Study Design and Characteristics
A thorough literature search, according to the previously established medical terms, yielded a total of 224 articles from the Western literature and 26 from the Chinese literature. Title screening precluded 176 of these articles (78.6%). The abstracts of the remaining 48 articles were read, and 11 articles were excluded. The full texts of the remaining 37 articles were retrieved. Studies that lacked a control group, verified evaluation system or randomization were excluded (Figure 1). Finally, 12 studies were included, six from Western sources and six from China. These 12 studies could also be categorized into groups by UDCA dosage, or by UDCA Monotherapy or UDCA combined with other drugs. All 12 studies included end-point results presented as concrete data or change in liver function and histology.
Summary of the article selection process.
The excluded articles included several informative studies. In one excluded study, published in Spanish, three patients were treated with UDCA for 1 year, with one showing ALT and AST normalization. Another excluded study, from the Cochrane Library, showed that UDCA plus pentoxyphylline had significant effects on ALT normalization and hepatic inflammation improvement. A third study showed that UDCA was more effective than gemfibrozil in improving biochemical parameters in patients with NASH patients. However, the full texts of the latter two articles were unavailable. One overlap study used the data from one trial to investigate concentrations of adipokines and apoptosis. Another, which reported that long-term treatment with UDCA and vitamin E significantly improved ALT, AST, and γGT concentrations and NASH score, as well as being well tolerated, had to be excluded because of a lack of a placebo control. Finally, a study comparing the effects of UDCA plus vitamin E with diet and weight management, which found significant ALT normalization in the former group, had to be excluded because of its retrospective design and the absence of histological evaluation after treatment.
The 12 included articles included a total 1160 patients, with average ages ranging from 30.5 to 50.2 years (Table 1). Six studies were from China, one from Turkey and five from Western countries. The trials were performed between 1996 and 2011, with seven trials assessing UDCA Monotherapy and five evaluating UDCA with additional agents, including vitamin E, polyene phosphatidylcholine, silymarin, glycyrrhizin and tiopronin. The duration of treatment ranged from 3 to 24 months. Two studies evaluated high-dose UDCA and six used specific drugs instead of placebo as a control. One study included three patient groups: UDCA plus vitamin E, UDCA alone and control. Compared with the control group, both treatment groups showed significant ALT improvements, with the UDCA plus vitamin E group also showing alleviation of steatosis. Therefore, the trials were separated into separate categories, including those testing UDCA Monotherapy, UDCA and vitamin E, and UDCA with other drugs.
Because of the stringency of this systematic review, we evaluated the methodological quality of the 12 included trials using a five-point quality scale, as described in the Methods section (Table 2). The average score for all 12 articles was 2.69, with the score being significantly lower for articles from China than for those from Western countries (2.2 ± 0.4 vs. 3.8 ± 1.1, respectively, p < 0.05). Only three articles adequately described the randomization procedure: two from Western countries and one from China (19,27,31). In most articles from Western countries, two to seven patients withdrew from the study, with withdrawals balanced in the treatment and control groups. In the Chinese articles, however, either no patient withdrew or the number was not reported, reducing the quality of these studies. Finally, only four of the 12 studies, all from Western countries, used double blinding. These drawbacks precluded a meta-analysis, resulting instead in a clinical review.
Outcome of Enrolled Studies
The studies tested UDCA Monotherapy or UCDA in combination with other drugs (Table 3). UDCA Monotherapy was found to significantly improve liver function, including ALT, AST or γGT, in five studies and to reduce steatosis and fibrosis in two studies. All five studies of UDCA combination therapy found significant improvements in liver function, with two also showing improvements in steatosis and inflammation. These data suggested that UDCA combination therapy was superior to UDCA Monotherapy in the treatment of NASH. The results of high-dose UDCA were contradictory, as one study found significant improvements in ALT, γGT and liver fibrosis while the other found no significant changes in ALT and liver pathology, as shown by the Brunt score and NAS score. Finally, improvements in liver function were easier to assess than improvements in liver histology, as eight of 12 studies reported liver function improvement while only four of 12 showed improvements in liver histology.
Several studies also found that UDCA alleviated metabolic markers in patients with NASH. For example, patients treated with high-dose UDCA showed significant reductions in serum glucose, glycosylated hemoglobin and insulin concentrations, as well a greater ability to reduce triglyceride concentrations than clofibrate. The combinations of UDCA with glycyrrhizin and tiopronin showed additive triglyceride lowering effects when compared with either drug alone.