Elsevier

Journal of Hepatology

Volume 66, Issue 5, May 2017, Pages 1022-1030
Journal of Hepatology

Research Article
Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis

https://doi.org/10.1016/j.jhep.2016.12.022Get rights and content

Background & Aims

The prevalence of fatty liver underscores the need for non-invasive characterization of steatosis, such as the ultrasound based controlled attenuation parameter (CAP). Despite good diagnostic accuracy, clinical use of CAP is limited due to uncertainty regarding optimal cut-offs and the influence of covariates. We therefore conducted an individual patient data meta-analysis.

Methods

A review of the literature identified studies containing histology verified CAP data (M probe, vibration controlled transient elastography with FibroScan®) for grading of steatosis (S0–S3). Receiver operating characteristic analysis after correcting for center effects was used as well as mixed models to test the impact of covariates on CAP. The primary outcome was establishing CAP cut-offs for distinguishing steatosis grades.

Results

Data from 19/21 eligible papers were provided, comprising 3830/3968 (97%) of patients. Considering data overlap and exclusion criteria, 2735 patients were included in the final analysis (37% hepatitis B, 36% hepatitis C, 20% NAFLD/NASH, 7% other). Steatosis distribution was 51%/27%/16%/6% for S0/S1/S2/S3. CAP values in dB/m (95% CI) were influenced by several covariates with an estimated shift of 10 (4.5–17) for NAFLD/NASH patients, 10 (3.5–16) for diabetics and 4.4 (3.8–5.0) per BMI unit. Areas under the curves were 0.823 (0.809–0.837) and 0.865 (0.850–0.880) respectively. Optimal cut-offs were 248 (237–261) and 268 (257–284) for those above S0 and S1 respectively.

Conclusions

CAP provides a standardized non-invasive measure of hepatic steatosis. Prevalence, etiology, diabetes, and BMI deserve consideration when interpreting CAP. Longitudinal data are needed to demonstrate how CAP relates to clinical outcomes.

Lay summary

There is an increase in fatty liver for patients with chronic liver disease, linked to the epidemic of the obesity. Invasive liver biopsies are considered the best means of diagnosing fatty liver. The ultrasound based controlled attenuation parameter (CAP) can be used instead, but factors such as the underlying disease, BMI and diabetes must be taken into account.

Registration: Prospero CRD42015027238.

Introduction

Hepatic steatosis is a frequent finding in chronic liver diseases of different etiologies such as viral hepatitis and alcoholic liver disease, and its prevalence is increasing along with the worldwide epidemic of non-alcoholic fatty liver disease (NAFLD) [1], [2], [3], [4].

Recent studies highlight the impact of steatosis on accelerating disease progression to fibrosis and ultimately cirrhosis [5], [6], [7], and demonstrate that steatosis reduces the efficacy of medical therapy [8], [9], especially in the context of the metabolic syndrome [10]. Therefore, steatosis detection and quantification have an increasing relevance both for clinical studies and routine patient care [11].

Liver histology is traditionally considered to be the gold standard for steatosis grading [12], [13], although it can be associated with complications and impaired accuracy due to sampling variability [14]. Furthermore, steatosis severity may change within weeks of therapeutic intervention and, therefore, cannot be sufficiently monitored by repetitive invasive procedures [15]. Imaging techniques provide potential alternatives for non-invasive steatosis characterization, because fat deposits alter the physical properties of liver tissue [11]. Magnetic resonance (MR) based-techniques assess triglyceride specific signal intensity and represent sensitive approaches for steatosis detection [16], but are not suitable as point-of-care methods due to high costs and limited comparability between different MR techniques [17], [18]. B-mode ultrasound displays a bright echo pattern in steatotic hepatic tissue and is widely used as a first-line assessment for screening fatty liver, but is imprecise in estimating the extent of steatosis [11], [19]. These limitations may be overcome by the controlled attenuation parameter (CAP) feature, which has been recently developed to quantify ultrasound attenuation during measurement of liver stiffness vibration controlled elastography (transient elastography; FibroScan®) [20]. CAP measurement is an easy and fast examination providing a numerical value, which correlates with the histological degree of steatosis [21]. During liver stiffness assessment with transient elastography, the CAP algorithm calculates the attenuation of the ultrasound signal and is expressed in dB/m [22]. It has been studied in more than 20 biopsy controlled studies which evaluated its correlation with histologically defined steatosis. However, the routine use of CAP is limited due to uncertainty as to the optimal cut-off values between different steatosis grades and regarding the influence of different covariates [11], [23]. Two recent meta-analyses have addressed these issues and quantified the potential diagnostic value of CAP for non-invasive steatosis grading [24], [25], but could not provide optimized cut-offs with high predictive values due to the heterogeneity of the analyzed studies and the limitations inherent in conventional meta-analyses [26], [27]. Therefore, we conducted an individual patient data meta-analysis (IPDMA) on CAP accuracy for non-invasive grading of liver steatosis.

Section snippets

Paper and patient selection

The term “controlled attenuation parameter” was used in PubMed to locate potential peer-reviewed original articles that were eligible if CAP measurements were taken with the FibroScan® M probe (3.5 MHz) and compared with liver biopsies. As a quality control measure, abstracts were not considered, since the rigor of peer review is lower if at all existent for abstracts. All English language papers available or known to have been accepted for publication by May 2015 were included and the search

Paper and patient selection

Of the initial 155 database hits, a total of 21 papers were identified that were in English language and reported on original histology verified CAP data using the M probe. Authors from all sites were contacted and two did not participate. Data and copies of the ethics committee votes were provided from the authors of all remaining 19 papers [22], [23], [29], [36], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], comprising 3830/3968 (97%) of the

Discussion

The recent advent of the CAP technology permits a standardized, and rapid quantification of steatosis for many patients at regular intervals. Our analysis confirms that the correlation between CAP and histologically determined steatosis is very good, and we were able to establish cut-offs on the basis of comprehensive data. Nonetheless, CAP results disagree with those found by histology in a relevant proportion of patients. Moreover, covariates such as etiology, BMI, and diabetes should be

Financial support

This project is supported in part by the German Federal Ministry of Education and Research (BMBF, FKZ 01EO1001). The company Echosens provided funding, but does not have access to the data, did not influence analyses and did not receive the manuscript before submission.

Conflict of interest

TK, DP, VK and JW received an unrestricted grant from Echosens, Paris France. MS is an Echosens scientific employee in the R&D department, but contributed in her role as scientist and author of papers in this meta-analysis. In particular, MS did not disclose scientific contents of this work to her employer. GF and CF were provided a Fibroscan device for research purposes. VW, GW and SM received lecture fees from Echosens. No other authors have conflicts of interest.

Authors’ contributions

TK, DP, VK, JW: study concept and design, collected data from participating centers, data review and analysis, interpretation of data, drafting of the manuscript, statistical analysis, obtained funding.

MS: study concept and design, drafting of protocol, coded and provided data, interpretation of data, statistical advice, critical revision of the manuscript.

PB: drafting of protocol, interpretation of data, critical revision of the manuscript.

All remaining authors: drafting of protocol, coded and

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    These authors contributed equally to this work.

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