Is liver stiffness measurement to stage fibrosis in patients with nonalcoholic fatty liver disease ready for clinical use?
Authors: Michelle Lai
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. See Article on Page 1101 For a highly prevalent disease such as nonalcoholic fatty liver disease (NAFLD) which presents with a wide range of severity, staging of hepatic fibrosis is key to the clinical evaluation to assess the patient's risk of liver‐related and overall mortality. It is vital to the clinician's, and the patient's, decision‐making process as to how closely to monitor the patient, whether to screen for hepatocellular carcinoma or varices. In addition, as therapeutic options loom on the horizon, the staging of disease will be important in the decision of who and when to treat with a pharmacologic agent. The limitations of the current gold standard, a liver biopsy, including sampling variability and risks of complications, are well recognized.1 With a high disease burden in the general population, the widespread use of a liver biopsy would result in a significant number of complications. The ideal tool for the evaluation and staging of a highly prevalent disease with a wide spectrum of severity such as NAFLD in the clinic is a noninvasive, rapidly performed, point‐of‐care test that allows the clinician to risk‐stratify the patient and make clinical decisions at the time of the clinic visit. Vibration‐controlled transient elastography (VCTE) by FibroScan (Echosens, Paris, France) has the potential to be such a tool. It measures liver stiffness as a surrogate marker of liver fibrosis. It is a rapid test, most validated in viral hepatitis, done at the bedside in the clinic to give an immediate result to inform the clinician and patient for their discussion of management. While it has been shown to be a reproducible and accurate test of liver fibrosis in patients with viral hepatitis, VCTE comes with its own set of limitations.5 Limitations of VCTE include reported short‐term variations and failed or unreliable readings in one‐fifth of patients and in a higher percentage of patients with body mass index (BMI) >30 kg/m2.6 The rate of failed and unreliable readings is of concern in nonalcoholic steatohepatitis where patients have higher BMI. This seems to be addressed with the XL probe, which has a lower fail rate in patients with higher BMI. Nascimbeni et al. reported >20% variations in liver stiffness measurement (LSM) in about half of the 531 patients they studied with chronic liver diseases on short‐term repeat LSM.7 Repeat VCTE had been performed on these patients more than 1 day and less than 1 year after their initial VCTE test. The short‐term variations observed produced a one‐stage difference in about one‐third of the patients and a two‐stage or more difference in another one‐tenth of the patients. They found both operator‐ and patient‐specific factors that were associated with variations. Operator factors associated with variations were having two different operators perform the VCTE and a nonsenior operator perform the VCTE. Patient factors included higher baseline BMI, higher baseline LSM, interquartile range to median ratio, and a two‐fold difference in alanine transaminase between measurements. The time interval between the VCTE testing was not associated with variations. In this issue of Hepatology, Petta et al. present their results from a prospective cohort study of patients from Palermo, Italy, evaluating the impact of severe hepatic steatosis on the LSM using VCTE in patients with NAFLD.8 They found that the median LSM was higher in patients with severe hepatic steatosis compared to those without severe hepatic steatosis for the same stage of fibrosis seen on liver biopsy. All subjects were assessed with a liver biopsy, LSM using VCTE with the M probe, and an ultrasound evaluation of the liver. Of the 306 subjects evaluated, there was unreliable LSM in 53 (17.3%). About one‐third of subjects with BMI >30 kg/m2 had unreliable LSM. Those with reliable LSM were younger, were male, had lower BMI, were less likely to have hypertension or diabetes mellitus, and had less severe steatosis, while those with unreliable LSM had higher BMI and worse metabolic syndrome. In essence, those at higher risk for nonalcoholic steatohepatitis and more significant fibrosis are also the ones who are likely to have unreliable LSM. This is a problem for a couple of reasons. First, it biases the results as the authors do not have reliable data on this subgroup with more severe steatosis to obtain a more accurate assessment of the effect of steatosis on LSM. Second, this tool is limited in the patient population at highest risk for having more severe disease. The authors found that the ideal LSM cutoffs increased by 1.1‐2.2 kPa with severe steatosis. Without accounting for severe steatosis, using a cutoff of 6.9 kPa to determine significant fibrosis would result in 13% of the subjects having false negatives and 17% of the subjects having false positives. Essentially, this would result in misclassification in about one‐third of the patients. What does this mean for clinical application? In evaluating a patient with NAFLD using VCTE, there needs to be quantification of steatosis in order to interpret the LSM score. Using another imaging modality for the quantification of steatosis undermines one of the biggest advantages of VCTE, which is to get an immediate result at the bedside while seeing the patient in the clinic for clinical decision making. The authors of this article also showed that the use of ultrasound to detect severe steatosis performed poorly, with a sensitivity rate of 48.6%. Echosens has addressed the fat quantification issue by adding the controlled attenuation parameter (CAP) function to the FibroScan machines. The CAP function has been shown to accurately measure the amount of steatosis,9 with an area under the receiver operating characteristic curve of 0.84 for detecting severe steatosis. However, patients with a high BMI also had a higher failure rate of CAP measurements, with a failure rate of 19.4% in patients with BMI >30 kg/m2 and 58.4% in those with BMI >40 kg/m2. Given the prevalence of NAFLD, there is a strong need for an accurate noninvasive tool to risk‐stratify and monitor patients, and VCTE has the potential to be such a tool. However, Petta et al.8 have shown that steatosis can significantly affect the LSM score. We therefore need good data to define the ideal LSM cutoffs in NAFLD for fibrosis staging for the M and XL probes that adjust for the amount of steatosis measured by CAP.