Reply:
Authors: Robert P. Myers
Journal: Hepatology (2012)

We thank Drs. Kemp and Roberts for their interest in our study describing the utility of the FibroScan XL probe for liver stiffness measurement (LSM) in overweight and obese patients with various liver disorders.1 The findings of their single-center Australian study, which included a lighter cohort than our own (mean body mass index [BMI] 26 kg/m2 versus 34 kg/m2), are largely confirmatory of our findings and support the generalizability of our results. First, both studies demonstrated that the XL probe increases the number of reliable LSMs in obese patients (BMI ≥30 kg/m2), while the M probe is sufficiently reliable in lighter individuals. In 16% (16/98) of their cohort, the XL probe produced reliable results despite unreliable findings using the M probe. In our study, 50% of patients had unreliable M probe results, due to the higher prevalence of obesity in our cohort, and 61% of these patients were successfully measured using the XL probe. Second, as in our report, the reliability rate of the M probe was influenced by BMI, particularly in patients with BMI over 35 kg/m2. The XL probe was largely immune to this effect, although we observed reduced reliability in patients with severe obesity (BMI ≥40 kg/m2), which were few in number in Kemp and Roberts' population. Finally, the authors observed lower mean LSMs with the XL probe compared with the M probe (6.1 versus 6.5 kPa). Interestingly, we observed a larger mean LSM difference between probes (2.3 kPa). We hypothesize that this discrepancy relates to greater overestimation of liver stiffness using the M probe caused by subcutaneous adipose tissue in our cohort of heavier patients. This discrepancy was eliminated when our M and XL probe data were recalibrated to measure the same region of interest (i.e., 36-65 mm and 35-75 mm below the skin).1 Drs. Petta and Craxi raise several points regarding our study that require clarification. As they have stated, the XL and M probes had similar diagnostic performance in predicting the severity of fibrosis in patients with successful LSMs using both probes.1 Importantly, because failure occurred in only 1% of patients using the XL probe compared with 16% using the M probe, the XL probe clearly improves the overall accuracy of LSM when one takes an intention-to-diagnose perspective. This finding is obviously crucial considering the rising prevalence of obesity worldwide. Second, Petta and Craxi are concerned that 27% of LSMs using the XL probe were deemed unreliable (compared with 50% using the M probe). It is important to note that this definition of reliability (valid shots ≥10, success rate ≥60%, and IQR/M ≤30%) is based on criteria advocated for the M probe; their applicability to the XL probe is debatable. In fact, we have shown that after adjustment for BMI and liver stiffness, these criteria are not associated with discordance between LSM measured using the XL probe and biopsy, nor performance of transient elastography (TE) as judged by areas under receiver operating characteristics curves (AUROCs).2, 3 In this study, BMI was the only independent predictor of discordance, with a 9% increase (95% confidence interval [CI], 1%-18%) in the odds of discordance per 1-kg/m2 increase in BMI.2 In light of these findings, additional empiric investigation is necessary to determine the optimal TE reliability criteria when using the XL probe. Third, the authors are concerned that our inclusion of patients with chronic viral hepatitis may have led to potentially misleading results regarding the performance of the XL probe in the general population of obese patients, who are largely affected by nonalcoholic fatty liver disease (NAFLD). As table 4 in our study confirms, disease-specific subgroup analyses revealed similar performance in patients with viral hepatitis and NAFLD.1 Importantly, the XL probe was designed for use in any obese patient, not just those with NAFLD. Furthermore, Petta and Craxi are concerned that our failure to assess interobserver reproducibility of TE using the XL probe between the five study centers may have biased our findings. Reassuringly, the study center was not a significant predictor of XL probe reliability in our multivariate analysis, nor did it influence the AUROCs for predicting fibrosis (data not shown).1 Finally, the authors have concluded that there is insufficient evidence to support use of the XL probe in overweight and obese patients, particularly in light of the availability of alternative tools, such as acoustic radiation force impulse imaging (ARFI). Although we agree that ARFI and other noninvasive methods (e.g., magnetic resonance elastography and serum markers) are promising, additional validation is necessary. In a recent meta-analysis of ARFI,4 only nine studies including fewer than 600 patients were identified. Contrary to Petta and Craxi's assertions, none of these studies were designed to specifically address the reliability of ARFI in obese patients (the mean BMI in the individual studies ranged from 24 to 27 kg/m2). Moreover, measurement failure with ARFI actually occurred in 3% of cases. Reported reasons for ARFI failure include high attenuation of the signal in obese patients (making it difficult for the system to identify the shear wave peak consistently as it propagates), excessive tissue motion (e.g., due to cardiac pulsations), and very high stiffness of the tissue impairing the shear wave velocity estimate.5 Moreover, ARFI is available on only a single device (ACUSON S2000; Siemens Healthcare), which limits the universal adoption of this technology. Until comparative studies of TE using the XL probe with tools such ARFI are conducted in obese patients with formal cost-effectiveness analyses, it is premature to define the optimal approach to noninvasive assessment of fibrosis in these patients. Dr. Myers is supported by grants from the Canadian Institutes of Health Research and Alberta Heritage Foundation for Medical Research (now Alberta Innovates – Health Solutions). Robert P. Myers MD, MSc, FRCPC*, * Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.