Page 2 - NON-INVASIVE TESTS FOR EVALUATION OF LIVER DISEASE SEVERITY AND PROGNOSIS
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Clinical Practice Guidelines
EASL-ALEH Clinical Practice Guidelines: Non-invasive tests
for evaluation of liver disease severity and prognosis
European Association for the Study of the Liver ⇑,
Asociación Latinoamericana para el Estudio del Hígado
Introduction is another potential limitation of liver biopsy which is related to
the discordance between pathologists in biopsy interpretation,
Liver fibrosis is part of the structural and functional alterations in although it seems to be less pronounced when biopsy assessment
most chronic liver diseases. It is one of the main prognostic fac- is done by specialized liver pathologists [12]. Beside technical
tors as the amount of fibrosis is correlated with the risk of devel- problems, liver biopsy remains a costly and invasive procedure
oping cirrhosis and liver-related complications in viral and non- that requires physicians and pathologists to be sufficiently
viral chronic liver diseases [1,2]. Liver biopsy has traditionally trained in order to obtain adequate and representative results –
been considered the reference method for evaluation of tissue this again limits the use of liver biopsy for mass screening. Last
damage such as hepatic fibrosis in patients with chronic liver dis- but not least, liver biopsy is an invasive procedure, carrying a risk
ease. Pathologists have proposed robust scoring system for stag- of rare but potentially life-threatening complications [13,14].
ing liver fibrosis such as the semi-quantitative METAVIR score These limitations have led to the development of non-invasive
[3,4]. In addition computer-aided morphometric measurement methods for assessment of liver fibrosis. Although some of these
of collagen proportional area, a partly automated technique, pro- methods are now commonly used in patients for first line
vides an accurate and linear evaluation of the amount of fibrosis assessment, biopsy remains within the armamentarium of
[5]. Liver biopsy gives a snapshot and not an insight into the hepatologists when assessing the etiology of complex diseases
dynamic changes during the process of fibrogenesis (progression, or when there are discordances between clinical symptoms and
static or regression). However, immunohistochemical evaluation the extent of fibrosis assessed by non-invasive approaches.
of cellular markers such as smooth muscle actin expression for
hepatic stellate cell activation, cytokeratin 7 for labeling ductular Methodological considerations when using non-invasive tests
proliferation or CD34 for visualization of sinusoidal endothelial
capillarization or the use of two-photon and second harmonic The performance of a non-invasive diagnostic method is
generation fluorescence microscopy techniques for spatial assess- evaluated by calculation of the area under the receiver operator
ment of fibrillar collagen, can provide additional ‘‘functional’’ characteristic curve (AUROC), taking liver biopsy as the reference
information [6,7]. All these approaches are valid provided that standard. However, biopsy analysis is an imperfect reference
the biopsy is of sufficient size to represent the whole liver [4,8]. standard: taking into account a range of accuracies of the biopsy,
Indeed, liver biopsy provides only a very small part of the whole even in the best possible scenario, an AUROC >0.90 cannot be
organ and there is a risk that this part might not be representa- achieved for a perfect marker of liver disease [15]. The AUROC
tive for the amount of hepatic fibrosis in the whole liver due to can vary based on the prevalence of each stage of fibrosis,
heterogeneity in its distribution [9]. Extensive literature has described as spectrum bias [16]. Spectrum bias has important
shown that increasing the length of liver biopsy decreases the implications for the study of non-invasive methods, particularly
risk of sampling error. Except for cirrhosis, for which micro-frag- in comparison of methods across different study populations. If
ments may be sufficient, a 25 mm long biopsy is considered an extreme stages of fibrosis (F0 and F4) are over-represented in a
optimal specimen for accurate evaluation, though 15 mm is con- population, the sensitivity and specificity of a diagnostic method
sidered sufficient in most studies [10]. Not only the length but will be higher than in a population of patients that has
also the caliber of the biopsy needle is important in order to predominantly middle stages of fibrosis (F1 and F2). Several ways
obtain a piece of liver of adequate size for histological evaluation, of preventing the ‘‘spectrum bias’’ have been proposed including
with a 16 gauge needle being considered as the most appropriate the adjustment of AUROC using the DANA method (standardiza-
[11] to use for percutaneous liver biopsy. Interobserver variation tion according to the prevalence of fibrosis stages that define
advanced (F2–F4) and non-advanced (F0–F1) fibrosis) [17,18] or
Received 9 April 2015; accepted 9 April 2015 the Obuchowski measure (designed for ordinal gold standards)
Chairmen: Laurent Castera & Henry Lik Yuen Chan (EASL), Marco Arrese (ALEH). [19]. What really matters in clinical practice is the number of
Clinical Practice Guidelines Panel members: Nezam Afdhal, Pierre Bedossa, Mireen patients correctly classified by non-invasive methods for a
Friedrich-Rust, Kwang-Hyub Han, Massimo Pinzani. defined endpoint according to the reference standard (i.e. true
⇑ Correspondence: EASL Office, 7 rue Daubin, CH 1203 Geneva, Switzerland. Tel.: positive and true negative).
+41 22 807 0360; fax: +41 22 328 0724.
E-mail address: easloffice@easloffice.eu.
Journal of Hepatology 2015 vol. xxx j xxx–xxx
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
EASL-ALEH Clinical Practice Guidelines: Non-invasive tests
for evaluation of liver disease severity and prognosis
European Association for the Study of the Liver ⇑,
Asociación Latinoamericana para el Estudio del Hígado
Introduction is another potential limitation of liver biopsy which is related to
the discordance between pathologists in biopsy interpretation,
Liver fibrosis is part of the structural and functional alterations in although it seems to be less pronounced when biopsy assessment
most chronic liver diseases. It is one of the main prognostic fac- is done by specialized liver pathologists [12]. Beside technical
tors as the amount of fibrosis is correlated with the risk of devel- problems, liver biopsy remains a costly and invasive procedure
oping cirrhosis and liver-related complications in viral and non- that requires physicians and pathologists to be sufficiently
viral chronic liver diseases [1,2]. Liver biopsy has traditionally trained in order to obtain adequate and representative results –
been considered the reference method for evaluation of tissue this again limits the use of liver biopsy for mass screening. Last
damage such as hepatic fibrosis in patients with chronic liver dis- but not least, liver biopsy is an invasive procedure, carrying a risk
ease. Pathologists have proposed robust scoring system for stag- of rare but potentially life-threatening complications [13,14].
ing liver fibrosis such as the semi-quantitative METAVIR score These limitations have led to the development of non-invasive
[3,4]. In addition computer-aided morphometric measurement methods for assessment of liver fibrosis. Although some of these
of collagen proportional area, a partly automated technique, pro- methods are now commonly used in patients for first line
vides an accurate and linear evaluation of the amount of fibrosis assessment, biopsy remains within the armamentarium of
[5]. Liver biopsy gives a snapshot and not an insight into the hepatologists when assessing the etiology of complex diseases
dynamic changes during the process of fibrogenesis (progression, or when there are discordances between clinical symptoms and
static or regression). However, immunohistochemical evaluation the extent of fibrosis assessed by non-invasive approaches.
of cellular markers such as smooth muscle actin expression for
hepatic stellate cell activation, cytokeratin 7 for labeling ductular Methodological considerations when using non-invasive tests
proliferation or CD34 for visualization of sinusoidal endothelial
capillarization or the use of two-photon and second harmonic The performance of a non-invasive diagnostic method is
generation fluorescence microscopy techniques for spatial assess- evaluated by calculation of the area under the receiver operator
ment of fibrillar collagen, can provide additional ‘‘functional’’ characteristic curve (AUROC), taking liver biopsy as the reference
information [6,7]. All these approaches are valid provided that standard. However, biopsy analysis is an imperfect reference
the biopsy is of sufficient size to represent the whole liver [4,8]. standard: taking into account a range of accuracies of the biopsy,
Indeed, liver biopsy provides only a very small part of the whole even in the best possible scenario, an AUROC >0.90 cannot be
organ and there is a risk that this part might not be representa- achieved for a perfect marker of liver disease [15]. The AUROC
tive for the amount of hepatic fibrosis in the whole liver due to can vary based on the prevalence of each stage of fibrosis,
heterogeneity in its distribution [9]. Extensive literature has described as spectrum bias [16]. Spectrum bias has important
shown that increasing the length of liver biopsy decreases the implications for the study of non-invasive methods, particularly
risk of sampling error. Except for cirrhosis, for which micro-frag- in comparison of methods across different study populations. If
ments may be sufficient, a 25 mm long biopsy is considered an extreme stages of fibrosis (F0 and F4) are over-represented in a
optimal specimen for accurate evaluation, though 15 mm is con- population, the sensitivity and specificity of a diagnostic method
sidered sufficient in most studies [10]. Not only the length but will be higher than in a population of patients that has
also the caliber of the biopsy needle is important in order to predominantly middle stages of fibrosis (F1 and F2). Several ways
obtain a piece of liver of adequate size for histological evaluation, of preventing the ‘‘spectrum bias’’ have been proposed including
with a 16 gauge needle being considered as the most appropriate the adjustment of AUROC using the DANA method (standardiza-
[11] to use for percutaneous liver biopsy. Interobserver variation tion according to the prevalence of fibrosis stages that define
advanced (F2–F4) and non-advanced (F0–F1) fibrosis) [17,18] or
Received 9 April 2015; accepted 9 April 2015 the Obuchowski measure (designed for ordinal gold standards)
Chairmen: Laurent Castera & Henry Lik Yuen Chan (EASL), Marco Arrese (ALEH). [19]. What really matters in clinical practice is the number of
Clinical Practice Guidelines Panel members: Nezam Afdhal, Pierre Bedossa, Mireen patients correctly classified by non-invasive methods for a
Friedrich-Rust, Kwang-Hyub Han, Massimo Pinzani. defined endpoint according to the reference standard (i.e. true
⇑ Correspondence: EASL Office, 7 rue Daubin, CH 1203 Geneva, Switzerland. Tel.: positive and true negative).
+41 22 807 0360; fax: +41 22 328 0724.
E-mail address: easloffice@easloffice.eu.
Journal of Hepatology 2015 vol. xxx j xxx–xxx
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
