Pentoxifylline improves nonalcoholic steatohepatitis: A randomized placebo-controlled trial

Abstract

Background The primary aim of this study was to compare the effects of pentoxifylline (PTX) versus placebo on the histological features of NASH. Methods 55 adults with biopsy-confirmed NASH were randomized to receive PTX at a dose of 400mg three times a day (n=26) or placebo (n=29) over 1 year. The primary efficacy endpoint was defined as improvement on histological features of NASH through reduction in steatosis, lobular inflammation, and/or hepatocellular ballooning as reflected by a decrease of ≥ 2 points in the NAFLD activity score (NAS). Results After 1 year, intention-to-treat analysis showed a decrease of >=2 points in the NAS in 38.5% of patients on PTX vs 13.8% of those on placebo (p=0.036). Per protocol analysis, a decrease of ≥ 2 points in the NAS from baseline was observed in 50% of the patients on PTX versus 15.4% of those on placebo (p=0.01). The mean change in NAS score from baseline was −1.6 in the PTX group, vs −0.1 in the placebo group (p<0.001). PTX significantly improved steatosis (mean change in score −0.9 vs −0.04 with placebo, p<0.001) and lobular inflammation (median change −1 vs 0 with placebo, p=0.02). No significant effects in hepatocellular ballooning were observed. PTX also improved liver fibrosis (mean change in fibrosis score was −0.2 among those on PTX versus +0.4 among those on placebo, p=0.038). Although not statistically significant (p=0.17), improvement in fibrosis was observed in a greater proportion (35%) of patients in the PTX group compared to placebo (15%). Adverse effects were similar in both groups. Conclusion PTX improved histological features of NASH compared to placebo. PTX was well tolerated in patients with NASH (ClinicalTrials.gov number NCT00590161).

Effects of pentoxifylline on inflammatory markers and blood pressure

“…Three studies investigated the effect of pentoxifylline in patients with nonalcoholic steatohepatitis (NASH) [22,33,34]. In studies conducted by Van Wagner et al 2011 [33] and Zein et al 2011 [34], pentoxifylline treatment did not alter serum TNF-α, concentrations, but improved liver enzymes and histology in patients with NASH, but did not appear to offer substantial benefit over placebo [33] with some benefit in liver fibrosis at one year [34].…”

“…In studies conducted by Van Wagner et al 2011 [33] and Zein et al 2011 [34], pentoxifylline treatment did not alter serum TNF-α, concentrations, but improved liver enzymes and histology in patients with NASH, but did not appear to offer substantial benefit over placebo [33] with some benefit in liver fibrosis at one year [34]. But pentoxifylline therapy reduced hepatic 15 expression of collagen-1, an important fibrogenic gene, and TIMP-1, which is also involved in fibrosis, however the latter effect was not statistically significant.…”

“…Thus pentoxifylline could have potential benefit on fibrosis. Both studies concluded that pentoxifylline treatment is well tolerated [33,34] In patients with coronary artery disease, pentoxifylline treatment has been shown to be associated with a statistically significant reduction in pro-inflammatory response (decreased CRP and TNF-α) and a trend towards increased concentrations of the anti-inflammatory mediator TGF-beta1. Although this study was small and did not measure clinical events, it nevertheless showed an anti-inflammatory effect of pentoxifylline treatment [23].…”

“…After assessment, 15 RCTs achieved the inclusion criteria and were used for the final meta-analysis [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] and these reported 18 treatment arms. A total of 739 individuals participated in the selected trials and 377 of them were allocated to the pentoxifylline group and 362 subjects to control group.…”

Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials

“…Seven RCTs (639 participants, 21% diabetic; three RCTs with post-treatment histology, five RCTs with a low risk of bias) evaluated UDCA in NAFLD (ESM Table 5) [82][83][84][85][86][87][88].…”