EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis

2015 Journal of Hepatology 63, 1 (237-264)

Non-invasive methods rely on two different approaches: a biological approach based on the quantification of biomarkers in serum samples or a physical approach based on the measurement of liver stiffness (LS). Although these approaches are complementary, they are based on different rationales. Serum biomarkers indicate several, not strictly liver specific clinical and serum parameters that have been associated with fibrosis stage, as assessed by liver biopsy, whereas LS corresponds to a genuine and intrinsic physical property of liver parenchyma. Serum biomarkers of liver fibrosis Many serum biomarkers have been proposed for staging liver fibrosis, mainly in patients with chronic hepatitis C.
They are summarized in Table 2. […] Table 2. Currently available serum biomarkers for non-invasive evaluation of liver fibrosis in chronic liver disease. HCV: Fibrometer (Echosens, Paris, France) patented formula combining platelet count, prothrombin index, AST, α-2-macroglobulin, hyaluronate, urea and age. Liver stiffness measurement Transient elastography Liver fibrosis can be staged using 1-dimensional ultrasound TE (FibroScan, Echosens, Paris, France), which measures the velocity of a low-frequency (50 Hz) elastic shear wave propagating through the liver. This velocity is directly related to tissue stiffness, called the elastic modulus (expressed as E = 3 qv2, where v is the shear velocity and q is the density of tissue, assumed to be constant). The stiffer the tissue, the faster the shear wave propagates.
Recommendations (Currently available non-invasive methods)
- Non-invasive tests should always be interpreted by specialists in liver disease, according to the clinical context, considering the results of other tests (biochemical, radiological and endoscopic) and taking into account the recommended quality criteria for each test and its possible pitfalls (A1)
- Serum biomarkers can be used in clinical practice due to their high applicability (>95%) and good interlaboratory reproducibility. However, they should be preferably obtained in fasting patients (particularly those including hyaluronic acid) and following the manufacturer’s recommendations for the patented tests (A1)
- TE is a fast, simple, safe and easy to learn procedure that is widely available. Its main limitation is the impossibility of obtaining results in case of ascites or morbid obesity and its limited applicability in case of obesity and limited operator experience (A1)
- TE should be performed by an experienced operator (>100 examinations) following a standardized protocol with the patient, fasting for at least 2 hours, in the supine position, right arm in full abduction, on the midaxillary line with the probe-tip placed in the 9th to 11th intercostal space with a minimum of 10 shots (A1)
- Correct interpretation of TE results in clinical practice must consider the following parameters: - IQR/ median value (<30%),
- Serum aminotransferases levels (25 mm),
- Absence of extra-hepatic cholestasis,
- Absence of right heart failure, or other causes of congestive liver
- Absence of ongoing excessive alcohol intake (A1) Recommendations (Performance of serum biomarkers for staging liver fibrosis)
- Serum biomarkers of fibrosis are well validated in patients with chronic viral hepatitis (with more evidence for HCV than for HBV and HIV/HCV coinfection). They are less well validated in NAFLD and not validated in other chronic liver diseases (A1)
- Their performances are better for detecting cirrhosis than significant fibrosis (A1)
- Caution is needed in patients with HIV-HCV coinfection because of the risk of false positive results related to HIV-induced thrombocytopenia, antiretroviral treatment-induced hyperbilirubinemia or increased serum γ-glutamyl transferase levels (A2) Recommendations (Performance of TE for staging liver fibrosis)
- TE can be considered the non-invasive standard for the measurement of LS (A1)
- TE is well validated in viral hepatitis with performance equivalent in hepatitis B and C and in HIV-HCV coinfection (A1)
- TE is less well validated in NAFLD and in other chronic liver diseases (A1)
- TE performs better for detection of cirrhosis than for detection of significant fibrosis (A1)
- TE is a reliable method for the diagnosis of cirrhosis in patients with chronic liver diseases, that generally performs better at ruling out than ruling in cirrhosis (with negative predictive value higher than 90%) (A1) Recommendations (Transient elastography vs. other techniques)
- Comparison between MR elastography and TE has provided conflicting results. Further data are needed (A1) Recommendations (Comparison of performance of TE and serum biomarkers for staging liver fibrosis) - TE and serum biomarkers have equivalent performance for detecting significant fibrosis in patients with viral hepatitis (A1)
- TE is the most accurate non-invasive method for detecting cirrhosis in patients with viral hepatitis (A1) Recommendations (Algorithms combining different tests (LS and/or serum biomarkers))
- Among the different available strategies, algorithms combining TE and serum biomarkers appear to be the most attractive and validated one (A2)
- In patients with viral hepatitis C, when TE and serum biomarkers results are in accordance, the diagnostic accuracy is increased for detecting significant fibrosis but not for cirrhosis. In cases of unexplained discordance, a liver biopsy should be performed if the results would change the patient management. Such strategy remains to be validated in patients with hepatitis B and NAFLD (A1) Recommendations (Indications for non-invasive tests for staging liver disease in viral hepatitis: HCV including HIV-HCV)
- All HCV patients should be screened to exclude cirrhosis by TE if available. Serum biomarkers can be used in the absence of TE (A1)
- HCV patients who were diagnosed with cirrhosis based on non-invasive diagnosis should undergo screening for HCC and PH and do not need confirmatory liver biopsy (A1) Recommendations (Indications for non-invasive tests for staging liver disease in viral hepatitis: HBV)
- TE has better prediction for advanced liver fibrosis and cirrhosis than serum biomarkers in chronic hepatitis B (B1)
- TE is best used to determine liver fibrosis in hepatitis B patients with active viraemia (HBV DNA >2000 IU/ml) but normal ALT (A1)
- TE can be used to exclude severe fibrosis and cirrhosis in inactive carriers (HBeAg-negative, low viral load (HBV DNA 10 x ULN) (A1) Recommendations (Use of non-invasive tests for staging liver disease in NAFLD) - Non-invasive assessment including serum biomarkers or TE can be used as first line procedure for the identification of patients at low risk of severe fibrosis/ cirrhosis (A1)
- The identification of significant fibrosis is less accurate with non-invasive tests as compared to liver biopsy and may necessitate, according to the clinical context, histological confirmation (A1)
- Follow-up assessment by either serum biomarkers or TE for progression of liver fibrosis should be performed among NAFLD patients at a 3 year interval (B1) Recommendations (Use of non-invasive tests for staging liver disease in other liver diseases)
- TE may be used to rule out severe fibrosis or cirrhosis in patients with ALD (B2)
- Non-invasive assessment of fibrosis, using TE should be considered in patients with PBC or PSC (B2)
- Follow-up assessment of liver fibrosis with TE should be performed in PBC and PSC since worsening of LS predicts patients’ outcomes. More data is needed to define the optimal time-frame between repeated examination (B2) Recommendations (Use of non-invasive methods when deciding for treatment in viral hepatitis: HCV including HIV-HCV)
- Non-invasive tests, using either TE or serum biomarkers, are adequate for diagnosis of severe fibrosis/cirrhosis in HCV and HIV-HCV coinfected patients and can be used to prioritize patients for HCV therapy based on disease stage (A1)
- For the diagnosis of significant fibrosis a combination of tests with concordance may provide the highest diagnostic accuracy (A2)
- Non-invasive tests should be utilized prior to therapy by treating non-specialists to make sure that patients with severe fibrosis/cirrhosis are referred for appropriate disease specific specialist evaluation (A1) Recommendations (Use of non-invasive methods when deciding for treatment in viral hepatitis: HBV)
- Non-invasive assessment of liver fibrosis, using either serum biomarkers or TE, should be considered for patients with significant viraemia (HBV DNA >2000 IU/ml) when liver cirrhosis is suspected (A1)
- Among patients who have HBV DNA >2000 IU/ml, antiviral therapy should be considered for patients who have advanced fibrosis or cirrhosis as determined by non-invasive assessment of liver fibrosis, either by serum biomarkers or TE, regardless of the ALT levels (A1) Recommendations (Use of non-invasive methods for monitoring treatment response in viral hepatitis: HBV)
- Non-invasive assessment with either serum biomarkers or TE can be used to monitor improvement in liver fibrosis during antiviral therapy. The correlation of fibrosis improvement predicted by non-invasive measurement with histology has yet to be determined (B2)
- The impact of ALT normalization by antiviral therapy has to be considered on interpretation of the noninvasive liver fibrosis assessment results (A1) Recommendations (Use of non-invasive tests for monitoring disease progression: Portal hypertension, Hepatocellular carcinoma)
- Non-invasive tests cannot replace HVPG for a detailed PH evaluation and upper GI endoscopy for detecting varices (A1)
- However, in settings where HVPG is not available, TE could be considered to stratify the risk of CSPH (A2)
- Although TE could be useful to identify patients at risk of developing HCC, more data are needed before it can be integrated into an HCC surveillance program (A1) Recommendations (Use of non-invasive tests for monitoring disease progression: Determining prognosis)
- There is increasing evidence for the prognostic value of non-invasive tests, particularly LS measurement using TE, in patients with cirrhosis (A1)
- Increase of LS values over time could be associated with a worse prognosis in patients with fibrosis or cirrhosis (A2)...

Pubmed : 25911335