The European Association for the Study of the Liver (EASL) guidelines on the use of non-invasive tests for the evaluation of liver diseases provide the latest updates on evaluation, severity, and prognosis. This article covers the key recommendations for non-invasive tests from the panel.

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Non-invasive tests 

Non-invasive tests (NITs) are important tools for the evaluation of liver disease severity and prognosis. The tests can be blood-based tests, methods assessing physical properties of the liver tissue such as liver stiffness, viscosity, and imaging methods that assess the anatomy of the liver and other abdominal organs.

In order to attain correct diagnoses and risk stratification, NITs need to be integrated with liver biopsy/invasive diagnostic methods, and clinical acumen.

The EASL has published clinical practice guidelines on the use of non-invasive tests for the evaluation of liver disease severity and prognosis. The guidelines provide recommendations on:

• Identification of advanced liver fibrosis
• Liver disease severity
• Prognosis in patients with chronic hepatitis B
• Alcohol abuse issues
• Non-alcoholic fatty liver disease
• Cholestatic and autoimmune liver disease
• Assessment of advanced chronic liver disease (cACLD) and portal hypertension

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General population

Non-invasive scores in patients at risk of liver disease from low-prevalence populations

In low-prevalence populations, non-invasive fibrosis tests are recommended to be used for ruling out advanced fibrosis. Non-invasive fibrosis tests should be specifically used in patients at risk of advanced liver fibrosis such as patients with metabolic risk factors and/or harmful use of alcohol.

Non-invasive scores, serum markers, liver stiffness and imaging methods can identify advanced fibrosis in patients at risk from low-prevalence populations significantly better than clinical acumen alone.

Individuals at risk of advanced fibrosis should be entered into appropriate risk stratification pathways using non-invasive fibrosis tests. It is recommended to consult a liver specialist for the selection of NITs and the design of diagnostics in such cases.

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Alcohol-related liver disease (ALD)

Non-invasive scores, serum markers, liver stiffness, and imaging methods for the diagnosis of ALD (liver fibrosis, alcoholic hepatitis and steatosis) in patients with chronic harmful alcohol use

In patients with ALD, liver stiffness measurement (LSM) using transient elastography (TE) <8 kPa is recommended to rule-out advanced fibrosis. If TE is unavailable, the following NITs can be used:

• Patented tests: ELF™ <9.8 or FibroMeter™ <0.45 or FibroTest® <0.48
• Non-patented tests: FIB-4 <1.3

In patients at risk of ALD, after considering causes of false positives, LSM by TE ≥12-15 kPa is recommended to rule-in advanced fibrosis. LSM by TE should be repeated (alcohol abstinence or reduced drinking of at least a week is required) in patients with elevated liver stiffness and biochemical evidence of hepatic inflammation (AST or gamma-glutamyltransferase (GGT) >2xULN).

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HCV post-SVR/post-antiviral therapy

Non-invasive scores and LSM by TE and other elastography methods are not accurate in detecting fibrosis regression after the sustained virological response (SVR) in HCV patients diagnosed with compensated cACLD prior to antiviral therapy

Hence, the routine use of non-invasive scores and LSM by TE and other elastography methods is not recommended to detect fibrosis regression in this patient group. Cut-offs of LSM by TE used in patients with untreated HCV should not be used to stage liver fibrosis after SVR.

Non-invasive scores, serum markers, liver stiffness, and imaging methods for the prediction of clinical outcomes (decompensation; HCC) in patients with HCV-related cACLD who achieved SVR

Statement: In patients with cACLD who achieved SVR, LSM can be used to refine the stratification of residual risk of liver-related complications. LSM can be repeated annually. Irrespective of the results of NITs post-SVR, patients with cACLD previous to antiviral therapy for HCV should be continually monitored for HCC and portal hypertension.

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NAFLD/NASH

Non-invasive scores and imaging methods for the diagnosis of steatosis in patients with metabolic risk factors and/or suspected NAFLD

Statements

1. Controlled attenuation parameter (CAP) is a promising point-of-care technique for rapid and standardised detection of steatosis. However, its limited availability and lack of direct comparative studies with ultrasound restrict its use as a first-line technique. Values (no consensual cut-offs exists) above 275 dB/m might be used to diagnose steatosis.
2. The use of non-invasive scores is not recommended for the diagnosis of steatosis in clinical practice. Conventional ultrasound should be used as a first-line tool for the diagnosis of steatosis in clinical practice. MRI-PDFF is the most accurate non-invasive method for detecting and quantifying steatosis. But it is more suitable for clinical trials due to its cost and limited availability.

Non-invasive scores, serum markers, liver stiffness, and imaging methods for the evaluation of NAFLD severity (presence of NASH and staging of liver fibrosis)

In patients with NAFLD, liver biopsy is the reference standard for the diagnosis of NASH. Currently, available NITs lack acceptable accuracy and are hence not an option. NITs recommended to rule-out advanced fibrosis in patients with NAFLD include:

• LSM by TE <8 kPa
• Patented tests: Enhanced liver fibrosis (ELF)™ <9.8 or FibroMeter™ <0.45 or FibroTest® <0.48
• Non-patented tests: Fibrosis-4 (FIB-4) <1.3 or NAFLD fibrosis score (NFS) <-1.455

TE and/or patented serum tests should be used to rule out/in advanced fibrosis upon referral of a patient with FIB-4 over 1.3. Despite being the most accurate non-invasive method for staging liver fibrosis, magnetic resonance elastography (MRE) is not recommended as a first-line NIT due to its cost and limited availability.

Serum scores [AST to platelet ratio (APRI), FIB-4, NFS, ELF™] and LSM by TE are recommended to risk-stratify liver-related outcomes in NAFLD.

Non-invasive tests compared to liver biopsy for patient selection and evaluation of treatment response in NAFLD therapeutic trials

Liver biopsy is the reference for patient selection in phase IIb and phase III therapeutic trials. A liver biopsy is also recommended to evaluate NASH resolution and liver fibrosis improvement.

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Cholestatic and autoimmune liver disease (PBC, PSC, AIH)

Non-invasive scores, serum markers, liver stiffness, and imaging methods for the assessment of disease severity in patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC)

In patients with PBC, serum markers of fibrosis and non-invasive scores are not recommended for fibrosis staging. LSM by TE is the best surrogate marker for ruling in severe fibrosis/cACLD and should be used for this purpose using a cut-off of 10 kPa.

Non-invasive scores, serum markers, liver stiffness, and imaging methods for the prediction of liver-related outcomes in patients with PBC and PSC

In patients with PBC, non-invasive discrimination of early and advanced-stage disease based on biochemical parameters (normal vs. abnormal albumin and bilirubin) and LSM by TE < or >10 kPa is recommended at baseline.

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Compensated advanced chronic liver disease and portal hypertension (cACLD)

Non-invasive scores, serum markers, liver stiffness, and imaging methods for the diagnosis of cACLD

Second-line tests such as patented serum tests or elastography should be used to diagnose cACLD. If available, Fibrotest® or FibroMeter™ or ELF™ should be used to rule out cACLD.

When using LSM by TE to rule out and diagnose cACLD, the following cut-offs are recommended:

• <8-10 kPa to rule-out
• >12-15 kPa to rule-in
• Intermediate values will require further testing

Non-invasive scores, serum markers, liver stiffness, and imaging methods for diagnosing clinically significant portal hypertension (CSPH) and monitoring portal hypertension

LSM by TE at a cut-off of >20-25 kPa is recommended to diagnose CSPH in cACLD. Platelet count, spleen size and spleen stiffness should be used for risk stratification.

The presence of portosystemic collaterals on ultrasound, CT or MRI is a sign of CSPH in patients with cACLD and should be routinely reported. Hepatic venous pressure gradient (HVPG) is the only validated tool for an exact assessment of the severity of portal hypertension in cACLD and the haemodynamic response to treatment.

Non-invasive scores, serum markers, liver stiffness, and imaging methods for diagnosing and excluding high-risk gastro-oesophageal varices

In patients with cACLD due to untreated viral hepatitis, HIV-HCV coinfection, alcohol, NAFLD, PBC and PSC, the finding of LSM by TE <20 kPa and platelet count >150 G/L (Baveno VI criteria) is a validated tool to rule-out high-risk varices and avoid endoscopic screening. These criteria should be used whenever TE is available.

The use of CT for primary screening of oesophageal and gastric varices is not recommended; however, varices should be looked for and reported when doing a routine CT. In cACLD, liver stiffness at diagnosis and liver function tests are recommended to stratify the risk of clinical decompensation and mortality.

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