Links To And Excerpts From “Vibration-controlled Transient Elastography to Assess Fibrosis and Steatosis in Patients With Nonalcoholic Fatty Liver Disease”

In this post I link to and excerpt from Vibration-controlled Transient Elastography to Assess Fibrosis and Steatosis in Patients With Nonalcoholic Fatty Liver Disease [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. Clin Gastroenterol Hepatol. 2019 Jan; 17(1): 156–163.e2.

The above article has been cited by 69 articles in PubMed Central.

All that follows is from the above resource.

Abstract

Background & aims: Vibration-controlled transient elastography (VCTE), which measures liver stiffness, has become an important tool for evaluating patients with nonalcoholic fatty liver disease (NAFLD). We aimed to determine the diagnostic accuracy of VCTE in detection of NAFLD in a multicenter cohort of patients.

Methods: We performed a prospective study of 393 adults with NAFLD who underwent VCTE within 1 year of liver histology analysis (median time, 49 d; interquartile range, 25-78 d), from July 1, 2014, through July 31, 2017. Liver stiffness measurement (LSM) cut-off values for pairwise fibrosis stage and controlled attenuation parameter cut-off values for pairwise steatosis grade were determined using cross-validated area under the receiver operating characteristics curve (AUROC) analyses. Diagnostic statistics were computed at a sensitivity fixed at 90% and a specificity fixed at 90%.

Results: LSM identified patients with advanced fibrosis with an AUROC of 0.83 (95% CI, 0.79- 0.87) and patients with cirrhosis with an AUROC of 0.93 (95% CI, 0.90-0.97). At a fixed sensitivity, a cut-off LSM of 6.5 kPa excluded advanced fibrosis with a negative predictive value of 0.91, and a cut-off LSM of 12.1 kPa excluded cirrhosis with a negative predictive value of 0.99. At a fixed specificity, LSM identified patients with advanced fibrosis with a positive predictive value of 0.71 and patients with cirrhosis with a positive predictive value of 0.41. Controlled attenuation parameter analysis detected steatosis with an AUROC of 0.76 (95% CI, 0.64-0.87). In contrast, the VCTE was less accurate in distinguishing lower fibrosis stages, higher steatosis grades, or the presence of NASH.

Conclusions: In a prospective study of adults with NAFLD, we found VCTE to accurately distinguish advanced vs earlier stages of fibrosis, using liver histology as the reference standard.

Keywords: Controlled Attenuation Parameter; Fibroscan; Fibrosis; NAFLD; Steatosis; VCTE; Vibration Controlled Transient Elastography.

Abbreviations
NAFLD Nonalcoholic Fatty Liver Disease
NASH Nonalcoholic Steatohepatitis
NASH CRN NASH Clinical Research Network
VCTE Vibration Controlled Transient Elastography
LSM Liver Stiffness Measurement
CAP Controlled Attenuation Parameter
IQR Interquartile range

INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in the U.S¹. NAFLD exists as two predominant histological subtypes: nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH)². NAFL is associated with a relatively benign clinical course, while NASH is associated with increased risk of progressive fibrosis and cirrhosis³. In NAFLD, liver biopsy remains the gold standard for diagnosis, assessing activity and staging fibrosis. However, routine use of liver biopsy is limited by its invasive nature, risk of complications, cost, sampling error, and poor patient acceptance^4,5. This underscores an urgent need for non-invasive and accurate methods for disease detection and staging. Although, there are currently no reliable non-invasive means of differentiating NAFL from NASH, non-invasive models that correlate with individual histological parameters have been developed^6,7. Hepatic steatosis and fibrosis are two of the most studied histological parameters as they are essential in disease diagnosis and staging, respectively. While several non-invasive methods for assessing steatosis and fibrosis have been evaluated, these all have major limitations⁸.

Vibration controlled transient elastography (VCTE) measures the speed of a mechanically generated shear wave across the liver to derive a liver stiffness measurement (LSM), a marker of hepatic fibrosis⁹. Measuring the attenuation of ultrasound signal through the liver is used to derive the Controlled Attenuation Parameter (CAP), which is measured simultaneously with LSM as a marker of hepatic steatosis¹⁰. The performance of VCTE using the standard M probe in NAFLD was limited by high failure rates in patients with higher body mass index (BMI) and skin to liver capsule distance¹¹. To circumvent the high failure rate in obese patients, an XL probe was developed¹². To further reduce the failure rate and standardize methodology, Fibroscan 502 Touch®, a probe selection software tool that automatically determines the choice of the probe based on skin to capsule distance, has been developed. With these improvements, the failure rate of VCTE was reported to be <5%¹³. Despite the growing literature with VCTE in NAFLD, there are only a few single center studies evaluating the accuracy of both M and XL probes in American cohorts^14,15. The aim of the current study is to examine the diagnostic accuracy of VCTE in assessing steatosis and fibrosis in a multi-center cohort of American adults with biopsy proven NAFLD.

METHODS

Study Design

All subjects included in this study were prospectively enrolled as part of the NIH funded NASH Clinical Research Network (NASH CRN) NAFLD Database 2 study with inclusion and exclusion criteria as previously reported¹³. Eligible adult subjects (age ≥ 18 years) were enrolled across eight medical centers in the United States¹³. All subjects had biopsy-proven NAFLD within twelve months of the VCTE examination. Data were stored, monitored and analyzed at the Data Coordinating Center at the John Hopkins Bloomberg School of Public Health. The Institutional Review Boards at participating centers approved the study (NCT01030484) and all participants provided written informed consent prior to enrollment. All authors reviewed and approved the manuscript prior to submission. This study was conducted according to Transparent Reporting of a multivariate prediction model for Individual Prognosis or Diagnosis for biomarker development (see supplementary material)¹⁶.

Study Visit and Procedures

All subjects were evaluated at their respective medical center by a study investigator and research nurse after an overnight fast. LProtocol driven anthropometric measurements, study-specific questionnaires, and blood tests were collected. All eligible subjects underwent VCTE examinations between July 1, 2014 and July 31, 2017.

Liver Biopsy

All liver biopsies were scored for features of NAFLD using the NASH CRN scoring system by the Pathology Committee of the NASH CRN, who were blinded to the VCTE and clinical data². Hepatic steatosis was graded ordinally from 0-3 [grade 0=<5% steatosis; grade 1=5-33% steatosis, grade 2=34-66% steatosis; grade 3=≥67% steatosis]. Hepatic fibrosis was quantified from stages 0-4 and for the purposes of this analysis advanced fibrosis was defined as fibrosis stage≥3 with cirrhosis as stage 4. The presence of definite NASH was defined according the NASH CRN criteria². Portal inflammation, lobular inflammation and cytological ballooning was graded ordinally according the NASH CRN histological scoring system.

Vibration Controlled Transient Elastography (VCTE)

VCTE was performed using Fibroscan® 502 Touch, which were provided by Echosens (Paris, France) to all the NASH-CRN sites through a Clinical Trial Agreement with the NIDDK.

Trained study coordinators or principal investigators performed all VCTE examinations using a standardized protocol¹³. Subjects were placed in supine position with the right arm in maximal abduction and measurements were taken over the right hepatic lobe through an intercostal space¹³. All studies were started using the M probe with transition to the XL probe only if prompted by the device’s automatic probe selection tool.

Discussion

An important unmet need in NAFLD is a point-of-care
test that can aid in the detection and identification of
advanced fibrosis. VCTE can detect steatosis and fibrosis
simultaneously, but there is a paucity of data defining the
optimal use of VCTE in American cohorts.14,15 The current
study evaluated the diagnostic accuracy of VCTE in a
multicenter cohort with histologically confirmed NAFLD
to assess parameters for clinical use by identifying
thresholds that are highly sensitive or specific.

In NAFLD, hepatic fibrosis is a key predictor of liver related outcomes3,17 and VCTE can be used to detect
fibrosis, especially in its advanced stage. Although VCTE is
not a confirmatory test, it can help identify patients in whom
additional histologic assessment may be warranted, while
avoiding liver biopsies in patients with none to minimal
fibrosis. Identifying optimal cut-off values of VCTE depends
on the context of use for VCTE. Noninvasive biomarkers aim
to either minimize false negatives (ie, high sensitivity) or to
minimize false positives (ie, high specificity), depending on
whether VCTE is being used as a screening modality or a tool
to identify NAFLD patients with fibrosis with a great degree
of certainty.

Moderate fibrosis is linked to liver-related
outcomes and mortality,17 and a LSM less than 5.6 kPa has
a NPV of 80% for excluding moderate fibrosis. Similarly, a
less invasive approach can be used in patients with a LSM
less than 6.5 kPa because the presence of advanced fibrosis
can be excluded with at least 91% certainty. Higher LSM
values allow for greater specificity and can be used to
identify individuals in whom additional confirmatory histologic assessment may be warranted. Furthermore, we also
applied the cut-off values proposed by the Baveno IV
consensus for the detection of advanced fibrosis in our
cohort and the published data.15,18 The cut-off value of
greater than 9.9 kPa had a PPV of 46% and 64% for
detecting advanced fibrosis in the cohorts studied by Tapper
et al15 and the NASH CRN, respectively (Supplementary
Table 3).

In summary, VCTE is a noninvasive point-of-care tool
that can be used in clinical practice for identifying steatosis and advanced fibrosis in patients with NAFLD. VCTE
may be useful in identifying patients in whom additional
histologic assessment may be warranted owing to the
presence of advanced fibrosis, while excluding patients
without significant fibrosis in whom a liver biopsy may be
unnecessary.