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Noninvasive Biomarkers of Liver Fibrosis: An Overview

Article · April 2014

DOI: 10.1155/2014/357287

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Advances in Hepatology
Volume 2014, Article ID 357287, 15 pages
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Review Article
Noninvasive Biomarkers of Liver Fibrosis: An Overview

Hind I. Fallatah
Fellowship of American College of Physicians (FACP) and Arab Board and Saudi Board of Internal Medicine, Medical Department,
King AbdulAziz University Hospital, P.O. Box 80215, Jeddah 21589, Saudi Arabia

Correspondence should be addressed to Hind I. Fallatah; hindfallatah@[Link]

Received 14 October 2013; Revised 11 January 2014; Accepted 27 February 2014; Published 15 April 2014

Academic Editor: Ned Snyder

Copyright © 2014 Hind I. Fallatah. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Chronic liver diseases of differing etiologies are among the leading causes of mortality and morbidity worldwide. Establishing
accurate staging of liver disease is very important for enabling both therapeutic decisions and prognostic evaluations. A liver biopsy
is considered the gold standard for assessing the stage of hepatic fibrosis, but it has many limitations. During the last decade,
several noninvasive markers for assessing the stage of hepatic fibrosis have been developed. Some have been well validated and are
comparable to liver biopsy. This paper will focus on the various noninvasive biochemical markers used to stage liver fibrosis.

1. Introduction 2. Is the Liver Biopsy Really

the Gold Standard and Reference Method
Chronic liver diseases of differing etiologies are among the for Evaluating Hepatic Fibrosis?
leading causes of morbidity and mortality worldwide [1–5].
Chronic liver disease progresses through different pathologi- 2.1. The Following Are Limitations of the Liver Biopsy. (1) The
cal stages that vary from mild hepatic inflammation without liver biopsy does not efficiently reflect the fibrotic changes
fibrosis to advanced hepatic fibrosis and cirrhosis [6–8]. occurring in the entire liver because an optimally sized biopsy
Assessment of the stage of liver disease is important for diag- contains 5–11 complete portal tracts and reflects only 1/50000
nosis, treatment, and follow-up both during treatment and the volume of the liver. (2) The process of hepatic fibrosis
after cessation of treatment. A liver biopsy is the oldest and is not linear, and biopsies from different areas have shown
most accurate method used to evaluate liver histology and different stages of fibrosis. (3) Several reports have shown that
the progression of chronic liver disease. Furthermore, dif- cirrhosis may be missed in 10–30% of patients. (4) A liver
ferent histological scoring systems have been developed biopsy cannot differentiate between early and advanced end-
stage cirrhosis; thus, it cannot be used as an ideal prognostic
and modified [9–12]. A liver biopsy is considered the gold
predictor. (5) Disagreements between pathologists occur,
standard for assessing liver histology [7, 12–14]. During the
which may correlate with the experience of the pathologist.
pathological progression of liver fibrosis, excessive amounts (6) There is a risk of complications arising from liver biopsy,
of extracellular matrix build up; furthermore, serum levels of and they can vary from mild symptoms, such as mild
various biomarkers change, in addition to the appearance of abdominal pain, to severe hemorrhage and injury to the
new biomarkers in the serum during the different stages of biliary system. (7) Due to the risk of complications, some
fibrosis [7, 8, 15]. Recently many noninvasive markers (NIMs) patients may refuse liver biopsy. (8) In hospital observa-
for assessing liver fibrosis have been developed, and they tion for 4–6 hours is usually required after liver biopsy.
are frequently used in clinical practice. They have been Furthermore, the use of ultrasound or the development of
validated in different studies, and some were found to be complications increases the cost of treatment and may also
highly accurate in the assessment of liver fibrosis compared prolong hospitalization [6, 7, 12, 13, 18, 20–22].
with liver biopsies [16–19], which have always been used as
the standard reference method for evaluating the accuracy of 2.2. The Importance of Noninvasive Markers of Liver Fibrosis.
noninvasive methods. NIMs are helpful in assessing the stage of fibrosis in patients
2 Advances in Hepatology

with no clear indication for a liver biopsy, such as patients with mild liver disease but increases in patients with
with chronic hepatitis B (CHB) and persistently normal moderate to severe cirrhosis [28–30].
serum alanine aminotransferase (ALT), patients with chronic (II) PCIIINP or PIIINP is another major component of
hepatitis C (CHC) or CHB and who require follow-up assess- connective tissue that has been extensively studied.
ment of the stage of fibrosis during or after treatment [13, Serum levels of PCIIINP reflect the stage of hepatic
23], and autoimmune hepatitis (AIH) patients who require fibrosis [31–33]. During cirrhosis, PCIIINP serum
assessment after prolonged immunosuppressive therapy [24]. levels correlate with serum bilirubin. An upper limit
The rapid development of new medications for the treatment of normal for PIIINP was defined by Gallorini et al.
of some liver diseases, such as CHB, CHC, and nonalcoholic as 0.8 U/mL [28]. Available data on PCIIINP in CHC
fatty liver disease (NAFLD), increases the requirement for and ALD show that it is increased and that its levels
more frequent evaluation of liver fibrosis to assess treatment correlate with the severity of liver disease [30, 33–
response. Liver biopsies are not ideal for frequent evaluations. 35]. Furthermore, a reduction in PCIIINP correlates
The ideal NIM for assessing hepatic fibrosis must be with the response of CHC patients to treatment with
simple, readily available, reliable, inexpensive, safe, and well interferon [28, 36]. The main limitation of using
validated in different forms of chronic liver disease. It must PCIIINP as a NIBM is that it is not specific to hepatic
also be useful in assessing the progression of liver disease fibrosis and that it can be detected in other conditions.
[7, 12, 13]. Furthermore, it shows lower efficacy compared with
type IV collagen and hyaluronic acid [12, 29, 32]. More
2.3. Mechanisms of Liver Injury That Result in the Produc- than a decade ago, PIIINP was evaluated in PBC and
tion of Biomarkers. The typical mechanism underlying the thought to be associated with histological severity of
development of hepatic fibrosis is an imbalance between the liver disease [37]. Similarly, McCullough et al. showed
deposition and removal of extracellular matrix (ECM). Hep- that PIIINP levels are increased in patients with AIH
atic stellate cells are the predominant producers of ECM, and and that levels decrease in patients who respond to
their activation and proliferation are mediated by different immunosuppressant treatment [38].
cytokines during the process of liver injury [7, 8, 15, 25]. The
(2) Type IV collagen is a component of ECM that was
activation and proliferation of Hepatic stellate cells ultimately
investigated as a surrogate marker of liver fibrosis [13]. It has
result in an excessive deposition of ECM [7, 12, 25, 26]. In
three different regions (an amino-terminal domain, a central
advanced fibrosis, the ECM may increase sixfold compared
helix domain, and a carboxy-terminal domain) [12]. Type
with that in normal liver [8, 26].
IV collagen has been studied extensively in liver diseases of
different etiologies [39]. It is increased in patients with liver
2.4. Noninvasive Biomarkers (NIBMs) for Assessing diseases and its levels correlate significantly with the extent
Liver Fibrosis of hepatic fibrosis [36, 40–42]. At a cutoff level of ≥5.0 ng/mL
type VI collagen had an AUC of 0.82 and NPV of 83,6% for
2.4.1. Classification of NIBMs for Liver Fibrosis. NIBMs for the detection of severe fibrosis in NAFLD [41]. Walsh et al.
liver fibrosis are grouped into two main categories: class 1 had shown that type VI collagen is elevated in hepatitis C
fibrosis markers, or direct biomarkers, and class 2 fibrosis patients compared to control (median of 127.1 ng/mL, range
markers, or indirect biomarkers [7, 12, 13, 15, 18]. The direct 17.7–317.4 and median 61.3 ng/mL, range 11.5–102.3), respec-
markers directly correlate with or are parts of the liver matrix tively [42].
produced by the Hepatic stellate cells during ECM turnover (3) Hyaluronic acid (HA) is a glycosaminoglycan, and it is
in the fibrosis process [7, 15, 18, 27]. In contrast, the indirect a component of the ECM that is produced by Hepatic stellate
markers reflect changes in liver functions and are molecules cells [7, 36, 43]. An upper limit of normal range was defined
released into the blood due to liver inflammation, but they do by Gallorini et al. as 98 𝜇g/L [28]. Variable cutoff point
not correlate with ECM turnover [7, 27]. had been defined by different authors; Sakugawa et al. and
Murawaki et al. had defined a cutoff level of ≥50 ng/mL for
(𝑎) Direct NIBMs detection of severe fibrosis; in another study Montazeri et al.
used a cut off level of 126.4 ng/mL [41]. HA has been studied
(𝑖) Direct Markers Linked to Matrix Deposition in CHC, NAFLD, alcoholic liver disease (ALD), and CHB,
(1) Procollagen type 1 and type III. but it has been more extensively studied in the former two
Procollagen is a collagen precursor. It is cleaved by two diseases. HA has been of great value in detecting advanced
different enzymes at its carboxy-terminal (type 1 (PC1CP)) fibrosis [36, 41, 44–46]. HA shows a negative predictive value
and amino-terminal (type III (PCIIINP)), leading to the of 98–100% for cirrhosis and is of great value in excluding
production of collagen. Mature collagen integrates into ECM cirrhosis [47–50]. In treated CHC patients, the response to
[7, 8, 12, 15]. treatment was reported to be associated with a reduction in
serum HA levels [51–53].
(I) The PCICP terminal peptide is major component of (4) Laminin is a noncollagenous glycoprotein component
the connective tissue [7]. It has a higher upper limit of the ECM that is produced by hepatic stellate cells. It is
of normal limit in male compared to females 202 𝜇g deposited in the basement membrane of the liver [7, 8].
and 170 𝜇g, respectively [28]. It is normal in patients Serum levels of laminin are elevated above the upper limit
Advances in Hepatology 3

of normal range (0.59–1.4 U/mL) or (9.74–2.46) as defined MMP-2. Boeker et al. had shown that serum levels of TIMP-1
by different authors [28, 41]. Furthermore Kropf et al. had increase 2.4 times in patients with cirrhosis compared to
proposed a cutoff value of 1.45 for laminin for the detection controls [7, 8, 15]. The serum levels of TIMPs increase with
of both liver fibrosis and cirrhosis [54] in patients with the progression of liver disease and directly correlate with
chronic liver disease, and they correlate with the degree of fibrotic stage [62–67].
perisinusoidal fibrosis [28, 33, 55, 56]. It showed an accuracy
of 77% in the detection of significant fibrosis in CHC [13, 36]. (𝑖𝑖𝑖) Cytokines and Chemokines Linked to Liver Fibrosis
Laminin has also been found to be of prognostic value, with a (1) Transforming growth factor-𝛽 (TGF-𝛽1) is the most
diagnostic accuracy of 70% for predicting the risk of variceal important stimulus for ECM deposition. It has pleiotropic
bleeding [55]. The data on basement membrane related to effects via membrane receptors on cells [68]. TGF-𝛽 levels
direct noninvasive markers showed that PICP, PIIINP, type were higher in hepatitis C virus infected patient and they were
VI collagen, and laminin levels decrease during abstinence found to correlate with the progression of hepatic fibrosis
from alcohol intake [36, 55, 57]. [69, 70]. A level less than 75 ng/mL was predictive of stable
YXL-40 chondrex is a member of the chitinase family, disease [69].
and it is involved in the remodeling and degradation of the (2) Transforming growth factor alpha (TGF-𝛼) was found
ECM [58]. Increased serum levels of YXL-40 chondrex to to enhance the proliferation of hepatic stellate cells by
(330 𝜇g/L), have been shown to correlate with the degree of inducing the entry of hepatic stellate cells into S-phase. In
fibrosis in all forms of liver disease and similar observations patients with liver disease, TGF-𝛼 was found to correlate with
were made for cirrhosis (425 𝜇g/L) as compared to age the progression of liver disease, Child-Pugh classification,
matched normal controls (102 𝜇g/L) [58, 59]. Saitou et al. had and it is increased in patients with HCC [71]. 3-Platelet-
defined different cutoff levels for fibrosis and cirrhosis 186.4 derived growth factor (PDGF) is the most potent mitogen
and 284.8 𝜇g/L, respectively [59]. YXL-40 levels have also of hepatic stellate cells in vitro [15, 72]. Studies on the role of
been observed to correlate with HA levels [58, 59]. The serum PDGF in liver fibrosis have shown that its levels correlate with
level of YXL-40 during postinterferon therapy for CHC the severity of hepatic fibrosis [73, 74]. Zhang et al. had shown
significantly decreased in both responder and nonresponder that PDGF at a cutoff value of 40.50 ng/L strongly correlates
patients [59]. with the stage of fibrosis and inflammation [73].

(𝑖𝑖) Direct Markers Linked to Matrix Degradation. Degra- (𝑏) Indirect Biochemical Markers of Hepatic Fibrosis
dation of the EMC is an action primarily of the family (1) Serum alanine aminotransferase (ALT) is one of the
of metalloproteinase enzymes (MMPs), three of which are oldest markers used to assess liver disease [12]. Pradat et al.
expressed in humans [60]. have shown that serum ALT is beneficial to measure due to
(1) MMP-1 (collagenases): Murawaki et al. showed that its high sensitivity and specificity (2.25-fold greater than the
the levels of MMP-1 are inversely correlated with histological normal levels predicts liver histology) [75]. However, serum
severity, including both necrosis and fibrosis. However, in ALT levels are affected by many factors, including gender,
contrast, MMP-1/TIMP-1 (tissue inhibitors of matrix metallo- body mass index, and the use of hepatotoxic medications
proteinases) complex levels correlate with the degree of portal [76, 77].
inflammation but not with the extent of hepatic fibrosis [61]. (2) The aspartate aminotransferase (AST)/ALT (AAR)
(2) MMP-2 (gelatinase-A): MMP-2 is secreted by hepatic ratio is one of the eldest markers of liver fibrosis that is easily
stellate cells during liver disease, but data on its role in the available and applicable. It has been validated in different
staging of fibrosis have been variable. There is currently no forms of liver disease, [78, 79] and a ratio of >1 is predictive of
clear association of MMP-2 with hepatic fibrosis [62, 63], but cirrhosis [80, 81]. An AAR of 1.16 has been found to predict
Boeker et al. showed that it has a high diagnostic accuracy of one-year mortality with high accuracy [80]. The BARD
92% for detecting cirrhosis secondary to CHC [62]. A cutoff score includes the AAR together with the BMI and diabetes
value of 0.550 was defined by Murawaki et al. and higher lev- measurements and was proposed by Harrison et al. in 2008.
els were associated with severe fibrosis [47], but Boeker et al. It showed NPVs of 96% and 81.3% and showed an enhanced
had shown that the cutoff value will be changed according performance compared with the NFAS [82, 83].
to the method that has been used for measuring MMP-2. (3) The AST/platelet ratio (APRI) was developed by Wai
However they showed that cirrhotic patients have 2.4-fold et al. in 2003 [84] and is measured as APRI = AS level (/ULN)
elevation of MMP-2 compared to controls [62]. H100/platelet count [84]. In the original study, the APRI of
(3) MMP-9 (gelatinase-B): a product of hepatic Kupffer more than 1.5 showed an area under the receiver operating
cells, MMP-9 was previously thought to be of value in the curve (AUC in the ROC) of 0.8, and showed an area under
diagnosis of hepatocellular carcinoma [64]. Recently, Badra the receiver operating curve (AUC in the ROC) of 0.8, and
et al. showed that MMP-9 correlated negatively with both a 0.89 for advanced fibrosis F3-F4 and cirrhosis respectively
TIMP-1 and histological severity in chronic hepatitis, with the [84]. Several other studies have been conducted to validate
lowest levels detected in patients with cirrhosis [64, 65]. the APRI [12, 13]. Multiple studies had shown that it is of great
(4) Tissue inhibitors of matrix metalloproteinases value and has high accuracy in predicting advanced fibrosis
(TIMPs): these proteins interfere with MMP functions and in different forms of liver disease [85–88]. Snyder et al. had
lead to the inhibition of ECM degeneration. TIMP-1 interacts shown that APRI at a cutoff 0.42 or less correctly detected
with most MMPs, and TIMP-2 interacts specifically with mild fibrosis with a NPV of 95% [89]. In contrast, some
4 Advances in Hepatology

studies showed that the APRI is only of moderate accuracy ACTI test: the Acti test is a modification of the Fibro test
in assessing fibrosis in CHC [90]. Loaeza-del-Castillo et al. in which ALT values are added. It reflects both necroinflam-
demonstrated that the APRI is not of diagnostic value in matory activity and liver fibrosis [103, 105]. Sebastiani et al.
assessing fibrosis in autoimmune hepatitis (AIH) patients. revealed that the Acti test showed a negative predictive value
Furthermore, in the same study, the authors showed that of 0.36 for excluding significant necrosis (85%) [85]. Together
this ratio was capable of predicting significant fibrosis in with the Fibro test, the Acti test may help assess both fibrosis
both CHC and NAFLD patients [79, 87]. Chrysanthos et and necrosis, and both tests may be reliable alternatives to
al. showed that when using the APRI alone, the stage of liver biopsies [106].
fibrosis is incorrectly classified in 40–65% of patients [91]. (7) The Fibro index: this index was developed in 2007
However Snyder et al. had shown that adding the FIBROSpect by Koda et al. to assess hepatic fibrosis in CHC [107]. It is
II to APRI will correctly classify hepatic fibrosis in additional obtained from the platelet count, AST, and gamma globulin
values. At a cutoff value of 2.25 it was associated with F2-F3
patients and will lower the indeterminate zone to 25.8% [89].
fibrosis and NPV of 90% [107]. This index showed an AUC
The diagnostic accuracy of APRI was improved by Lok et al.
of 0.83 for the detection of significant fibrosis [107]; however,
by the incorporation of ALT and the international normalized subsequent validations have shown this index to be less robust
ratio (INR) [92]. Furthermore, the APRI was also found to be [108].
of high diagnostic accuracy in assessing the progression of (8) The FIB-4 score: This score is calculated based on
fibrosis in postliver transplant patients [93]. age, platelet count, AST, and ALT. It was first developed
(4) The Forns index: this index was described by Forns by Sterling et al. to assess fibrosis in HIV/HCV coinfected
et al. in 2002. It is calculated based on the age of the patient patients at a cutoff value of 3.25; 87% of patients were correctly
and three routine laboratory tests, namely, platelet count, classified, with an AUC of 0.765 for significant fibrosis [109].
cholesterol level, and 𝛾 glutamyl transferase (GGT) [94]. At a The Fib-4 score was subsequently validated for detection of
cut of value of 6.9, it was noted to be of value in differentiating the monoinfections HCV and HBV. It showed AUCs of 0.85
mild fibrosis (F0-F1) from severe fibrosis (F2–F4), but it is less and 0.81 for the detection of severe fibrosis, for isolated HCV
accurate in the differentiation of F2 from F4 [7]. Similar to and HBV infection, respectively [110, 111]. Fib-4 showed a
the APRI, the Forns index may misclassify half of a patient better performance in NAFLD compared with the AAR,
population [13, 85, 94]. APRI, and NAFLD fibrosis score (NFSA) [79, 112].
(5) The PGA index was proposed by Poynard et al. in 1977 (9) The FibroQ test: this test was proposed by Hsieh et al.
in 2009. It is calculated based on age, AST, prothrombin time
as a marker to assess alcoholic liver disease. It is generated
(PT-INR), platelet count, and ALT [113]. In that study, using
via a combination of GGT, the prothrombin index, and
a cutoff value of 1.6 the AUC for the detection of significant
apolipoprotein A [95]. This index was additionally modified
fibrosis was 0.783, and the negative predictive value was 100%
by including 𝛼2 macroglobulin (PGAA) as a contributing for the exclusion of cirrhosis. These values were both higher
factor, which increased its accuracy from 65% for PGA to 70% than those obtained when using the APRI and AAR in the
for PGAA [96]. same cohort [113, 114]. More recently, a similar study showed
(6) Fibro test and Fibrosure: these tests are identical but that FibroQ was superior to FIB-4, AAR, APRI, and Lok’s
are marketed under different names [7]. The test is conducted model in predicting significant fibrosis in patients with
based on the patient age, gender, serum haptoglobin, 𝛼2 chronic hepatitis C [113, 114].
macroglobulin, apolipoprotein A1, GGT, and bilirubin [97, (10) Currently, with the increase in the incidence of
98]. Variable ranges of Fibro test had been obtained according metabolic syndromes, NAFLD is considered the most fre-
to the stage of fibrosis; a result of 0.75–1 and 0.73–0.74 was quent cause of liver disease in the world [115]. NAFLD specific
obtained for stage F4 and stages F3-F4, respectively [97]. The markers for fibrosis have been developed. The simple test was
accuracy of the Fibro test has been assessed in CHC, CHB, proposed to assess the stage of hepatic fibrosis in NAFLD. The
NAFLD, and ALD patients. It is the most validated nonin- test is based on body mass index, age, glycemic status, platelet
vasive test used to detect hepatic fibrosis [7, 13, 99–101]. The count, albumin level, and the AST/ALT ratio [116]. Using this
Fibro test may be less useful for the detection of intermediate test, 90% of patients were correctly staged, with AUCs of 0.88
stages of fibrosis (F2) compared with the extreme stages of F0- and 0.82 in the two groups that were studied, and advanced
1 and F4 [12]. Recently, Poynard et al. confirmed the accuracy fibrosis was excluded with high accuracy (NPV of 93% and
of the Fibro test in the diagnosis of advanced fibrosis and cir- 88% in the two groups) [116].
rhosis. That study included 1289 patients with CHC and 604 (11) Steato test: this test was proposed by Poynard et al.
controls. The specificity/sensitivity for advanced fibrosis was to assess NAFLD. It incorporates the five components of the
0.93/0.70 and, in the case cirrhosis, the specificity/sensitivity Fibro test (𝛼2 macroglobulin, haptoglobin, apolipoprotein
was 0.87/0.41 [102]. In a study of patients with severe obesity, A1, GGT, and total bilirubin) and the Acti Test (ALT in
Poynard et al. demonstrated high accuracy of the Fibro test in addition to body mass index, serum cholesterol, triglycerides,
diagnosing cases of steatohepatitis, with an AUC of 0.85 [103]. and glucose, adjusted for age and gender). A cutoff value of
Furthermore, and in a more recent publication on the Fibro 0.7 resulted in a 90% specificity, permitting the authors to
test, Poynard et al. validated the use of the Fibro test during achieve NPV and PPV values of 93% and 63%, respectively,
follow-up to monitor the progression of the most frequent with a steatosis prevalence of 30% [117]. The AUCs ranged
forms of chronic liver disease [104]. from 0.72 to 0.86 for the three validation groups in that
Advances in Hepatology 5

study, [117] and similar result was obtained by Poynard et al. which has been validated in patients with ALD and showed
[103]. Furthermore, Poynard et al. proposed other algo- AUC similar to that of Fibro test, Fibrometer for detection of
rithms that combined 13 parameters, including age, gender, advanced fibrosis with an AUC of 0.83 ± 0.03 [129].
height, weight, and serum levels of triglycerides, cholesterol, (5) European liver fibrosis panel (ELF) test was proposed
𝛼2 macroglobulin, apolipoprotein A1, haptoglobin, gamma- by the ELF panel [13, 130]. Its calculation is based on
glutamyltranspeptidase, transaminases, ALT, AST, and total age, hyaluronic acid, amino-terminal properties of type III
bilirubin. Using this algorithm at a value of 0.75, they collagen (PIIINP), and the tissue inhibitor of matrix metallo-
obtained an AUC of 0.79 for the diagnosis of NASH in the val- proteinase 1. In the original calculation, age was included and
idation group and an AUC of 0.83 for a diagnosis of no NASH the value was called the OELF [130], but the calculation was
in the same group [118]. The Nash test has also been validated then simplified to a set of parameters that did not include age.
in combination with other tests, including the Fibro test The sensitivity of ELF for the detection of stage 3 or 4 fibrosis
and the Steato test [119]. was 90%. ELF at a result of more than 0.102 showed a negative
predictive value for significant fibrosis F3-F4 of 92% and an
(𝑐) Combined Direct and Indirect Markers AUC of 0.804 [130]. The ELF has been found to be of value
(1) The Fibrometer test was described by Calès et al. for assessing fibrosis in chronic viral hepatitis, autoimmune
in 2005. It is performed by combining the platelet count, liver disease, ALD, and NAFLD because the AUC in different
prothrombin index, aspartate aminotransferase, 𝛼2 - studies has ranged from 0.773 for CHC to 0.98 for NAFLD
macroglobulin (A2M), hyaluronate, urea, and age. The test [45, 130, 131].
results indicate the amount of hepatic fibrosis as a percent
of fibrous tissue within the liver [120]. The test has been
2.5. Noninvasive Markers That Are Less Commonly Studied
validated in viral hepatitis and ALD and demonstrates AUCs
of 0.883 and 0.962, respectively, for the detection of advanced and Validated for the Assessment of Liver Fibrosis
fibrosis at stages F2–F4 [120]. The Fibrometer has also been
(1) 13 C-methacetin breath test (MBT) and 13 C-caffeine breath
validated by the same author in NAFLD, with a reported
test (CBT) are tests that assess cytochrome P450-dependent
AUC of 0.943 [121]. When compared to other indirect tests
hepatocellular function [132, 133]. 13 C-methacetin is metab-
the Fibrometer showed an AUC of 0.892 for detecting stage
olized by healthy liver into acetaminophen and 13 CO2 . An
F2–F4 fibrosis in CHC and CHB. This value was higher
increase in breath levels of 13 CO2 may be measured using
than those obtained for the Fibro test, Forns index, and
mass spectrometry or infrared spectroscopy. Dinesen et al.
APRI, which were 0.808, 0.82, and 0.794, respectively [121].
showed that the MBT had AUCs of 0.827 and 0.958 for
Similarly the same study showed that Fibrometer in NAFLD
the detection of advanced fibrosis and cirrhosis, respec-
performed better than NFSA, with AUCs of 0.943 and 0.884, tively [134]. Similarly, caffeine undergoes extensive hepatic
for both tests, respectively, for detecting significant fibrosis metabolism, principally via demethylation by cytochrome
[121]. P450. This metabolism results in the production of CO2 . Cir-
(2) Fibrospect II test combines three parameters: rhotic patients show reduced caffeine metabolism that results
hyaluronic acid, TIMP-1, and 𝛼2 macroglobulin. At a cutoff in significantly lower levels of 13 CO2 compared with those of
value of 42, it can differentiate mild F0-F1 from severe control individuals when 13 C-caffeine is administered orally
fibrosisF2–F4 [122]. It was validated in CHC patients, and [134]. A significant inverse relationship exists between the
it showed an AUC of 0.831 for the detection of significant CBT and Child-Pugh score (𝑃 = 0.002) [134].
fibrosis at stages F2–F4 [123]. Furthermore a similar AUC (2) Proteomics and glycomics: proteins and glycoproteins
0.83 for detection of advanced fibrosis F2–F4 was obtained by are assessed using mass spectrometry. Using serum samples
Jeffers et al. in a study of 145 CHB and CHC patients [124]. [135], initial proteomics and glycomics studies of liver fibrosis
Subsequent similar studies using Fibrospect II showed higher showed promising results [136, 137]. However, more recent
AUC [99, 125]. data have shown that these methods are of limited value for
(3) SHASTA index is based on serum hyaluronic acid, the assessment of liver fibrosis [138].
AST, and albumin. In a study of 95 HIV/HCV coinfected (3) Kam et al. proposed the Fibro-Glyco index for assess-
patients, an index of 0.3 showed a sensitivity of >88% and a ing liver fibrosis; it is based on the N-glycome level deter-
negative predictive value of >94%, and a level of 0.8 showed mined using mass spectrometry. They reported a significant
a specificity of 100% and a positive predictive value of 100% correlation between this index and the degrees of liver fibrosis
for detection of severe fibrosis of F3 or more [126]. Using this (𝑟 = 0.784, 𝑃 = 0.01). In addition, the index is useful in the
index only, 42% of patients were correctly classified, whereas detection of liver fibrosis and cirrhosis, with an ROC of 0.91
the remaining 58% showed values between 0.3 and 0.8 [126]. for both [139].
(4) The Hepascore model was proposed by Adams et al. (4) King’s score: this score is the most recently proposed
in 2005. It combines age, gender, serum bilirubin, GGT, noninvasive index [140]. It is calculated using the formula
hyaluronic acid, and 𝛼2 macroglobulin. At a cutoff value of ks = Age (years) × AST (IU/L) × INR/Platelets × 109 /L. It
0.5, it showed AUCs of 0.82, 0.9, and 0.89 for the detection of shows AUCs for detecting advanced fibrosis and cirrhosis of
significant fibrosis, advanced fibrosis, and cirrhosis, respec- 0.82 and 0.89, respectively [140].
tively, in CHC [127]. More recently, Guéchot et al. showed (5) Noninvasive hepatitis C-related cirrhosis early detec-
similar findings when using the automated Hepascore [128], tion (NIHCED) index was suggested by Bejarano-Redondo
6 Advances in Hepatology

et al. in 2009 for the detection of F2–F4 fibrosis. It is assessed accuracy of the Castéra algorithm for diagnosing cirrhosis
based on age (≥60 years), prothrombin time (≥1.1), platelets was greater than that of the SAFE algorithm (95.7% versus
(≤100,000), and AST/ALT (≥1). In addition to the presence 88.7%) [149]. Similarly, Sebastiani et al. evaluated a stepwise
of right hepatic lobe atrophy, caudate lobe hypertrophy is combination algorithm that included the APRI, Fibro test,
observed upon ultrasound examination. This test at score of and liver biopsy for the diagnosis of CHB. They demonstrated
more than 6 shows an accuracy of 72% and an AUC of 0.787 AUCs of 0.96 and 0.95 for the detection of significant fibrosis
[141]. and cirrhosis, respectively, with a 50–80% reduction in the
(6) Two Chinese models that involve different NIBMs requirement for liver biopsy [150]. The Fibropaca algorithm
have been suggested for assessing CHB [142, 143]. In the had been proposed by Bourliere et al. in 2006, and it involved
first model, Liu et al. used haptoglobin, GGT, and platelet combining the Fibro test, APRI, and Forns index for the
counts, and their model was of high diagnostic value in diagnosis of 235 CHC patients. Using this algorithm, 81.3%
assessing patients with HBeAg-positive and HBeAg-negative of patients were correctly diagnosed, and only 18.7% of
CHB [142]. In the second model, Tu et al. used APRI, GGT, patients required a liver biopsy [151]. Leroy et al. evaluated the
INR, and HBeAg. The model was effective in differentiating performance of different combinations of NIM for assessing
early and advanced fibrosis and active cirrhosis [143]. hepatic fibrosis in 180 CHC patients: MP3 score (combination
(7) More recently, data on the use of surface-enhanced of PIIINP and MMP-1), FT, Frons index, Hepascore, Fibrom-
laser desorption/ionization time of flight mass spectrometry eter, and APRI. They noted that MP3 and APRI were the only
(SELDI-ATAOF-MS) in HCC identified a panel of serum independent variables associated with significant fibrosis
proteins of value in differentiating HCC patients from those [152]. In that study, the optimum combination was reliable
with cirrhosis or normal controls [144, 145]. in 1/3 of patients [152]. In another study, Bourlier et al. used
different stepwise combinations of the Hepascore, Fibro test,
APRI, and Forns index; they reported that the SAFE biopsy
2.6. Viral Hepatitis/HIV Coinfected Patients. As mentioned
algorithm proposed by Sabastiani et al. showed an accuracy of
above SHASTA index was used for HIV/CHC coinfected
90% in CHC patients, and biopsy was required in only 44% of
patients [126]. The FIB-4 index was found to be superior
patients [153]. In the same study, when the APRI was used as
to APRI in the diagnosis of mild from severe fibrosis in
a screening tool followed by the Hepascore, liver biopsy was
HIV/CHC coinfected patients [146]. Furthermore, Bottero et
avoided in 45% of patients [153].
al. evaluated the use of different indirect noninvasive markers
Several studies were conducted that compared different
for assessing liver fibrosis in HBV/HIV coinfected patients.
algorithms that combined direct NIBMs. The majority of
Based on the AUC, they concluded that the Fibrometer, Hep-
studies showed comparable results for different combinations
ascore, and Zeng’s score were the most accurate noninvasive
of NIBMs. Furthermore, the combination algorithms showed
biochemical scores for assessing liver fibrosis for HIV/HBV
significantly better performances compared with individual
coinfection. In addition, the performance of the biomarkers
markers [49]. A combination algorithm of different direct
was not significantly improved by combining two biochemi-
noninvasive markers was proposed by Patel et al. In that study,
cal scores [147].
hyaluronic acid, TIMP-1, and 𝛼2 -macroglobulin were com-
bined for the assessment of fibrosis in CHC patients, and an
3. Combination of Markers accuracy of 75% was demonstrated for the detection of F2–F4
fibrosis [154].
Several authors have attempted to combine NIMs to assess
hepatic fibrosis, and they have suggested that these combina-
tions improved sensitivity. In 2006, Sebastiani et al. proposed 4. Comparison of Algorithms Incorporating
the SAFE algorithm (sequential algorithm for fibrosis evalua- Different Indirect NIBMs
tion) for use in CHC patients. In that study, 190 CHC patients
were assessed using the APRI, Forns index, and Fibro test at Several studies have compared the accuracies of different
the time of liver biopsy. The authors observed that the optimal NIBMs for detecting advanced fibrosis and cirrhosis. In
combination was APRI followed by the Fibro test. Using this Bourliere’s study, the Fibro test and Hepascore showed similar
algorithm, advanced fibrosis and cirrhosis were diagnosed diagnostic profiles for fibrosis of stages F2–F4 [153]. Simi-
with accuracies >94% and 95%, respectively, and the require- larly, Sebastiani et al., using another combination algorithm,
ment for liver biopsy was reduced by 60–70% [85]. The same showed that the Fibro test was more accurate compared with
group had previously validated the SAFE biopsy algorithm both the APRI and Forns index [85]. In the study of Lackner
in a larger number of patients (2035). They demonstrated et al., the APRI showed greater accuracy than the AAR for
accuracies of 90.1% and 92.5% for detecting advanced fibrosis the detection of both advanced fibrosis and cirrhosis in CHC
and cirrhosis, respectively [148]. Furthermore, Castéra et al., patients (𝑃 < 0.05) [155]. More recently, in a study of both
in another study of 314 CHC patients recently compared CHC and CHB patients with postresection hepatocellular
the SAFE biopsy with the Castéra algorithm (combination carcinoma, Lin et al. confirmed the superiority of APRI over
of transient elastography and Fibro test) and demonstrated AAR in the detection of both advanced fibrosis and cirrhosis
that the Castéra algorithm prevented more liver biopsies [156]. In their study of different combinations of NIBMs
than the SAFE biopsy in cases of significant fibrosis, but it for assessing fibrosis in CHC using six noninvasive tests,
showed reduced accuracy (87.7% versus 97%). In contrast, the Leroy et al. demonstrated that the Fibrometer showed the
Advances in Hepatology 7

Table 1: AUROC for the direct markers that have been used in assessment of fibrosis in various liver diseases.
Liver disease evaluated by the markers AURCO for AURCO for
Marker References
CHC CHB NAFLD ALD advanced fibrosis cirrhosis
PCICP NA — — NA NA NA [28–30, 82]
PCIIINP 0.69–0.78 — NA 0.67–0.867 0.67–0.867 0.734 [31, 36, 37, 58, 154, 159]
Type IV collagen 0.73–0.83 — 0.82 NA 0.583–0.83 NA [30, 41, 42, 58, 154, 159]
HA∗ [31, 32, 41, 44, 46–
0.821–0.92 0.98 0.97 0.69–0.93 0.69–0.98 0.85–0.93
48, 115, 154, 159–162]
Laminin 0.542–0.82 — NA NA 0.46–0.82 NA [30, 33, 42, 56, 159]
YXL-40 0.7–0.81 NA NA 0.7–0.81 0.79 [57–59, 154]
MMP-2 0.59 0.59 0.97 [47, 62]
MMP-3 0.88 — — — 0.88 NA [152]
MMP-9 ∗∗ — — — NA NA [64, 65]
TIMP-1 0.71–0.773 — — — 0.68–0.73 0.91 [31, 62, 63, 154]
TIMP-2 0.73 — — — 0.73 NA [63]
TGF-𝛽1 NA — — — — — [70, 71]
TGF-𝛼 NA — — — — — [70, 71]
PDGF NA — — — — — [72, 73]
∗
HA: Hyaluronic acid.
∗∗
Negative association, MMP-9 decreases with the progression of fibrosis.
NA: Area under receiver operating characteristic (AUROC) is not available.

best performance, followed by the Fibro test, with AUCs (1) They are noninvasive and can be measured in outpa-
of 0.86 and 0.84, respectively. In contrast, the Forns index tient departments.
and Hepascore showed the lowest performance, with AUCs (2) They cost less compared with liver biopsies.
of 0.78 and 0.79, respectively [152]. The Fibro test was also
found to be more accurate and cost-effective compared with (3) They can be easily repeated for confirmation.
Fibrospect II in testing liver fibrosis in HCV genotype 1 (4) If they are well validated, they may be used for follow-
patients [157]. up and monitoring in the future.
(5) They are not associated with the liver biopsy morbid-
4.1. The Role of NIBMs in Assessing the Development of ity and mortality risks.
Varices in Liver Disease. Stefanescu et al. recently validated
the guidelines for the use of NIBMs in detecting large varices Limitations of NIBMs:
compared with endoscopy. They used the APRI, FIB-4, Forns (1) Some of markers like APRI, Hepascore, and Fibr-
index, and Lok score in addition to the Fibroscan. They ospect II need more validation in intermediate stages
concluded that a combination of the Lok score and the of liver fibrosis [99].
Fibroscan was optimal for detecting large varices [158].
Summary of NIBMs for assessment of different forms (1) In spite that the effectiveness of NIBM in assess-
of liver disease (Tables 1, 2, 3, and 4) [159–170], CHC was ment of liver fibrosis was demonstrated by many
the first and most extensively studied liver disease with studies some studies had shown that they may
respect to the utilization of different NIBMs, but NIBMs not be of diagnostic value in the detection of
have been evaluated much less in CHB compared to CHC. liver fibrosis [171].
Different studies have used different NIBM cutoffs levels for (2) They remain of limited value in assessing the
detecting advanced fibrosis and/or cirrhosis for the same development of complications, like esophageal
liver diseases. The results demonstrated differences in the varices and chance of variceal bleeding [99].
sensitivity, specificity, and accuracy of the same markers or (3) Both direct and indirect markers of liver fibrosis
scores. Another possible reason underlying the differences in are not liver-specific and can be altered by
the results may be the selection bias in the study populations pathological conditions in other organs.
of different studies. For example, a cohort study that includes (4) Some of the biomarkers lack standardization
more patients with advanced liver fibrosis will show different due to variable values and the different upper-
NIBM results compared with a study that utilizes a cohort in normal ranges used by different laboratories.
which fewer patients have advanced liver fibrosis. (5) All studies that evaluated the accuracy of
NIBMs used the liver biopsy as the gold stan-
4.2. Pros and Cons of NIBMs for Detecting Liver Fibro- dard reference; this protocol is also a limitation
sis. NIBMs are advantageous compared with liver biopsies because even the best liver biopsy retains a risk
because of the following reasons. of sampling error.
8 Advances in Hepatology

Table 2: AUROC for the indirect markers that have been used in assessment of fibrosis in various liver diseases.
Liver disease evaluated by various markers AURCO for AURCO
Marker References
CHC CHB NAFLD ALD advanced fibrosis for cirrhosis
ALT (2.25) the normal 0.716–0.815 0.716–0.815 — [75, 163]
[78, 80, 112, 114, 155,
AST/ALT ratio 0.54–0.709 NA 0.742–0.83 NA 0.54–0.83 0.67
162, 164]
[79, 87–91, 112, 120,
APRI 0.65–0.87 0.67–0.72 0.564–0.866 — 0.564–0.87 0.75–0.92
150, 156, 164–167]
Frons index 0.78–0.86 NA — — 0.78–0.86 [94, 152]
PGAA index — — — NA — — [95, 96]
[99–101, 104–
Fibro test 0.72–0.87 0.76–0.85 0.82–0.89 0.83–0.91 0.72–0.87 0.77–0.94 106, 112, 120, 129, 152,
153, 159, 169, 170]
Acti test NA 0.77 SH [97, 105, 106]
Fibro index 0.804–0.83- NA — — 0.82 0.845 [107, 108, 120, 164]
Fib-4∗ 0.785–0.86 0.81 — — 0.785–0.86 — [109–111, 114, 166]
NA
FibroQ 0.789 — — 0.783 0.791 [113, 114]
NA
The simple test
— — 0.82–0.89 — 0.82–0.89 — [116, 121, 131]
(NAFLD) fibrosis score
Steato test — — 0.799–0.86 0.799–0.86 — [117]
SELDI-TOF protein chip 0.88 0.926 — — 0.88–0.906 0.921 [137, 170]
13C metacetin breath test 0.83- — — — 0.83 0.96 [133, 164]
∗
Used to assess fibrosis in HCV/HIV coinfected patients.
NA: studied but AUROC is not available.

Table 3: AUROC for liver fibrosis biomarkers that are a mix of direct and indirect markers.
Liver disease evaluated by various markers AURCO for AURCO
Marker References
CHC CHB NAFLD ALD advanced fibrosis for cirrhosis
The Fibrometer 0.892∗∗ 0.943 0.83–0.962 0.883–0.962 0.94 [120, 121, 129, 152]
Fibrospect II 0.77–0.831 NA — 0.83 0.77–0.831 [122, 124, 125]
SHASTA index∗∗∗ 0.878 — — — 0.878 — [126]
Hepascore 0.82 0.83 0.82–0.9 0.89–0.92 [127, 129, 152, 153]
ELF 0.773 0.93–0.98 0.873 0.944 0.773–0.98 [130, 131]#
— —
∗∗
mixed population of 337 HCV and 46 HBV patients.
∗∗∗
HVC and HIV co-infected patients.
#
1021 subjects recruited; the numbers in each diagnostic category were as follows: chronic hepatitis C, 496; ALD, 64; fatty liver, 61; hepatitis B, 61; primary biliary
cirrhosis or primary sclerosing cholangitis, 53; recurrent disease after liver transplantation, 48; autoimmune hepatitis, 45; hemochromatosis, 32; cryptogenic
cirrhosis, 19; hepatitis B and C, 4; 138 patients with other causes of liver disease like granuloma and abnormal liver enzymes from unknown cause.
NA: studied but AUROC is not available.

Table 4: AUROC for performance of combination algorithms in assessing liver fibrosis.

Liver disease evaluated by various markers AURCO AURCO

Combination algorithm References
CHC CHB NAFLD ALD for advanced fibrosis for cirrhosis
SAFE biopsy 0.89–1 — — — 0.97–1 0.87 [85, 148, 158]
Stepwise SAFE
— NA — 0.96 0.95
algorithm + biopsy
Castera 0.97 — — — 0.97 0.93 [149]
Bourliere algorithms NA — — — — — [153]
NA: studied but AUROC is not available.
Advances in Hepatology 9

(6) A selection bias of the studied population may histology can significantly reduce, but not completely replace,
have biased the results; for example, if a larger the requirement for liver biopsies in patients with chronic
number of patients with advanced or minimal viral hepatitis and NAFLD. For the other types of liver
fibrosis are included, this bias will affect the disease, NIBMs are not well validated and more studies are
accuracy of the markers [18]. required. Furthermore, future studies on the currently avail-
(7) In a large population of patients with liver dis- able NIBMs may reveal more important prognostic capabili-
eases, for example, patients with autoimmune ties of these markers.
liver disease, NIBMs remain poorly evaluated
and validated. Abbreviations
(8) The majority of the direct markers that have
been evaluated are not routinely available in all NIBM: Noninvasive biomarkers
laboratories. NAFLD: Nonalcoholic fatty liver disease
Investigators must work to overcome the limita- ALD: Alcoholic liver disease
tions of NIBMs for liver fibrosis. Several studies ECM: Extracellular matrix
of marker combinations or stepwise algorithms AUROC: Area under receiver operating characteristic.
have shown improved performance compared
with the performance of individual markers Conflict of Interests
[49]. Furthermore, the recent use of NIBMs
together with transient elastography for assess- The author declares that there is no conflict of interests
ing hepatic fibrosis has demonstrated improved regarding the publication of this paper.
outcome without requiring liver biopsy in most
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