Page 16 - NON-INVASIVE TESTS FOR EVALUATION OF LIVER DISEASE SEVERITY AND PROGNOSIS
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not reported separately. In the case of PBC, although histological JOURNAL OF HEPATOLOGY
proof of the disease is no longer considered mandatory to make
the diagnosis, assessment of the disease stage remains useful Recommendations
for both prognostic (patients with more advanced disease have
reduced survival than those in earlier stage) and therapeutic rea- • TE may be used to rule out severe fibrosis or cirrhosis
sons (patients with earlier histological stage respond more favor- in patients with ALD (B2)
ably to UDCA administration and in patients with advanced
disease surveillance of HCC is indicated) [237]. Thus, PBC patients • Non-invasive assessment of fibrosis, using TE should
often undergo a liver biopsy and the use of non-invasive tests of be considered in patients with PBC or PSC (B2)
liver fibrosis may be advantageous in this setting. Several reports
have tested the usefulness of serum biomarkers of liver fibrosis • Follow-up assessment of liver fibrosis with TE should
including serum levels of hyaluronic acid, procollagen III amino- be performed in PBC and PSC since worsening of
terminal propeptide, collagen IV, and FibroTestÒ in patients with LS predicts patients’ outcomes. More data is needed
PBC [238–240]. While earlier studies did not provide estimates of to define the optimal time-frame between repeated
diagnostic accuracy to readily assess clinical performance more examination (B2)
recent reports do provide AUC values of ROC curves which in
most of the cases are below 0.8. Thus, current evidence allows • Untreated dominant stricture of the common bile duct
the conclusion that no single serum measurement has the ability or primary hepatic ducts must be ruled out in PSC
to differentiate between early and advanced fibrosis in PBC [241]. patients since obstructive cholestasis influences LS
In the case of PSC, no specific studies are available in this regard. assessment (A1)
Reported data on the use of TE in PBC is encouraging. The • No recommendation can be made with current
report by Corpechot et al. of two cohorts of PBC patients evalu- evidence on the use of non-invasive tests in AIH (A1)
ated with TE showed that this technique is currently one of the
best surrogate markers of liver fibrosis in this disease [164]. Use of non-invasive methods when deciding for treatment in viral
This data is in agreement with findings from Floreani’s group in hepatitis
Italy [242] and with an earlier study by Gomez-Dominguez from
Spain [243]. In addition, TE may be useful to monitor PBC pro- HCV including HIV-HCV
gression. In fact, prospective data from Corpechot et al. showed The current recommendations for treatment of HCV vary signifi-
that progression of LS over time is predictive of poor outcome cantly between countries and healthcare systems according to
[164]. As for PSC, a recent study from the same group [244] the availability of therapy. However, the EASL and AASLD guide-
showed that TE efficiently differentiates severe from non-severe lines are clear as to the prioritization of treatment based on dis-
liver fibrosis stages in this disease, and that both baseline LS mea- ease stage [213,214]. There is some controversy in how best to
surements and increase over the time are able to predict patients’ use non-invasive tests in HCV therapeutic decisions. In countries
outcomes. Thus, TE seems to be a reliable non-invasive method where antiviral treatment is only indicated in patients with sev-
for assessing biliary fibrosis in PSC patients [163,244]. However, ere fibrosis or cirrhosis, both TE and serum biomarkers are
untreated dominant stricture of the common bile duct or primary effective – either alone, or in combination – to assess liver fibro-
hepatic ducts should be ruled out in PSC patients since obstruc- sis. However the controversy is with significant fibrosis, where
tive cholestasis influences LS assessment [72]. Finally, with the all staging parameters including non-invasive tests and liver
availability of smaller probes (S1, S2), the use of TE has recently biopsy have the greatest discordance and risk for inaccuracy.
been tested in children with biliary atresia, a disease where fibro- Since the diagnostic accuracy of non-invasive tests in differ-
sis monitoring may help predict outcomes before surgery [245]. entiating between stage F1 and F2 has the most variability, this
However, more data on non-invasive fibrosis evaluation in represents a challenge for clinicians [17,18]. Although cut-offs
patients with cholestatic liver diseases is needed to make firm for both TE and serum tests have been suggested for significant
recommendations on the use of TE in this disease. fibrosis, they have not been well validated and in a large,
prospective US biopsy controlled study in over 700 HCV
Autoimmune hepatitis patients, TE, APRI, and FIB-4 all performed less well for signifi-
AIH may have insidious onset in a significant proportion of the cant fibrosis [129]. Combination of serum biomarkers with TE
cases, which result in a large number of cases (30% to 80%) may marginally improve differentiation of F0–F1 from F2–F4
being at the cirrhotic stage at the moment of diagnosis. Since but has never been validated in actually differentiating between
a significant number of cases could be diagnosed without per- the single stages of F1 from F2.
forming a liver biopsy [246], non-invasive tests for liver fibrosis
may have a role in liver disease staging. Non-invasive tests In HIV-HCV coinfected patients, a priority has been given to
could be also useful for monitoring response to immunosup- treat all patients since this special population shows a more rapid
pressive treatment in AIH, since fibrosis and cirrhosis can be disease progression so disease staging is less important for thera-
reversible in this setting [247,248]. However, specific data of peutic decisions. However, in some countries anti-HCV treatment
either serum markers of fibrosis or imaging techniques is scarce in HIV/HCV coinfected patients follows the same guidelines as for
to make recommendations. Of note, disproportionally high HCV monoinfection. There may be a reduced diagnostic accuracy
results of TE [249] have been reported in patients with AIH, of serum biomarkers for fibrosis in HIV-HCV patients and TE
which is likely related to the inflammatory activity considering should be preferred.
that values decreased rapidly upon induction of disease
remission. There have been suggestions that as therapy becomes sim-
pler and more effective with the advent of new direct-acting
antiviral (DAA) agents and an increased uptake of HCV
Journal of Hepatology 2015 vol. xxx j xxx–xxx 15
Please cite this article in press as: EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J
Hepatol (2015), http://dx.doi.org/10.1016/j.jhep.2015.04.006
proof of the disease is no longer considered mandatory to make
the diagnosis, assessment of the disease stage remains useful Recommendations
for both prognostic (patients with more advanced disease have
reduced survival than those in earlier stage) and therapeutic rea- • TE may be used to rule out severe fibrosis or cirrhosis
sons (patients with earlier histological stage respond more favor- in patients with ALD (B2)
ably to UDCA administration and in patients with advanced
disease surveillance of HCC is indicated) [237]. Thus, PBC patients • Non-invasive assessment of fibrosis, using TE should
often undergo a liver biopsy and the use of non-invasive tests of be considered in patients with PBC or PSC (B2)
liver fibrosis may be advantageous in this setting. Several reports
have tested the usefulness of serum biomarkers of liver fibrosis • Follow-up assessment of liver fibrosis with TE should
including serum levels of hyaluronic acid, procollagen III amino- be performed in PBC and PSC since worsening of
terminal propeptide, collagen IV, and FibroTestÒ in patients with LS predicts patients’ outcomes. More data is needed
PBC [238–240]. While earlier studies did not provide estimates of to define the optimal time-frame between repeated
diagnostic accuracy to readily assess clinical performance more examination (B2)
recent reports do provide AUC values of ROC curves which in
most of the cases are below 0.8. Thus, current evidence allows • Untreated dominant stricture of the common bile duct
the conclusion that no single serum measurement has the ability or primary hepatic ducts must be ruled out in PSC
to differentiate between early and advanced fibrosis in PBC [241]. patients since obstructive cholestasis influences LS
In the case of PSC, no specific studies are available in this regard. assessment (A1)
Reported data on the use of TE in PBC is encouraging. The • No recommendation can be made with current
report by Corpechot et al. of two cohorts of PBC patients evalu- evidence on the use of non-invasive tests in AIH (A1)
ated with TE showed that this technique is currently one of the
best surrogate markers of liver fibrosis in this disease [164]. Use of non-invasive methods when deciding for treatment in viral
This data is in agreement with findings from Floreani’s group in hepatitis
Italy [242] and with an earlier study by Gomez-Dominguez from
Spain [243]. In addition, TE may be useful to monitor PBC pro- HCV including HIV-HCV
gression. In fact, prospective data from Corpechot et al. showed The current recommendations for treatment of HCV vary signifi-
that progression of LS over time is predictive of poor outcome cantly between countries and healthcare systems according to
[164]. As for PSC, a recent study from the same group [244] the availability of therapy. However, the EASL and AASLD guide-
showed that TE efficiently differentiates severe from non-severe lines are clear as to the prioritization of treatment based on dis-
liver fibrosis stages in this disease, and that both baseline LS mea- ease stage [213,214]. There is some controversy in how best to
surements and increase over the time are able to predict patients’ use non-invasive tests in HCV therapeutic decisions. In countries
outcomes. Thus, TE seems to be a reliable non-invasive method where antiviral treatment is only indicated in patients with sev-
for assessing biliary fibrosis in PSC patients [163,244]. However, ere fibrosis or cirrhosis, both TE and serum biomarkers are
untreated dominant stricture of the common bile duct or primary effective – either alone, or in combination – to assess liver fibro-
hepatic ducts should be ruled out in PSC patients since obstruc- sis. However the controversy is with significant fibrosis, where
tive cholestasis influences LS assessment [72]. Finally, with the all staging parameters including non-invasive tests and liver
availability of smaller probes (S1, S2), the use of TE has recently biopsy have the greatest discordance and risk for inaccuracy.
been tested in children with biliary atresia, a disease where fibro- Since the diagnostic accuracy of non-invasive tests in differ-
sis monitoring may help predict outcomes before surgery [245]. entiating between stage F1 and F2 has the most variability, this
However, more data on non-invasive fibrosis evaluation in represents a challenge for clinicians [17,18]. Although cut-offs
patients with cholestatic liver diseases is needed to make firm for both TE and serum tests have been suggested for significant
recommendations on the use of TE in this disease. fibrosis, they have not been well validated and in a large,
prospective US biopsy controlled study in over 700 HCV
Autoimmune hepatitis patients, TE, APRI, and FIB-4 all performed less well for signifi-
AIH may have insidious onset in a significant proportion of the cant fibrosis [129]. Combination of serum biomarkers with TE
cases, which result in a large number of cases (30% to 80%) may marginally improve differentiation of F0–F1 from F2–F4
being at the cirrhotic stage at the moment of diagnosis. Since but has never been validated in actually differentiating between
a significant number of cases could be diagnosed without per- the single stages of F1 from F2.
forming a liver biopsy [246], non-invasive tests for liver fibrosis
may have a role in liver disease staging. Non-invasive tests In HIV-HCV coinfected patients, a priority has been given to
could be also useful for monitoring response to immunosup- treat all patients since this special population shows a more rapid
pressive treatment in AIH, since fibrosis and cirrhosis can be disease progression so disease staging is less important for thera-
reversible in this setting [247,248]. However, specific data of peutic decisions. However, in some countries anti-HCV treatment
either serum markers of fibrosis or imaging techniques is scarce in HIV/HCV coinfected patients follows the same guidelines as for
to make recommendations. Of note, disproportionally high HCV monoinfection. There may be a reduced diagnostic accuracy
results of TE [249] have been reported in patients with AIH, of serum biomarkers for fibrosis in HIV-HCV patients and TE
which is likely related to the inflammatory activity considering should be preferred.
that values decreased rapidly upon induction of disease
remission. There have been suggestions that as therapy becomes sim-
pler and more effective with the advent of new direct-acting
antiviral (DAA) agents and an increased uptake of HCV
Journal of Hepatology 2015 vol. xxx j xxx–xxx 15
Please cite this article in press as: EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J
Hepatol (2015), http://dx.doi.org/10.1016/j.jhep.2015.04.006
