Coltescu C, Atkinson EJ, Heathcote EJ, Lazaridis KN, Amos CI, Siminovitch KA. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med 2009; 360(24): 2544–2555
doi: 10.1056/NEJMoa0810440 pmid:19458352
35 Ala A, Stanca CM, Bu-Ghanim M, Ahmado I, Branch AD, Schiano TD, Odin JA, Bach N. Increased prevalence of primary biliary cirrhosis near Superfund toxic waste sites. Hepatology 2006; 43(3): 525–531
doi: 10.1002/hep.21076 pmid:16496326
36 Howel D, Fischbacher CM, Bhopal RS, Gray J, Metcalf JV, James OF. An exploratory population-based case-control study of primary biliary cirrhosis. Hepatology 2000; 31(5): 1055–1060
doi: 10.1053/he.2000.7050 pmid:10796879
[1] Yunfang Liu,Zhiping Yang,Jing Cheng,Daiming Fan. Barriers and countermeasures in developing traditional Chinese medicine in Europe[J]. Front. Med., 2016, 10(3): 360-376.
[2] Zhaoyun Zhu,Ting Wang,Dehuan Fu,Yali Gui,Jingkun Wang,Tao Cui. Innovative development path of ethnomedicines: an overview of ethnomedicines in China[J]. Front. Med., 2016, 10(2): 166-177.
[3] Yan Ma,Kehua Zhou,Jing Fan,Shuchen Sun. Traditional Chinese medicine: potential approaches from modern dynamical complexity theories[J]. Front. Med., 2016, 10(1): 28-32.
[4] Jiabo Wang,Zhijie Ma,Ming Niu,Yun Zhu,Qingsheng Liang,Yanling Zhao,Jingyuan Song,Zhaofang Bai,Yaming Zhang,Ping Zhang,Na Li,Yakun Meng,Qi Li,Lushan Qin,Guangju Teng,Junling Cao,Baosen Li,Shilin Chen,Yonggang Li,Zhengsheng Zou,Honghao Zhou,Xiaohe Xiao. Evidence chain-based causality identification in herb-induced liver injury: exemplification of a well-known liver-restorative herb Polygonum multiflorum[J]. Front. Med., 2015, 9(4): 457-467.
[5] Yan Ma,Shuchen Sun,Chung-Kang Peng. Applications of dynamical complexity theory in traditional Chinese medicine[J]. Front. Med., 2014, 8(3): 279-284.
[6] Jian Wang,Biyan Liang,Xiaoping Zhang,Liran Xu,Xin Deng,Xiuhui Li,Lu Fang,Xinghua Tan,Yuxiang Mao,Guoliang Zhang,Yuguang Wang. An 84-month observational study of the changes in CD4 T-lymphocyte cell count of 110 HIV/AIDS patients treated with traditional Chinese medicine[J]. Front. Med., 2014, 8(3): 362-367.
[7] Guozheng Li,Xuewen Zuo,Baoyan Liu. Scientific computation of big data in real-world clinical research[J]. Front. Med., 2014, 8(3): 310-315.
[8] Yang Zhang,Yuji Feng,Zhi Qu,Yali Qi,Siyan Zhan. Current situation and challenge of registry in China[J]. Front. Med., 2014, 8(3): 294-299.
[9] Yixin Zhong,Baoyan Liu,Hua Qu,Qi Xie. Methodological challenges to human medical study[J]. Front. Med., 2014, 8(3): 328-336.
[10] Li Ma,Baoyan Liu,Qi Xie,Shusong Mao,Zhiwei Cui. Ontological reconstruction of the clinical terminology of traditional Chinese medicine[J]. Front. Med., 2014, 8(3): 358-361.
[11] Runshun Zhang,Yinghui Wang,Baoyan Liu,Guangli Song,Xuezhong Zhou,Shizhen Fan,Xishui Pan. Clinical data quality problems and countermeasure for real world study[J]. Front. Med., 2014, 8(3): 352-357.
[12] Xuezhong Zhou,Yubing Li,Yonghong Peng,Jingqing Hu,Runshun Zhang,Liyun He,Yinghui Wang,Lijie Jiang,Shiyan Yan,Peng Li,Qi Xie,Baoyan Liu. Clinical phenotype network: the underlying mechanism for personalized diagnosis and treatment of traditional Chinese medicine[J]. Front. Med., 2014, 8(3): 337-346.
[13] Junhua Zhang,Boli Zhang. Clinical research of traditional Chinese medicine in big data era[J]. Front. Med., 2014, 8(3): 321-327.
[14] Guanli Song,Yinghui Wang,Runshun Zhang,Baoyan Liu,Xuezhong Zhou,Xiaji Zhou,Hong Zhang,Yufeng Guo,Yanxing Xue,Lili Xu. Experience inheritance from famous specialists based on real-world clinical research paradigm of traditional Chinese medicine[J]. Front. Med., 2014, 8(3): 300-309.
[15] Dan Xiao, Nanshan Zhong, Chunxue Bai, Qingyu Xiu, Canmao Xie, Dayi Hu, Yun Mao, Roland Perfekt, Elisabeth Kruse, Qing Li, John Jiangnan Liu, Chen Wang. Nicotine gum or patch treatment for smoking cessation and smoking reduction: a multi-centre study in Chinese physicians[J]. Front Med, 2014, 8(1): 84-90.
Full text