The main finding of this pooled analysis is that serum ALT and AST declined in placebo-treated patients with NASH. Similar reductions are seen in mean changes in NASH associated histologic parameters. The greatest decline in mean histologic scores is seen in the steatosis score, which is statistically significant. Overall decrease in these parameters is small but depending upon how an outcome measure is defined it may become statistically significant. One point reduction in any of the NASH associated histologic parameters can be seen in up to one-third of patients but two-point improvement in these parameters is rarely seen. This study provides important information regarding the natural history of NASH and supports the notion that serum ALT alone is unreliable as an outcome measure of severity of NASH or efficacy of treatment.
A possible explanation for why placebo-group ALT and AST decreases during follow-up is that these values fluctuate in NASH, and that decisions to biopsy may be based on high(er) ALT values. Thus, the patients who have higher serum ALT values are more likely to receive a liver biopsy or a referral to a tertiary care center and enter into clinical trials (later fluctuating to a lower serum ALT value), while the patients with lower serum ALT values are less likely to receive a liver biopsy or a referral to a tertiary care center and not enter into clinical trials. Therefore, there may be a selection bias in favor of recruiting patients who have higher serum ALT levels into clinical studies. Another explanation for decline in serum ALT and AST during follow-up in placebo treated patients could be due to the phenomenon of regression to the mean. Additionally, one-point improvement in the NASH histologic scores could occur in up to a third of patients possibly because of repeat measurement or sampling variability. Furthermore, it also signifies that up to two-thirds of patients either do not improve or worsen. Therefore, a one-point improvement in an individual NASH score in an individual patient with NASH should not signify a positive treatment effect.
However, if the majority of patients in a treatment-arm achieve a one-point improvement in a particular NASH histologic parameter it may signify a positive drug effect and may be suggestive of mechanism of action of a drug in NASH. In this pooled analysis, we report that a two-point, rather than mean decline or one-point, improvement in the NASH histology parameters is rarely seen in placebo-treated patients and therefore, it may be a more reliable indicator of treatment effect. A two-point decline in one or more parameters of NASH activity index may be better in certain settings. Placebo-treated individuals who achieved a two-point improvement in any histologic parameter may have significantly improved their eating habits or changed their life-style by incorporating regular exercise. However, it was not possible to extract these data from the available studies to evaluate the reasons for these changes. As the ballooning degeneration, lobular inflammation and fibrosis scores did not change in the placebo treated patients, it would be desirable to construct outcome criteria that would not allow improvement in steatosis alone (even a 2 point improvement) to be considered “clinically significant histologic improvement”. In order to suggest “clinically significant histologic improvement” in a clinical trial the cohort as a whole should show improvement in more than one histologic parameter in a consistent manner.
These data have important implications for designing future clinical trials and reporting study results. We propose that future studies utilize composite histologic response criteria as utilized by the NASH-Clinical Research Network or similar previously proposed criteria. This would greatly enhance the generalizability and set a stage for standard approach in nomenclature and reporting in NASH studies that is critically required. In future NASH clinical trials, authors should consider providing detailed changes in histologic scores either as shown by Belfort et al or Lindor et al along with summary estimates. This would facilitate future meta-analyses to estimate true medication (and placebo) effects in diverse international settings.
Although the average BMI in these studies was 31 kg/m2, (in the obese range), there was no weight loss in the placebo-arms on an average. These data suggest that weight loss in placebo-arms is seldom seen in NASH patients.
Strengths of the analysis
The strengths of this study include the good quality level of the studies included in the meta-analysis. The results were uniform across studies with minor variability. The patients included in the meta-analysis were derived from three continents and there was adequate follow-up. Importantly, all patients had biopsy-proven NASH. Additional analyses were conducted to address the effect of treatment duration on the results of the research synthesis.
Limitations of this analysis
Racial/ethnic or gender based differences in these four studies could not be analyzed due to unavailability of these data. Only three studies reported detailed histologic data before and after placebo. The internal validity of histologic findings is satisfactory as most patients were enrolled in these three studies (Lindor et al., Belfort et al. and Ratziu et al.) and these three studies also had a better quality score as described in the Results Section. Studies included in this research synthesis used different histologic criteria for entry into the study and used different end point and histologic scoring systems to assess treatment responses. In addition, the score range for ballooning degeneration and steatosis differs between various NASH histologic scoring system, which makes it difficult to compare the magnitude of change in these parameters across treatment trials. Despite this limitation, unidirectional change consistently across two or three histologic scoring system may be a reliable finding that may be suggestive of true treatment effect. However, this limitation may increase the generalizability of our findings and at the same time underscores the need for standardization of outcomes, histologic scoring system, and reporting in future NASH clinical trials. Due to unavailability of the data, we could not assess the effect of placebo on subjective measures such as fatigue, right upper quadrant pain or quality of life. It is possible that the placebo-treated patients may have received varied nutritional counseling and lifestyle intervention in each study. We believe that it is unlikely to affect the results of our study as none of the trials showed any significant weight loss in placebo patients. This research synthesis is not able to assess the placebo-mind effects and their impact in NASH.
Implications and Conclusions
Serum ALT and AST change during follow-up in NASH patients and may not reflect histologic improvement. Minor improvements in NASH associated histologic scores are seen in up to a third of patients although a two-point improvement in steatosis, ballooning degeneration or lobular inflammation is rarely seen in placebo-treated individuals. These data have important implications for designing and reporting future clinical trials in NASH and suggest a need for standardization of terminologies, histologic scoring system and treatment end-points.