Systematic review with meta‐analysis: non‐invasive assessment of non‐alcoholic fatty liver disease – the role of transient elastography and plasma cytokeratin‐18 fragments

Abstract

Summary Background Non‐alcoholic fatty liver disease (NAFLD) affects 15–40% of the general population. Some patients have non‐alcoholic steatohepatitis (NASH) and progressive fibrosis, and would be candidates for monitoring and treatment. Aim To review current literature on the use of non‐invasive tests to assess the severity of NAFLD. Methods Systematic literature searching identified studies evaluating non‐invasive tests of NASH and fibrosis using liver biopsy as the reference standard. Meta‐analysis was performed for areas with adequate number of publications. Results Serum tests and physical measurements like transient elastography (TE) have high negative predictive value (NPV) in excluding advanced fibrosis in NAFLD patients. The NAFLD fibrosis score comprises of six routine clinical parameters and has been endorsed by current American guidelines as a screening test to exclude low‐risk individuals. The pooled sensitivities and specificities for TE to diagnose F ≥ 2, F ≥ 3 and F4 disease were 79% and 75%, 85% and 85%, and 92% and 92% respectively. Liver stiffness measurement often fails in obese patients, but the success rate can be improved with the use of the XL probe. A number of biomarkers have been developed for the diagnosis of NASH, but few were independently validated. Serum/plasma cytokeratin‐18 fragments have been most extensively evaluated and have a pooled sensitivity of 66% and specificity of 82% in diagnosing NASH. Conclusions Current non‐invasive tests are accurate in excluding advanced fibrosis in NAFLD patients, and may be used for initial assessment. Further development and evaluation of NASH biomarkers are needed.

Imaging-Based Assessment of Steatosis, Inflammation and Fibrosis in NAFLD

“…Overall, SSI performed best for the detection of significant fibrosis, advanced fibrosis and cirrhosis (AUROCs for SSI, FibroScan™ and ARFI were 0.86, 0.82 and 0.77 for diagnoses of ≥ F2; 0.89, 0.86 and 0.84 for ≥ F3; and 0.88, 0.87 and 0.84 for F4; respectively) [45••]. The results are similar to prior individual studies [39,55]. It appears that none of the three imaging methods could accurately predict < F2 fibrosis, so further optimization of ultrasound techniques is needed [45••].…”

“…A recent meta-analysis of the use of TE in patients with NAFLD (9 studies, 1047 patients) suggests that TE has excellent diagnostic accuracy for cirrhosis (92% specificity and 92% sensitivity), good accuracy for F3 (82% specificity and 85% sensitivity), but modest accuracy for F2 (75% specificity, 79% sensitivity) [39]. Despite this, TE can rule out cirrhosis with a high NPV (~90%) [40].…”

“…However, intermediate LSM readings are less accurate, and the choice of a specific cut-off becomes a real balance between specificity and sensitivity. For example, for a diagnosis of cirrhosis, LSM cut-offs between 10.3-17.5 kPa will yield sensitivity of 78 to 100% and specificity of 82 to 98% [39]. Therefore, clinicians may use different cut-offs for different stages of fibrosis in different environments depending whether they want to exclude or diagnose a fibrosis stage with high probability.…”

Editorial: novel association between serum Pentraxin‐2 levels and advanced fibrosis in well‐characterised patients with non‐alcoholic fatty liver disease

“…Considering serum biomarkers in NAFLD, either singly or in combination biomarkers may be a surrogate for the presence and degree of hepatic steatosis or steatohepatitis or may be associated with the presence and progression of liver fibrosis. 3,4 In their proof of concept study, Verna et al 5 identified that serum levels of Pentraxin-2 (PTX-2), a serum protein known to inhibit fibrosis in vitro, 6 appears to be significantly associated with both the presence and progression of NAFLD. Verna et al demonstrate a significant association between PTX-2 levels and the presence of NAFLD, with mean PTX-2 levels being significantly lower in patients with NAFLD compared with normal controls.…”

NAFLD therapy and monitoring disease progression

“…36 The plasma cytokeratin levels are increased in patients with NASH compared to simple steatosis with 66% sensitivity and 82% specificity. 37 However it has limited utility as a single marker to identify NASH. The FIB-4 calculator estimates fibrosis using the patient's age, aminotransferase levels and platelet count.…”